Memoire Online - An assessment of adherence to antihypertensive treatment and associated factors in patients at the Yaounde general hospital

AN ASSESSMENT OF ADHERENCE TO ANTIHYPERTENSIVE TREATMENT AND ASSOCIATED FACTORS IN PATIENTS AT THE YAOUNDE GENERAL HOSPITAL

Thesis Presented and Defended Publicly in Partial Fulfilment of the Requirements for the Award of a Pharmaciae Doctor (Pharm.D.) Degree

PREFACE

DEDICATION

ACKNOWLEDGEMENTS

I thank GOD ALMIGHTY for His unceasing love, for keeping strong and healthy and for His numerous graces shown to me throughout these years of pharmacy training.

This work will not have been a success without the contributions of the following people:

Ø My supervisor, Prof MENANGA Alain, for his continuous support, patience, motivation and immense knowledge. His guidance helped me throughout the research period and also during the writing of this thesis. I could not have imagined having a better advisor and mentor for my end of course thesis.

Ø My cosupervisor, Dr. TEMBE Estella, for her insightful comments and encouragements but also for the hard questions which motivated me to widen my research from various perspectives! Thank you Doctor for being a mentor for me and for sharing your experiences with me throughout these years. I am forever grateful.

Ø The cardiologists and the nurses of the external consultation unit, who facilitated my integration into the healthcare team. Without their precious support it would not have been possible to conduct this research.

Ø All the participants in my study, who willingly spared their precious time to answer my questions.

Ø All the lecturers of the Faculty of Medicine and Biomedical Sciences (FMBS) for grooming me throughout these years of pharmaceutical studies.

Ø My parents for all the sacrifices, encouragements and support they have made on my behalf. Your prayers for me was what sustained me this far.

Ø My brothers, CHIABI Edmond, CHIABI Valery and CHIABI Leslie, and the rest of my family for their support and the love they have always been showing me.

Ø Dr. NGANGUE NSEKE Rose, Dr. ABONG BWEMBA Therese and Dr. KIMA Tessa for their mentorship, assistance, and dedicated involvement in one level or another in my training. I would like to thank you very much for your support, advice and understanding throughout these years.

Ø All my classmatesand friends for the love, the friendship, the support, the stimulating scientific discussions, the fun and the patience.

Ø The Director of the Yaounde General Hospital for granting me the authorization to pursue this research.

LIST OF ADMINISTRATIVE AND ACADEMIC STAFF OF THE FACULTY OF MEDICINE AND BIOMEDICAL SCIENCES FOR THE 2017/2018 ACADEMIC YEAR

S/N	1. ADMINISTRATIVE PERSONNEL
1.	Pr ZE MINKANDE Jacqueline	Dean
2.	Pr NTSAMA ESSOMBA Claudine Mireille	Vice- Dean in charge of programs and academic activities follow-up
3.	Pr Gloria Enow ASHUNTANTANG	Vice-Dean in charge of School, Statistics and Students follow-up
4.	Pr KAMGNO Joseph	Vice- Dean in charge of Research and Cooperation
5.	Mr MEKA Gaston	Director of Administrative and Financial affairs
6.	Pr BENGONDO MESSANGA Charles	Director of Academic, School and Research affairs
7.	Pr MOUAFO TAMBO Faustin	General Coordinator of Specialisation Cycle
8.	Mr. ADAMOU	Chief of Financial Service
9.	Dr SAMBA Odette NGANO ép. TCHOUAWOU	Chief of General Administration and Personnel Service
10.	Mme ASSAKO Anne DOOBA	Chief of Service : Certificates
11.	Dr NSEME Eric	Chief of Service : School and Statistics
12.	M. MPACKO NGOSSO Charles Romuald	Chief of Service : Materials and Maintenance
13.	Mme FROUISSOU née MAME Marie-Claire	Interim Chief of the Library
14.	Mme ANDJISSILE ENAM Suzel Chanel	Material Accountant
	2. COORDINATORS AND HEAD OF DEPARTMENTS
1.	Pr BENGONDO MESSANGA Charles	Coordinator of Dentistry Department
2.	Pr NTSAMA ESSOMBA Claudine	Coordinator of Pharmacy Department
3.	Pr ONGOLO ZOGO Pierre	Coordinator of Internist Department
4.	Pr ESSAME OYONO Jean Louis	Coordinator of Specialisation Cycle in Anatomy Pathology Department
5.	Pr ZE MINKANDE Jacqueline	Coordinator of Specialisation Cycle in Anaesthesiology and Reanimation Department
6.	Pr NGO NONGA Bernadette	Coordinator of Specialisation Cycle in General Surgery Department
7.	Pr MBU ENOW Robinson	Coordinator of Specialisation Cycle in Gynaecology and Obstetrics Department
8.	Pr NGANDEU Madeleine	Coordinator of Specialisation Cycle in Internal Medicine Department
9.	Pr CHIABI Andreas	Coordinator of Specialisation Cycle in Paediatrics Department
10.	Pr GONSU Hortense	Coordinator of Specialisation Cycle in Clinical Biology Department
11.	Pr NKO'O AMVENE Samuel	Coordinator of Specialisation Cycle in Radiology and Medical Imagery Department
12.	Pr TAKOUGANG Innocent	Coordinator of Specialisation Cycle in Public Health Department
	HONORARY DIRECTORS OF CUSS
1.	Pr MONEKOSSO Gottlieb (1969-1978)	Internal Medicine/Neurology
2.	Pr EBEN MOUSSI Emmanuel (1978-1983)	Physiologic Science/Biochemistry; Pharmacology
3.	Pr NGU LIFANJI Jacob (1983-1985)	Internal Medicine/Nephrology
4.	Pr CARTERET Pierre (1985-1993)	Physiologic Sciences/Biochemistry; Physiology
	HONORARY DEANS OF FMBS
1.	Pr SOSSO Maurice Aurélien (1993-1999)	Surgery and Specialties: General Surgery
2.	Pr NDUMBE Peter (1999-2006)	Haematology, Microbiology and Parasitology
3.	Pr TETANYE EKOE Bonaventure (2006-2012)	Paediatrics
4.	Pr EBANA MVOGO Côme (2012-2015)	Opthalmology/ORL
	3. TEACHING STAFF
	DEPARTMENT OF SURGERY AND SPECIALTIES
	A. Professor Emeritus
1.	SOSSO Maurice Aurélien (CD)	General Surgery
2.	AFANE ELA Anatole	Anaesthesiology-Intensive care
3.	ANGWAFO III Fru	Surgery: Urology
4.	DJIENTCHEU Vincent de Paul	Surgery: Neurosurgery
5.	ESSOMBA Arthur	General Surgery
6.	NGOWE NGOWE Marcellin	General surgery
7.	ZE MINKANDE Jacqueline	Anaesthesiology- Intensive care
	B. Associate Professors
1.	BEYIHA Gérard	Anaesthesiology- Intensive care
2.	ELOUNDOU NGAH J.	Surgery: Neurosurgery
3.	ESIENE Agnès	Anaesthesiology- Intensive care
4.	EYENGA Victor Claude	Surgery: Neurosurgery
5.	FARIKOU Ibrahima	Orthopaedic Surgery
6.	FOUDA Pierre	Surgery: Urology
7.	MOUAFO TAMBO Faustin	Paediatric Surgery
8.	NGO NONGA Bernadette	General Surgery
9.	ONDOBO ANDZE Gervais	Paediatric Surgery
10.	PISOH Christopher	General Surgery
	C. Senior Lecturers
1.	AHANDA ASSIGA	General Surgery
2.	GUIFO Marc Leroy	General Surgery
3.	HANDY EONE Daniel	Orthopaedic Surgery
4.	OWONO ETOUNDI Paul	Anaesthesiology- Intensive care
5.	TSIAGADIGI Jean Gustave	Orthopaedic Surgery
	D. Lecturers
1.	AMENGLE Albert Ludovic	Anaesthesiology- Intensive care
2.	BANG GUY Aristide	General surgery
3.	BENGONO BENGONO Roddy Stéphan	Anaesthesiology- Intensive care
4.	BWELE Georges	General surgery
5.	JEMEA Bonaventure	Anaesthesiology- Intensive care
6.	NGO YAMBEN Marie Ange	Orthopaedic Surgery
	DEPARTMENT OF INTERNAL MEDICINE AND SPECIALTIES
	A. Professors Emeritus
1.	NJOYA OUDOU (CD)	Internal Medicine/Gastro-enterology
2.	AFANE ZE Emmanuel	Internal Medicine/Pulmonology
3.	BIWOLE SIDA Magloire	Internal Medicine/Hepato-Gastro-enterology
4.	KINGUE Samuel	Internal Medicine/Cardiology
5.	MBANYA Jean Claude	Internal Medicine/Endocrinology
6.	NDJITOYAP NDAM Elie Claude	Internal Medicine/Hepato-Gastro-enterology
7.	NDOM Paul	Internal Medicine/ Oncology
8.	NJAMNSHI Alfred K.	Internal Medicine/Neurology
9.	NOUEDOUI Christophe	Internal Medicine/ Endocrinology
10.	SINGWE Madeleine épse NGANDEU	Internal Medicine/Rhumatology
	B. Associate Professors
1.	ANKOUANE ANDOULO	Internal Medicine/Hepato-Gastro-enterology.
2.	ASHUNTANTANG Gloria Enow	Internal Medicine/ Nephrology
3.	BISSEK Anne Cécile	Internal Medicine/Dermatology
4.	KAZE FOLEFACK François	Internal Medicine/Nephrology
5.	KUATE TEGUEU Calixte	Internal Medicine/Neurology
6.	MENANGA Alain Patrick	Internal Medicine/Cardiology
7.	NGOUNOU NOUBISSIE Marie ép. DOUALLA BIJA	Internal Medicine/Rheumatology
8.	SOBNGWI Eugène	Internal Medicine/Endocrinology
9.	YONE PEFURA	Internal Medicine/Pulmonology
	C. Senior Lecturers
1.	ETOUNDI MBALLA Alain	Internal Medicine/Pulmonology
2.	FOUDA MENYE Hermine Danielle	Internal Medicine/Nephrology
3.	HAMADOU BA	Internal Medicine/Cardiology
4.	KAMGA OLEN Jean Pierre Olivier	Internal Medicine/Psychiatry
5.	KOUOTOU Emmanuel Armand	Internal Medicine/Dermatology
6.	KOWO Mathurin Pierre	Internal Medicine/Hepato- Gastro-enterology
7.	LOBE Emmanuel	Internal Medicine/Nephrology
8.	NDONGO AMOUGOU Sylvie	Internal Medicine/Cardiology
9.	NTONE ENYIME Félicien	Internal Medicine/Psychiatry
10.	ZE Jean Jacques	Internal Medicine/Pulmonology
	D. Lecturers
1.	BOOMBHI Jérôme	Internal Medicine/Cardiology
2.	KUATE née MFEUKEU KWA Liliane Claudine	Internal Medicine/Cardiology
3.	NGANOU Chris Nadège	Internal Medicine/Cardiology
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1.	ZEH Odile Fernande (CD)	Radiology/Medical Imagery
	A. Professors Emeritus
1.	GONSU Joseph	Radiology/Medical Imagery
2.	MOUELLE SONE	Radiotherapy
3.	NKO'O AMVENE Samuel	Radiology/Medical Imagery
	B. Associate Professors
1.	ZEH Odile Fernande	Radiology/Medical Imagery
2.	GUEGANG GOUJOU. E.	Radiology/Neuroradiology
3.	MOIFO Boniface	Radiology/Medical Imagery
4.	ONGOLO ZOGO Pierre	Radiology/Medical Imagery
	C. Lecturer
1.	MBEDE Maggy	Radiology/Medical Imagery
	DEPARTMENT OF GYNAECOLOGY AND OBSTETRCS
	A. Professors Emeritus
1.	KASIA Jean Marie (CD)	Gynaecology/Obstetrics
2.	BELLEY PRISO Eugène	Gynaecology/Obstetrics
3.	MBOUDOU Émile	Gynaecology/Obstetrics
4.	MBU ENOW Robinson	Gynaecology/Obstetrics
	B. Associate Professors
1.	FOUMANE Pascal	Gynaecology/Obstetrics
2.	KEMFANG NGOWA J.D.	Gynaecology/Obstetrics
3.	NANA NJOTANG Philip	Gynaecology/Obstetrics
4.	NKWABONG Elie	Gynaecology/Obstetrics
5.	TEBEU Pierre Marie	Gynaecology/Obstetrics
	C. Senior Lecturers
1.	BELINGA Etienne	Gynaecology/Obstetrics
2.	DOHBIT Julius SAMA	Gynaecology/Obstetrics
3.	FOUEDJIO Jeanne H.	Gynaecology/Obstetrics
4.	ESSIBEN Félix	Gynaecology/Obstetrics
5.	MVE KOH Valère Salomon	Gynaecology/Obstetrics
6.	NGO UM Esther Juliette épse MEKA	Gynaecology/Obstetrics
7.	NOA NDOUA Claude Cyrille	Gynaecology/Obstetrics
	DEPARTMENT OF OPHTALMOLOGY, ENT AND STOMATOLOGY
	A. Professors Emeritus
1.	NDJOLO Alexis (CD)	ENT
2.	BELLA Assumpta Lucienne	Ophthalmology
3.	EBANA MVOGO Côme	Ophthalmology
4.	NJOCK Richard	ENT
	B. Associate Professors
1.	DJOMOU François	ENT
3.	ELLONG Augustin	Ophthalmology
4.	ÉPÉE Émilienne	Ophthalmology
	C. Senior Lecturers
1.	BILLONG Yannick	Ophthalmology
2.	DOHVOMA Andin Viola	Ophthalmology
3.	EBANA MVOGO Stève Robert	Ophthalmology
4.	KAGMENI Gilles	Ophthalmology
5.	KOKI Godefroy	Ophthalmology
6.	NGABA Olive	ENT
	DEPARTMENT OF PAEDIATRICS
	A. Professors Emeritus
1.	KOKI NDOMBO Paul (CD)	Paediatrics
2.	MONEBENIMP Francisca	Paediatrics
	B. Associate Professors
1.	CHELO David	Paediatrics
2.	CHIABI Andreas	Paediatrics
3.	MAH Evelyn	Paediatrics
4.	NGUEFACK Séraphin	Paediatrics
	C. Senior Lecturers
1.	KALLA Ginette Claude épse MBOPI KEOU	Paediatrics
2.	MBASSI AWA	Paediatrics
3.	NGO UM KINJEL Suzanne épse SAP	Paediatrics
4.	NGUEFACK épouse DONGMO Félicitée	Paediatrics
5.	NOUBI N. épouse KAMGAING M.	Paediatrics
6.	ONGOTSOYI Angèle H.	Paediatrics
	DEPARTMENT OF MICROBIOLOGY, PARASITOLOGY, HEMATOLOGY AND INFECTIOUS DISEASES
	A. Professors Emeritus
1.	MBOPI KEOU François-Xavier (CD)	Bacteriology/Virology
2.	ADIOGO Dieudonné	Microbiology/Virology
3.	LUMA Henry	Bacteriology/Virology
4.	MBANYA Dora	Haematology
	B. Associate Professors
1.	NKOA Thérèse	Microbiology /Haematology
2.	OKOMO ASSOUMOU Marie C.	Bacteriology/ Virology
3.	GONSU née KAMGA Hortense	Bacteriology
4.	TAYOU TAGNY Claude	Microbiology/Haematology
5.	TOUKAM Michel	Microbiology
	C. Senior Lecturers
1.	CHETCHA CHEMEGNI Bernard	Microbiology/Haematology
2.	KINGE Thomson Njie	Infectious Diseases
3.	LYONGA Emilia ENJEMA	Medical Microbiology
	D. Lecturers
1.	BEYELA Frédérique	Infectious Diseases
2.	NDOUMBA NKENGUE Annick épse MINTYA	Virology
3.	VOUNDI VOUNDI Esther	Virology
	DEPARTMENT OF PUBLIC HEALTH
	A. Professor Emeritus
1.	MONEBENIMP Francisca (CD)	Paediatrics
	B. Associate Professors
1.	KAMGNO Joseph	Public Health/Epidemiology
2.	TAKOUGANG Innocent	Public Health
3.	TANYA née NGUTI K. A.	Nutrition
4.	ESSI Marie Josée	Public Health /Medical Anthropology
5.	NGUEFACK TSAGUE	Public Health /Biostatistics
	C. Senior Lecturer
1.	BILLONG Serges Clotaire	Public Health
2.	BEDIANG Georges Wylfred	Medical Information Technology/ Public Health
3.	KEMBE ASSAH Félix	Epidemiology
4.	KWEDI JIPPE Anne Sylvie	Epidemiology
5.	NJOUMEMI ZAKARIAOU	Public Health /Health Economy
	DEPARTMENTOF MORPHOLOGIC-ANATOMY PATHOLOGIC SCIENCES
1.	SANDO Zacharie (CD)	Anatomy Pathology
	A. Professors Emeritus
1.	ESSAME OYONO	Anatomy Pathology
2.	FEWOU Amadou	Anatomy Pathology
	B. Associate Professors
1.	SANDO Zacharie	Anatomy Pathology
	C. Senior Lecturers
1.	AKABA Désiré	Human Anatomy
2.	KABEYENE OKONO Angèle	Histology/Embryology
3.	MENDIMI NKODO Joseph	Anatomy Pathology
	D. Lecturers
1.	NSEME Eric	Legal Medicine
	DEPARTMENT OF BIOCHEMISTRY
1.	NDONGO EMBOLA épse TORIMIRO Judith (CD)	Physiology/Molecular Biology
	A. Professor Emeritus
1.	MBACHAM Wilfried	Biochemistry
	B. Associate Professors
1.	NDONGO EMBOLA épse TORIMIRO Judith	Physiology/Molecular Biology
2.	PIEME Constant Anatole	Biochemistry
	C. Senior Lecturers
1.	AMA MOOR Vicky Joceline	Clinical Biology/Biochemistry
	D. Lecturers
1.	BONGHAM BERINYUI	Biochemistry
	DEPARTMENT OF PHYSIOLOGY
	A. Professor Emeritus
1.	ETOUNDI NGOA Laurent Serges (CD)	Physiology
	B. Senior Lecturers
1.	ASSOMO NDEMBA Peguy Brice	Physiology
2.	AZABJI KENFACK Marcel	Physiology
	C. Lecturers
3.	DZUDIE TAMDJA Anastase	Physiology
	DEPARTMENT OF PHARMACOLOGY AND TRADITIONAL MEDICINE
1.	NGONO MBALLA Rose ABONDO (CD)	African Pharmaco-therapeutics
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1.	NGADJUI CHALEU Bonaventure	Pharmacy/Phytochemistry
	B. Senior Lecturers
1.	NGONO MBALLA Rose ABONDO	African Pharmaco-therapeutics
2.	NDIKUM Valentine	Pharmacology
	DEPARTMENT OF BUCCAL SURGERY, MAXILLO-FACIAL AND PARODONTOLOGY
	A. Professors Emeritus
1.	BENGONDO MESSANGA Charles(CD)	Stomatology
	B. Senior Lecturers
1.	MINDJA EKO David	ORL/ Maxillo-Facial Sugery
	C. Lecturers
1.	BITHA BEYIDI Thècle Rose Claire	Maxillo Facial Surgery
2.	GAMGNE GUIADEM C.M	Dental Surgery
3.	NOKAM TAGUEMNE M.E.	Dental Surgery
	DEPARTMENT OF PHARMACOTOXICOLOGY AND PHARMACOKINETICS
1.	NGUIDJOE Evrard Marcel (CD)	Pharmacology
	A. Associate Professors
1.	FOKUNANG Charles	Molecular Biology
2.	MPONDO MPONDO Emmanuel	Pharmaco-toxicology/ Pharmacokinetics
	B. Senior Lecturers
1.	NGUIDJOE Evrard Marcel	Pharmacology
2.	TEMBE Estella épse FOKUNANG	Clinical Pharmacology
3.	TABI OMGBA	Pharmacy
	DEPARTMENT OF PHARMACOGNOSY AND PHARMACEUTIC CHEMISTRY
	A. Associate Professors
1.	NTSAMA ESSOMBA Claudine (CD)	Pharmacognosy / Pharmaceutic Chemistry
2.	GUEDJE Nicole Marie	Ethnopharmacology/ Plant Biology
3.	NGAMENI Barthélémy	Phytochemistry/ Organic Chemistry
4.	NGOUPAYO Joseph	Phytochemistry/General Chemistry
	DEPARTMENT OF GALENICAL PHARMACY AND PHARMACEUTIC LEGISLATION
	A. Associate Professors
1.	NNANGA NGA Emmanuel (CD)	Galenical Pharmacy
	B. Lecturers
1.	MBOLE Jeanne Mauricette épse MVONDO M.	Quality Management, Quality Control of Health Products and Food
2.	SOPPO LOBE Charlotte Vanessa	Quality Control of Medicines

GALEN'S OATH

To honour those who educated me in the precepts of my art and to show them my gratitude by remaining faithful to their teaching.

To exercise, in the interest of public health, my profession with consciousness and to respect not only the legislation in effect, but also the rules of honour, probity and disinterestedness.

To never forget my responsibility and duties towards the sick person and his human dignity; in no case, I shall consent to use my knowledge and my status for corrupt mores and favour criminal acts.

That men grant me their esteem if I am faithful to my promises. May I be covered with opprobrium and despised by my colleagues if I don't.

ABSTRACT

BACKGROUND: Cardiovascular diseases account for about 17 million deaths per year globally.Hypertension is responsible for at least 45% of deaths due to heart disease. The number of people with uncontrolled hypertension is increasing because of population growth and ageing. A very high prevalence rate of hypertension of 29.7% was reported in Cameroon. Hypertension requires long term management and follow-up. Adherence to therapy is a key component of a successful management. Few studies have been done in Cameroon regarding antihypertensive treatment adherence. This study was therefore designed to assess the adherence status and associated factors to antihypertensive therapy in hypertensive patients followed-up at Yaounde General Hospital.

METHODS: This was a cross-sectional analytic study conducted at the external consultation service of the cardiology unit of the Yaounde General Hospital. This study was carried out over a period of seven months (November 2017 - May 2018). Patients admitted into this study were selected consecutively and those that met our inclusion criteria were selected prior to interviewing. Two sitting blood pressure measurements were taken on both arms with a pretested electronic sphygmomanometer. We assessed the adherence level of the study population by using the validated Morisky 8-item medication adherence scale. Patients with a score of 8 on the scale were termedhighly adherent, medium adherers were those with a score of 6 to <8, and those classified as lowadherers were those with a score of <6. Bivariate and multivariate analyses were carried out to assess associations of each independent variable with the dependent variable. Odds ratio and 95% confidence interval were used to identify the presence and strength of association. Statistical significance was considered at P-value < 0.05.

RESULTS:Of the 181 patients screened, 175 were retained for the study. Sex ratio of participants was 1.2 with male predominance of 54.90%. The mean age was 60 years. Most participants (88.60%) lived in urban areas and 51.43% had a non-liberal profession, the majority (66.30%) lived as couples and 40.00% had a higher level of education. Trip duration to the hospital was less than one hour for84.60% of participants. The high socioeconomic status (60%) was highly representedin this study and 10.9% of participants had a health insurance.The High Normal blood pressure group was most represented (24.60%) and 57.70% had acontrolled BP. The most frequently encountered comorbidity was heart failure(24.57%). Only 18.29% of participants had a handicap. Calcium channel blockers were the most encountered monotherapy (31.90%). The mean treatmentcost was 14543FCFA and most participants were in the 10000-20000FCFAmonthly drug cost range. Poor adherence was observed in 32.60% of study participants. After multivariate analysis with logistic regression, 9 variables were significantlyassociated with poor adherence: first cycle secondary education (p=0.0209; odds ratio=4.6623), living singly(p=0.0003; odds ratio=4.6623), tripduration of one hour or more (p=0.008; odds ratio=7.3925), middle socioeconomic status (p=0.006; odds ratio=2.6814), uncontrolled blood pressure status(p<0.0001; odds ratio=5.5704),presence of handicap (p=0.0117; odds ratio=4.1222), monotherapy (p=0.0295; odds ratio=2.0721), presence of side effects (p<0.0001; odds ratio=11.5143), and taking medication inthe evening (p=0.0399; odds ratio=2.5452).Of the 74 patients with uncontrolled BP, 86.49% had poor adherence. Only 54.30% of participants were knowledgeable about hypertension.

CONCLUSION: 9 predictive factors of poor adherence were identified: first cycle secondary education, living singly, tripduration of one hour or more, middle socioeconomic status, uncontrolled BP status,presence of handicap, monotherapy, presence of side effects, and taking medications inthe evening. Addressing these factors could help health care providers better foster drug adherence.

RESUME

CONTEXTE: Les maladies cardiovasculaires causent environ 17 millions de décès par an dans le monde. L'hypertension est responsable d'au moins 45% des décès dus à une maladie cardiaque. Le nombre de personnes souffrant d'hypertension incontrôlée augmente en raison de la croissance démographique et du vieillissement. Un taux très élevé de prévalence de l'hypertension de 29,7% a été signalé au Cameroun. L'hypertension nécessite une prise en charge à long terme et un suivi. L'observance aux traitements est un élément clé d'une prise en charge réussie. Peu d'études ont été réalisées au Cameroun concernant l'observance aux traitements antihypertenseurs. Cette étude a donc été conçue pour évaluer le niveau d'observance et les facteurs associés aux traitements antihypertenseurs chez des patients hypertendus suivis à l'Hôpital général de Yaoundé.

METHODES: C'est une étude analytique et transversale et réalisée au service de consultations externe de l'unité de cardiologie de l'Hôpital Général de Yaoundé. Elle a été menée sur une période de sept mois (novembre 2017 - mai 2018). Les patients admis dans cette étude ont été sélectionnés consécutivement et ceux qui répondaient à nos critères d'inclusion ont été sélectionnés avant d'être interviewés. Deux mesures de la pression artérielle étant assis, ont été prises sur les deux bras avec un sphygmomanomètre électronique prétesté. Nous avons évalué le niveau d'observance de la population étudiée en utilisant l'échelle d'observance des médicaments en 8 points de Morisky. Les patients avec un score de 8 sur l'échelle ont été considérés comme hautement observant, les observant moyens ont été ceux avec un score de 6 à <8, et ceux classés comme faiblesobservant étaient ceux avec un score <6. Des analyses bi-variées et multivariées ont été réalisées pour évaluer les associations de chaque variable indépendante avec la variable dépendante. L'Odds ratio et intervalle de confiance à 95% ont été utilisés pour identifier la présence et la force de l'association. La signification statistique a été considérée à la valeur P <0,05.

RÉSULTATS:Après avoir identifié 181 patients, 175 ont été retenus pour l'étude. Le sex-ratio des participants était de 1,2 avec une prédominance masculine de 54,90%. L'âge moyen était de 60 ans. La plupart des participants (88,60%) vivaient en milieu urbain et 51,43% avaient une profession non libérale, la majorité (66,30%) vivait en couple et 40,00% avaient un niveau de scolarité plus élevé. La durée du trajet à l'hôpital était de moins d'une heure pour 84,60% des participants. Le statut socioéconomique élevé (60%) était largement représenté dans cette étude et 10,9% des participants avaient une assurance santé. Le groupe Haut Normal de pression artérielle était le plus représenté (24,60%) et 57,70% avaient une pression artérielle contrôlée. La comorbidité la plus fréquente était l'insuffisance cardiaque (24,57%). Seulement 18,29% des participants avaient un handicap. Les inhibiteurs calciques ont été les monothérapies les plus rencontrées (31,90%). Le coût moyen du traitement était de 14543FCFA et la plupart des participants se situaient dans la fourchette des coûts mensuels de 10000-20000FCFA. La mauvaise observance a été retrouvée chez 32,6% des participants. Après analyse multivariée avec régression logistique, 9 variables étaient significativement associées à une mauvaise observance: enseignement secondaire de premier cycle(p=0.0209; odds ratio=4.6623), vie seule(p=0.0003; odds ratio=4.6623), durée du trajet d'une heure ou plus(p=0.008; odds ratio=7.3925), statut socioéconomique moyen(p=0.006; odds ratio=2.6814), état de PA incontrôlé(p<0.0001; odds ratio=5.5704), présence d'un handicap(p=0.0117; odds ratio=4.1222), monothérapie(p=0.0295; odds ratio=2.0721), présence d'effets secondaires(p<0.0001; odds ratio=11.5143) et prise médicamenteuse le soir(p=0.0399; odds ratio=2.5452). Sur les 74 patients avec une pression artérielle non contrôlée, 86,49% avaient une mauvaise observance. Seulement 54,30% des participants connaissaient l'hypertension.

CONCLUSION: 9 facteurs prédictifs de mauvaise observance ont été identifiés: enseignement secondaire de premier cycle, vie seule, durée de voyage d'une heure ou plus, statut socioéconomique moyen, état de PA incontrôlé, présence d'un handicap, monothérapie, présence d'effets secondaires et prise de médicaments le soir. S'attaquer à ces facteurs pourrait aider les fournisseurs de soins de santé à mieux favoriser l'observance aux médicaments antihypertenseurs.

LIST OF FIGURES

LIST OF TABLES

LIST OF ABBREVIATIONS/ACRONYMS/SYMBOLS

CHAPTER I: INTRODUCTION

I.1 BACKGROUND AND RATIONALE

According to the World Health Organization (WHO), cardiovascular diseases account for about 17 million deaths per year globally i.e. nearly one third of the total[1].Of these cardiovascular diseases, hypertension accounts for 9.4 million deaths worldwide and7.0% of global disability adjusted life-years (DALY) in 2010[2].Hypertension is a serious medical condition and a key public health problem.It has been defined as the level of blood pressure above which intervention has been shown to reduce the associatedcardiovascular risk[3].Hypertension is responsible for at least 45% of deaths due to heart disease, and 51% of deaths due to stroke[1]. In 2008, approximately 40% of adults aged 25 and over had been diagnosed with hypertension worldwide[4].The number of people with uncontrolled hypertension increased from 605 million in 1980, to 978 million in 2008, because of population growth and ageing[5].Systolic blood pressure (SBP) is currently highest in low-income and middle-income countries[1,5,6];the prevalence of hypertension is highest in the African continent at 46% of adults aged 25 and over, while the lowest prevalence at 35% is found in the Americas[1]. In developing countries, its morbidity andmortality are increasing due tosedentary life and changes in lifestyle[7]. In 2015, Kingue et al. reported a very high prevalence rate of hypertension (29.7%) in Cameroon, with the tendency of a steady rise towards a super epidemic in the next 20 years to come[8].Kamadjeu et al. reported in a 2003 population survey that only 23% of all hypertensive patients were aware of their status, 10.8% were taking antihypertensive medication and 2% were controlled[9]. These findings suggest that medication nonadherence might be responsible for the prevalence of high BP levels in Cameroon. With this in mind, effective strategies have to be developed in order to foster adherence to antihypertensive treatments by patients. The latter must be encouraged to participate in medical decisions by actively getting involved in the selection, adjustmentof drug treatment and in changes in lifestyle in orderto maximize the usefulness of the therapeuticregimen[10].

The adverse health effects of hypertensionare compounded because manyaffected people also have other health risk factorsthat increase the odds of heart attack,stroke and kidney failure[1]. These risk factorsinclude tobacco use, obesity, high cholesteroland diabetesmellitus. In 2008, 1 billion people weresmokers and the global prevalence of obesity increased by about two-fold since 1980[1]. The global prevalenceof high cholesterol was 39% and prevalenceof diabetes was 10% in adults above 25 years[4].Populations around the world are rapidly ageing and prevalence of hypertensionincreases with age[11].

Treatment of hypertension involves both non-pharmacological and pharmacological interventions to reduce blood pressure, as well as assessment and treatmentof any other cardiovascular risk factors[3].Adopting a healthy lifestyle is beneficial for all individuals, and any patient with raised blood pressure should be encouraged to make lifestyle changes that will reduce theircardiovascular risk. Depending on treatment guidelines, different drug regimens may be used with differing pharmacological actions. Historically, thiazide diuretics and beta blockers have been the mainstay of drug therapy for hypertension, but calcium channel blockers, angiotensin-converting enzyme inhibitors, antagonists of angiotensin II receptors, and alpha blockers are now also widely used[3].

Hypertension requires long term management and follow-up. Adherence to therapy is a key component of a successful management. Adherence to a medication regimen is generally defined as the extent to which patients take medications as prescribed by their health care providers[10].Both medications andlifestyle changes are prescribed to hypertensive patients with the expectation that they will be adherent[1,12].However, the problem of non-adherence tomedical treatment remains a challenge for the medicalprofessions asmany patients fail to adhere totreatment recommendations resulting inpoor health outcomes,lower quality of life and increased health care costs[7,13].Poor adherence to anti-hypertensive therapy is one of the biggest hindrances in therapeutic control of high blood pressure[14].It also compromises the efforts of healthcare systems, policy makers and health care professionalsto improve the health of populations. Failure to adherecauses medical and psychological complications of thedisease, reduces patients' quality of life, wastes healthcare resources and erodes public confidence in healthsystems[15].

Few studies have been done in Cameroon regarding antihypertensive treatment adherence and the few that have been carried out portray low levels of therapeutic adherence.Mbouemboue et al. found that adherence to antihypertensive drug treatment is poor in their study population in Garoua with an adherence rate of 12.9%[16].In a survey conducted in the Buea Regional Hospital, it was noted that 94% of patients were aware of the necessary measures to control their blood pressure, although 54.5% affirmed having difficulties in respecting recommended dietary and other lifestyle measures because they were too constraining[17]. Tufon et al. however reported a high overall level ofadherence of patients to antihypertensive treatment (80.0%) in a rural setting (Mankon sub divisional health centre)[18].Essomba et al. reported that 26.2% of their study population in Douala had good adherence to antihypertensive treatment[19]. Akoko et al. found a slightly greater adherence rate of 49.3% among adult patients in the Bamenda Health District[20].

Poor adherence to antihypertensive therapy is usually associated with adverse clinical outcome of the disease andwastage of limited health care resources[10,15,21]. The intention of addressing adherence issues is to contribute in achieving the third sustainable goals which seeks to «ensure healthy lives and promote wellbeing for all at all ages»; especially target 24 which seeks to reduce by 2030, one third of premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being[22].

The choice to undertake this study in the Yaounde General Hospital was because it is a first category referral hospital with a well-equipped cardiology service where many patients with various cardiovascular diseases especially hypertensive patients are regularly followed by cardiologists.

In Cameroon, there is a paucity of research regarding adherence rates and their correlates in urban settings.This study was therefore designed toassess the adherence statusand associated factors to antihypertensive therapy in hypertensive patients followed-up at the Cardiology Unit of the Yaounde General Hospital.

I.2 RESEARCH QUESTION

What is the level of adherence to antihypertensive treatment and associated factors in hypertensive patients followed up at the Yaounde General Hospital?

I.3 RESEARCH HYPOTHESIS

Adherence to antihypertensive treatments by patients followed up at the Yaounde GeneralHospital is low and may beassociated with certain factors.

I.4 OBJECTIVES

To assess the adherence level and its associated factors to antihypertensive therapy among adult hypertensive patients followed-up at the Yaounde General Hospital.

1. Document the sociodemographic and socioeconomic characteristics of the study population.

2. Describe the clinical andtherapeutic characteristics of the study population.

3. Assess their adherence to antihypertensive treatment using a standard validated questionnaire.

CHAPTER II: LITERATURE REVIEW

· Adherence (to a medication regimen): The World Health Organization (WHO) defines adherence as ``the extent to which a person's behaviour taking medication, following a diet, and/or executing life style changes corresponds with agreed recommendations from a health care provider''[23].

· Disability-Adjusted Life Year (DALY):Measure of years of life lost from deaths which occur before some theoretically achievable age (e.g., international reports use 80 years for men and 82.5 years for women) and attributing this loss to death rates. DALYs for a disease or health condition are calculated as the sum of the Years of Life Lost due to premature mortality in the population and the Years Lost due to Disability for people living with the health condition or its consequences[24].

· Compliance: Term suggesting that a patient is passively following the doctor's orders and that the treatment plan is not based on a therapeutic alliance or contract established between the patient and the physician[10].

· Hypertension:Systolic blood pressure equal to or above 140 mm Hg and/or diastolic blood pressure equal to or above 90 mm Hg[1].

In 2010, the three leading risk factors for global disease burden were high bloodpressure (7.0% of global DALYs), tobacco smoking includingsecond-hand smoke (6.3%), and alcohol use (5.5%)[2]. Hypertension alone accounts for 9.4 million deaths worldwide[1].Dietaryrisk factors and physical inactivity collectively accounted for 10.0% of globalDALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high insodium[2].Hypertension is responsible for at least 45% of deaths due toheart disease, and 51% of deaths due tostroke[1].Figure 1 shows the total stroke mortality rate in the world.Globally, the overall prevalence of raised blood pressure in adults aged 25 and over was around 40% in 2008[4].Figure 2 shows the global age-standardized prevalence of raised blood pressure in adults aged 25+ years.The proportion of the world's population with high blood pressure, or uncontrolled hypertension, fell modestly between 1980 and 2008. However, because of population growth and ageing, the number of people with hypertension rose from 600 million in 1980 to nearly 1 billion in 2008[4]. Still in 2008, the prevalence of raised blood pressure was highest in the African continent, where it was 46% for both sexes combined[4].

Figure 2: Age-standardized prevalence of raised blood pressure in adults aged 25+ years[4]

The lowest prevalence of raised blood pressure was in the WHO Region of theAmericas, with 35% for both sexes[4]. In all WHO regions, men have slightly higher prevalence of raised blood pressure than women, but this difference was only statistically significant in the American and European continents[4].Across the income groups of countries, the prevalence of raised blood pressure was consistently high in low and lower-middle income countries while upper-middle-income countries all had rates of around 40%for both sexes. The prevalence in high-income countries was lower, at 35% for both sexes[4].Not only is hypertension more prevalent in low- and middle-income countries, there are also more people affected because more people live in those countries than in high-income countries[1,5].Further, because of weak health systems, the number of people with hypertension who are undiagnosed, untreated and uncontrolled are also higher in low- and middle-income countries compared to high-income countries. The increasing prevalence of hypertension is attributed to population growth, ageing and behavioural risk factors[1,11].Figure 3 shows the 2015 distribution of the world's population by age and sex.

The adverse health consequences of hypertensionare compounded because many peopleaffected also have other health risk factorsthat increase the odds of heart attack,stroke and kidney failure. These risk factorsinclude tobacco use, obesity, high cholesteroland diabetesmellitus[1].In 2008, 1 billion people weresmokers and the global prevalence of obesity has nearly doubled since 1980[1]. The global prevalenceof high cholesterol was 39% and prevalenceof diabetes was 10% in adults over 25years[4]. Tobacco use, unhealthy diet, harmfuluse of alcohol and physical inactivity are alsothe main behavioural risk factors of all majornoncommunicable diseases, i.e. cardiovasculardisease, diabetes, chronic respiratory disease and cancer.If appropriate action[1] is not taken, deaths dueto cardiovascular disease are projected to rise further [25].Figure 4 shows the projected global deaths for selected causes for the 2004-2030 timeframe.

Between 1994 and 2003, blood pressure levels havedeteriorated over time in rural and urban Cameroonian menand women with the prevalence of hypertension increasing by twofold to fivefold[26].This has beenattributed to the rapid urbanization associated with thehigh rates of obesity, physical inactivity, diabetes,increased salt consumption, and tobacco use[27].In 2011, Dzudie A et al. reported a prevalence rate for hypertension of up to 47.5% in self-selectedurban dwellers in Cameroon[28].In a more recent nationwide study, Kingue et al. found a prevalence rate of 29.7% in urban areas of Cameroon;indicating asteadyrise in the trend of hypertension toward a super epidemic in 20 years to come[8].

In the majority of cases, high BP is termedprimary or essentialhypertensionand isprobably multifactorial in origin, with genotype, as well asexternal factors such as diet and body-weight, playing arole. Hypertension may also be associated with surgery[29]or pregnancy[30] and is prevalent in diabetics[31]. In a limitednumber of cases hypertension is secondaryto some othercondition, such as renal disease, Cushing's syndrome,phaeochromocytoma, or to the adverse effects of drugs suchas oestrogens, and such causes may be suspected particularlyin resistant or malignant hypertension[32].

Although it has frequently been indicated that the causes ofessential hypertension are unknown, this is only partially true because little information is available on genetic variationsor genes that are over-expressed or under-expressed as well asthe intermediary phenotypes that they regulate to cause hypertension.Variation in BP that is genetically determined is called «inherited BP,»although the genes which cause BP to vary are not known; it is known from familystudies that inherited BP can range from low normal BP tosevere hypertension. Factors that increase BP, (such as obesity, insulin resistance, high alcohol intake, high salt intake (in salt-sensitive patients), ageing and perhapssedentary lifestyle, stress, low potassium intake, and low calcium intake) are called «hypertensinogenic factors.» Some of these factors have inherited,behavioural, and environmental components. Inherited BPcould be considered core BP, whereas hypertensinogenicfactors cause BP to increase above the range of inherited BPs. Figure 5 illustrates the additive effect of hypertensinogenic factors on hereditary systolic and diastolic BP. It shows that patients with normalor high normal inherited BP become hypertensive stage 1 whenBP is increased by a hypertensinogenic factor. In patients withinherited hypertension in stages 1 to 3, their hypertensionbecomes more severe when hypertensinogenic factors areadded.

Figure 5: Additive effect of hypertensinogenic factors (hatched areas) on hereditary systolic (white areas) and diastolic blood pressure (black areas)[33]

Hypertension related to a specific aetiology is termed secondaryhypertension,markedly differing from essential hypertension, ofwhich the aetiology cannot be clearly identified. Secondary hypertension is often resistant hypertension,for which a target blood pressure is difficult to achieve bystandard treatment. However, BP can be effectivelyreduced by identifying its aetiology and treating the condition.

Frequent etiological factors for secondary hypertension includerenal parenchymal hypertension, primary aldosteronism (PA), renovascularhypertension and sleep apnea syndrome. As other etiological factors for secondary hypertension, the following conditions have been reported in endocrine hypertension: pheochromocytomaand Cushing's syndrome which are related to an excessiveproduction of catecholamines and cortisol, respectively. Hypo-/hyperthyroidism, hyperparathyroidism and acromegaly are alsoetiologically involved in hypertension. In vascular hypertension, angiitissyndrome, such as aortitis syndrome, polyarteritis nodosa (PN)and systemic scleroderma, aortic coarctation and aortic insufficiencyhave been reported. Compression of the rostral ventrolateral medullaby brainstem blood vessels causes hypertension through hyperactivityof the sympathetic nerves. Furthermore, hypertension is also observedin patients with brain tumours or cerebrovascular disease. In addition,drug-induced hypertension has been reported (by drugs such as NSAIDs, oral contraceptive, liquorice, sympathomimetics, glucocorticoids, cyclosporine, tacrolimus, erythropoietin, tricyclic/tetracyclic antidepressants, monoamine oxygenase inhibitors, Anti-VEGF antibody preparations).

It has been recognized that secondary hypertension accounts for about 10% of hypertensive patients. According to several studies, PA accounts for approximately 5-10% of hypertensive patients, and it is the most frequent in endocrine hypertension.

Generally, the presence of severe or resistant hypertension, juvenile hypertension and the rapid onset of hypertension suggest the possibility of secondary hypertension. In such hypertensive patients, a close inquiry on medical history, medical examination and adequate examinations must be performed, considering the possibility of secondary hypertension. The possibility of secondary hypertension should be considered in the diagnosis and treatment of all hypertensive patients. It is important to conduct appropriate examinations without overlooking findings of secondary hypertension.

There is a common misconceptionthat people with hypertensionalwaysexperience symptoms, but the reality isthat mosthypertensive people have nosymptoms at all. The condition is a silent killer. Therefore it is important for everybody to know their blood pressure reading.

Sometimes hypertensioncauses symptoms such as headache, shortnessof breath, dizziness, chest pain, palpitationsof the heart and nose bleeds. It canbe dangerous to ignore such symptoms,but neither can they be relied upon to signifyhypertension.

Left untreated, high BP can have damaging effects. Theprimary way it causes harm is by increasing the workload of the heart and arteries,which causes damage to the circulatory system over time. Also, high BP can cause the heart to enlarge because it has to work harderto supply the blood the body needs. It is also a contributing factor toatherosclerosis, in which the walls of the arteries become stiff and brittle as fattydeposits build up inside them. Other conditions caused by hypertension include coronary heart disease, heart failure, heartattack, stroke, kidney damage, angina (chest pain related to heart disease), peripheralartery disease, and other serious conditions (aneurysms, cognitive changes, eye damage). In fact, people with BP over 140/90 are far more likely to havethese dangerous conditions thus hypertension is a serious warning sign that significant lifestyle changes have to be adopted.

Current options for BP measuring devices include mercury sphygmomanometers, aneroid manometers, semiautomatic devices and fully automatic electronic devices. Validated and affordable electronic BP measuring devices, that have the option to select manual readings, appear to be the preferred option for lowresource settings according to WHO[39].Semi-automatic devices enable manual readingsto be taken when batteries run down,a common problem in resource-constrainedsettings. Given that mercury is toxic,it is recommended that mercury devices bephased out in favour of electronic devices[39].Aneroid devices should be considered only if calibrated at regular intervals (every 6 months for example) and users should be trained and assessed in measuring BP using such devices[1,39].

Diagnostic procedures aim at: 1) establishing blood pressurelevels; 2) identifying secondary causes of hypertension;3) evaluating the overall cardiovascular risk bysearching for other risk factors, target organ damageand concomitant diseases or accompanying clinicalconditions.The diagnostic procedures comprise[40]:

Some ofthese should be considered part of the routine approachin all subjects with high BP; some arerecommended and may be used extensively in thedeveloped health systems; some are indicatedonly when suggested by the basic examination or theclinical course of the patient[40].

Blood pressure is characterized by large spontaneousvariations both during the day and between days, monthsand seasons.Therefore the diagnosis of hypertension should be based on multiple BP measurements, taken on separate occasions over a period of time. If BP is only slightly elevated, repeated measurements should be obtained over a period of several months to define the patients ``usual'' BP as accurately as possible. On the other hand, if the patient has a more marked BP elevation, evidence of hypertension-related organ damage or a high or very high cardiovascular risk profile, repeated measurements should be obtained over shorter periods of time (weeks or days). In general, the diagnosis of hypertension should be based on at least 2 blood pressure measurements per visit and at least 2 to 3 visits, although in particularly severe cases the diagnosis can be based on measurements taken at a single visit. Blood pressures can be measured by the doctor or the nurse in the office or in the clinic (office or clinic blood pressure), by the patient or a relative at home, or automatically over 24 h. Based on specific recommendations of the European Society of Hypertension[40], these procedures can be summarized as follows:

BP can be measured by a mercury sphygmomanometer the various parts of which (rubber tubes, valves, quantity of mercury, etc.) should be kept in proper working order. Other non-invasive devices (auscultatory or oscillometric semiautomatic devices) can also be used and will indeed become increasingly important because of the progressive banning of the medical use of mercury[39]. However, these devices should be validated according to standardized protocols[43], and their accuracy shouldbe checked periodically by comparison with mercurysphygmomanometric values. Table I shows the instructions for correctoffice BP measurements.

Several devices (mostly oscillometric) are available forautomatic BP measurements in patients allowed to conduct a near normal life. They provide information on 24-hour average BP as well as on mean values over more restricted periods such as the day, night or morning. This information should not be regarded as a substitute for information derived from conventional BP measurements. Studies have shown that ambulatory BP : 1) correlates with hypertension-related organ damage and it changes by treatment more closely than does office blood pressure, 2) has a relationship with cardiovascular events that is steeper than that observed for clinic BP, with a prediction of cardiovascular risk greater than the prediction provided by office BP values in populations of untreated and treated hypertensives[44-46] and 3) measures more accurately than clinic BP the extent of BP reduction induced by treatment, because of a higher reproducibility over time and an absent or negligible ``white coat''[47] and placebo effect[48].

Although some of the aboveadvantages can be obtained by increasing the number ofoffice BP measurements, 24-hourambulatory BP monitoring may be useful atthe time of diagnosis and at varying intervals duringtreatment[40]. Efforts should be made to extend ambulatory BP monitoring to 24 hours in order to obtaininformation on both daytimeand night-timeBP profiles, day-night BP difference, morning BP rise and BP variability.Daytimeand night-time blood pressure values and changes bytreatment are related to each other, but the prognosticvalue of night-time blood pressure has been found tobe superior to that of daytime blood pressure[45,49]. Evidence is also available thatcardiac and cerebrovascular events have a peak prevalencein the morning,possibly in relation to thesharp blood pressure rise occurring at awaking fromsleep, as well as to an increased plateletaggregability, a reduced fibrinolytic activity and a sympatheticactivation[40,41].

· Use cuffs of appropriate size and compare the initial values with those from a sphygmomanometer to checkthat the differences are not greater than #177; 5mmHg

· Set the automatic readings at no more than 30 min intervals to obtain an adequate number of values and have most hours represented if some readings arerejected because of artefact.

· Automatic deflation of the equipment should be at arate of no more than 2mmHg/s.

· Instruct the patients to engage in normal activities but to refrain from strenuous exercise, and to keep the armextended and still at the time of cuff inflations.

· Ask the patient to provide information in a diary on unusual events and on duration and quality of nightsleep.

· Obtain another ambulatory BP if the first examination has less than 70% of the expected number of valid values because of frequent artefacts. Ensure that the proportion of valid values is similar for the dayand night periods.

· Remember that ambulatory BP is usually several mmHg lower than office BP. Different population studies indicate that office values of 140/90mmHg correspond to average 24-h values of either 125-130mmHg systolic and 80mmHg diastolic, the corresponding average daytime and night-time values being 130-135/85 and 120/70mmHg. These values may be regarded as approximate threshold values for diagnosinghypertension by ambulatory BP. Table II indicates blood pressure thresholds for the definition of hypertension with different types of measurement

· Clinical judgement should be mainly based on average 24-hour, day and/or night values. Other information derived from ambulatory blood pressure (e.g. morning blood pressure surge and blood pressure standard deviations) is clinically promising, but the field shouldstill be regarded as in the research phase.

Table II: Blood pressure thresholds (mmHg) for definition of hypertension with different types of measurement[40]

A comprehensive family history should be obtained withparticular attention to hypertension, diabetes, dyslipidaemia,premature coronary heart disease, stroke, peripheralartery or renal disease.The clinical history should include: a) duration andprevious levels of high blood pressure; b) symptomssuggestive of secondary causes of hypertension andintake of drugs or substances that can raise blood pressure,such as liquorice, nasal drops, cocaine, amphetamines,oral contraceptives, steroids, nonsteroidal anti-inflammatory drugs, erythropoietin, and cyclosporin;c) lifestyle factors, such as dietary intake of fat (animalfat in particular), salt and alcohol, quantification of smokingand physical activity, weight gain since early adultlife; d) past history or current symptoms of coronarydisease, heart failure, cerebrovascular or peripheralvascular disease, renal disease, diabetes mellitus, gout,dyslipidaemia, asthma or any other significant illnesses,and drugs used to treat those conditions; e) previousantihypertensive therapy, its results and adverse effects;and f) personal, family and environmental factors thatmay influence blood pressure, cardiovascular risk, as wellas the course and outcome of therapy. Also, physiciansshould enquire after the patient and/or partner aboutsnoring which may be a sign of sleep apnoea syndromeand increased cardiovascular risk.

In addition to BP, heart rate should be carefullymeasured (pulse counting over at least 30s or longer ifarrhythmias are reported) because the repeated findingof values above normal may be an indication of greaterrisk, increased sympathetic or decreased parasympatheticactivity[51], or of heart failure. Physical examinationshould search for evidence of additional risk factors, forsigns suggesting secondary hypertension, and for evidenceof organdamage. Table III highlights the physical examination for secondary hypertension, organ damage and visceral obesity.Waist circumference should be measuredwith the patient standing and body weight and heightshould be obtained to calculate the body mass index.

Laboratory tests are directed at providing evidencefor additional risk factors, searching for secondaryhypertension and looking for the absence or presenceof organ damage. Investigations should progress from themost simple to the more complicated. The youngerthe patient, the higher the BP and the fasterthe development of hypertension, the more detailed thediagnostic work-up should be. However, the minimum laboratory investigations needed remain a matter ofdebate.

Table III: Physical examination for secondary hypertension, organ damage and visceral obesity[40]

Where cardiovasculardiseases are the primary cause of morbidityand mortality, routine laboratory investigations shouldinclude: blood chemistry for fasting glucose, total cholesterol,LDL-cholesterol, HDL-cholesterol, triglycerides(fasting), urate, creatinine, potassium, haemoglobin andhaematocrit; urinalysis by a dipstick test that permits thedetection of microalbuminuria; urine microscopic examinationand an electrocardiogram[40].

Serum creatinine values should be used to estimatecreatinine clearance via the Cockroft Gault formula[52], easy procedures allowing identificationof patients with reduced glomerular filtration andincreased cardiovascular risk but in whom serum creatininevalues are still in the normal range. When fasting plasma glucose is =5.6 mmol/L(100 mg/dL), a post-load plasma glucose (glucose tolerancetest) is recommended[53]. The repeated findingof a fasting plasma glucose =7.0 mmol/L (126 mg/dL),and an abnormal glucose tolerance test are consideredindicative of diabetes mellitus[53].

Although highsensitivity C reactive protein (hsCRP)has been reportedto predict the incidence of cardiovascular events inseveral clinical settings[54], its added value in determiningtotal cardiovascular risk is uncertain,except in patients with metabolic syndrome in whomhsCRP values have been reported to be associatedwith a further marked increase in risk[55].Table IV gives a summary of the possible laboratory investigations.

Most of what follows is linked to primary or essential hypertension in adults.Hypertension may be discovered because of adverse vascularevents, especially in the eyes, brain, kidneys, orheart, but is more often asymptomatic and only discoveredon routine measurement of blood pressure[1,38]. Once diagnosed,decisions have to be made about the need for treatment.It is well-established that hypertension is a risk factorfor the development of stroke, heart failure, and renaldamage, and to a lesser extent ischaemic heart disease, anda reduction in blood pressure is generally beneficial, althoughmortality remains higher than in non-hypertensives[56].

Treatment of hypertensionmay involve both non-pharmacological and pharmacologicalinterventions to reduce blood pressure, as well asassessment and treatment of any other cardiovascular riskfactors; anyco-existing diseases should also be treated[3]. Differences inthe detail of guidelines on the management of hypertensionreflect varying judgements on the justification for interventionand the relative risks and benefits of differenttreatments.

Adopting a healthylifestyle is beneficial for all individuals, and any patientwith raised blood pressure should be encouraged to makelifestyle changes that will reduce their cardiovascular risk.Some of these changes may also reduce blood pressure,and in those who are at low overall risk no other treatment may be needed[57,58]. A trial of non-pharmacologicaltreatment is recommended in most patients beforestarting drug therapy, but should not unnecessarily delaytreatment, especially if the patient is at high risk[40,59-61]. Interventionsthat have been shown to reduce blood pressureinclude[1,3]:

Other interventions that have been tried, but with less evidenceof benefit, include[3]:

These lifestyle changes may also be promoted in the populationas a whole, or in individuals most likely to develophypertension, in strategies for the primary preventionofhigh blood pressure[1,62].

The main decisions in drugtreatment relate to the blood pressure at which therapyshould be begun, the target blood pressure, and the mostappropriate drug regimen to use[3]. Controversies exist in allthese areas.When to intervenewith antihypertensive drugs dependson factors including both the measured blood pressure andthe overall cardiovascular risk. Several guidelines have been published on the measures which entail pharmacological treatment[40,59,60]:

· Patients with grade 3 hypertension (180/110 mmHg or higher) should receive prompt drug treatment.

· In grade 2 hypertension, drug therapy is indicated if blood pressure remains at 160/100 mmHg or higher after a period of lifestyle modification, which varies depending on the overall level of risk; prompt drug therapy is advised for those at high or very high risk.

· For patients with grade 1 hypertension, the need for treatment is less well established; those with associated risk factors should be given drug therapy if lifestyle modification is inadequate, but some guidelines suggest that antihypertensives are not indicated in those at lower risk, or state that priority should be given to those at highest risk.

· Lower thresholds may apply in patients with renal disease or diabetes, but whether there is any benefit in treating uncomplicated patients with prehypertension is controversial.

Guidelines therefore generallyrecommend that treatment decisions should not be basedon age, although slower titration of drugs has beensuggested[40] in older patients since they may be more susceptibleto adverse effects. In the very old (those over 80years) the benefit of starting therapy is less clear[63,64], althougha study[65] in patients aged 80 years and over found a reduction in mortality. Those already being treated shouldcontinue[40,60].

Target blood pressuresare also controversial. The HOT study found that effective control to maintain the diastolic pressure at about 85 mmHg reduced therate of cardiovascular events, but lower pressures (ofaround 70 mmHg) did not provide any further benefit[66]. Target blood pressures of below140/90 mmHg[40,61], or below 140/85 mmHg[60] are now recommended;lower targets may be considered if toleratedby the patient, particularly in patients at high risk[40]. A lowertarget of below 130/80 mmHg has also been suggested for patients with established ischaemic heart disease[67], andlower targets may also be appropriate in diabetics and patients with renal disease.

Antihypertensive drugs comprise several classes of active pharmaceutical ingredients (APIs) with the therapeutic objective of controlling hypertension. Table V shows the different classes and subclasses of antihypertensives.

Table V: Classes and subclasses of antihypertensive medications with common examples[68]

The classes of antihypertensive drugs differ in their chemical structures thence their varying functions. Antihypertensive drugs are frequently used in other unrelated conditions, for
example, â-blockers in thyrotoxicosis[69]and anxiety[70], or angiotensin-converting enzyme inhibitors (ACEIs) in heart failure.

The following subsections will focus on the applied pharmacology of agents used in the management of hypertension, some of their side-effects, as well as some drug interactions.

Three drug classes directly target points of the RAS pathway. They act to reduce production of the peptide hormone angiotensin II, or reduce its receptor binding. Figure 6 shows the different sites of action of drugs affecting the renin-angiotensin system.

Figure 6: Sites of action of drugs affecting the renin-angiotensin system.[68]

Angiotensin II has high affinity for AT1 G-protein-coupled receptors, activation of which causes increased arteriolar tone and systemic vascular resistance (SVR). It also causes sympathetic nervous system activation, increased pituitary secretion of antidiuretic and adrenocortocotrophic hormones, and increased adrenocortical secretion of aldosterone[71].By antagonizing the RAS pathway, SVR and arterial pressure are reduced. This effect is potentiated by a reduction in aldosterone secretion with resultant reduction in renal sodium and water retention. Negative feedback results in increased renin release by the juxtaglomerular apparatus.

The discovery that the venom of the Brazilian pit viper, which causes a massive decrease in arterial pressure, works by inhibition of angiotensin-converting enzyme (ACE) led to the development of synthetic, orally administered ACEIs. ACEIs are among the first-line treatment in non-black patients under 55 years of age with primary hypertension.They are also indicated in heart failure, post-myocardial infarction, diabetic nephropathy, and chronic kidney disease (although not acute kidney injury). The renaland cardiac protective effects of ACEIs are greater than those expected by arterial pressure control alone.

ACE is a metallopeptidase enzyme which occurs mainly within the pulmonary vasculature. The inhibition of ACE reduces the cleavage of the decapeptide hormone angiotensin I to the octapeptide angiotensin IIand reduces metabolism of the peptide bradykinin to inactivesubstances. The reduction in angiotensin II is responsible formost of the therapeutic effects.

Perindopril is available as oral tablets and when taken as the erbumine salt should be taken before food. Perindopril is also available as the arginine salt; 5 mg ofperindopril arginine is equivalent to about 4 mg ofperindopril erbumine.In the treatment of hypertension perindopril is givenin an initial dose of 4 mg of the erbumine or 5 mg of thearginine salt once daily.

Perindopril acts as a prodrug of the diacid perindoprilat, its active form. After oral doses perindopril is rapidly absorbed with a bioavailability of about 65 to 75%. It is extensively metabolised, mainly in the liver,to perindoprilat and inactive metabolites including glucuronides. The presence of food is reported to reducethe conversion of perindopril to perindoprilat. Peakplasma concentrations of perindoprilat are achieved 3to 4 hours after an oral dose of perindopril. Perindoprilat is about 10 to 20% bound to plasma proteins. Perindopril is excreted predominantly in the urine, asunchanged drug, as perindoprilat, and as other metabolites. The elimination ofperindoprilat is biphasic witha distribution half-life of about 5 hours and an elimination half-life of 25 to 30 hours or longer, the latter half-life probably representing strong binding to angiotensin-converting enzyme. The excretion of perindoprilat is decreased in renal impairment.

Perindopril, as well as other ACE inhibitors, inhibit ACE, which isinvolved in the conversion of angiotensin I to angiotensin II. Angiotensin II stimulates the synthesis andsecretion of aldosterone and raises blood pressure via apotent direct vasoconstrictor effect.The pharmacological actions of ACEinhibitors are thought to be primarily due to the inhibition of the renin-angiotensin-aldosterone system, butsince they also effectively reduce blood pressure in patients with low renin concentrations other mechanismsare probably also involved.

The accumulation of bradykininhas some therapeutic advantage through vasodilatation, but isalso responsible for a dry cough in susceptible individuals.
ACEIs can also precipitate renal dysfunction by decreasing renal efferent arteriolar tone, thereby decreasing effective renal perfusion pressure, a particular risk in renal artery stenosis. Otherside-effects include hyperkalaemia due to reduced aldosterone secretion, agranulocytosis, skin rashes, and taste disturbance. A rare idiosyncratic reaction to ACEIs can cause angioedema with potential upper airway obstruction; this can occur several years after initiation of ACEI therapy. ACEIs are contraindicatedin pregnancy as they are associated with birth defects. ACEIs may interactwith drugs used perioperatively. For example, non-steroidal anti-inflammatory drugs can precipitaterenal dysfunction in combination with ACEIs. They can also reduce the efficacy of ACEIs by decreasing prostaglandin synthesis.Interactions with diuretics may cause hypovolaemia and hyponatraemia, while concurrent use of potassium supplements orpotassium-sparing diuretics may result in hyperkalaemia.Drugs which are renally excreted (e.g. digoxin and lithium) may accumulatein patients taking ACEIs.

ARAs are commonly used in patients who are intolerant to ACEIsas they are less likely to cause a dry cough.

Losartan is given orally as the potassium salt in tablet and sachet forms.In hypertension the usual dose of losartan potassiumis 50 mg once daily. The dose may be increased, if necessary, to 100 mg daily as a single dose or in two divided doses. An initial dose of 25 mg once daily should begiven to patients with intravascular fluid depletion, and is recommended in the UK in patients over 75 years ofage. Similar reductions may be appropriate in patients with hepatic or renal impairment

Losartan is readily absorbed from the gastrointestinal tract after oral doses, but undergoes substantial firstpass metabolism resulting in a systemic bioavailability of about 33%. It is metabolized to an active carboxylic acid metabolite E-3174 (EXP-3174), which has greater pharmacological activity than losartan; some inactive metabolites are also formed. Metabolism is primarilyby cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Peak plasma concentrations of losartan andE-3174 occur about 1 hour and 3 to 4 hours, respectively, after an oral dose. Both losartan and E-3174 aremore than 98% bound to plasma proteins. Losartan isexcreted in the urine, and in the faeces via bile, asunchanged drug and metabolites. About 4% of an oraldose is excreted unchanged in urine and about 6% is excreted in urine as the active metabolite. The terminal elimination half-lives of losartan and E-3174 are about1.5 to 2.5 hours and 3 to 9 hours, respectively.

Losartan is a competitive angiotensin II receptor antagonist with antihypertensive activity due mainly to selectiveblockade of AT1 receptors and the consequent reducedpressor effect of angiotensin II.

The therapeutic andside-effects are broadly similar to those of ACEIs, with evidenceof reduced risk of new onset diabetes, stroke, progression of cardiac failure, and all-cause mortality in patients with chronic kidney disease.Direct targeting of angiotensin II receptors has theoretical advantages over ACE inhibition. Angiotensin II may be producedthrough non-ACE pathways, for example, by the enzyme chymase in kidney tissue, which is not affected by ACEIs. ARAs do not inhibit bradykinin metabolism, and therefore, the incidence of cough is much less than with ACEIs. The risk of angiooedema is greatly reduced with ARAs compared with ACEIs. Losartan is contra-indicated in pregnancy.It should be used with caution in patients with renal artery stenosis. Losartan is excreted in urine and in bileand reduced doses may therefore be required in patients with renal impairment and should be consideredin patients with hepatic impairment. Patients with volume depletion (for example those who have receivedhigh-dose diuretic therapy) may experience hypotension; volume depletion should be corrected beforestarting therapy, or a low initial dose should be used.Since hyperkalaemia may occur, serum-potassium concentrations should be monitored, especially in theelderly and patients with renal impairment, and potassium-sparing diuretics should generally be avoided.

Aliskiren, a piperidine derivative, is the only available drug in this
class and is used by specialists in patients who are unresponsive to, or intolerant of, other antihypertensives.

Aliskiren is given as the fumarate. Doses are expressed in terms of the base; 165.8 mg of aliskiren fumarate is equivalent to about150 mg of aliskiren. The usual initial oral dose of aliskiren is 150 mg once daily, increased to 300 mg oncedaily if necessary. Doses may be taken before or afterfood, but patients should establish a routine patternwith regard to meals.

Aliskiren is poorly absorbed from the gastrointestinal tract with a bioavailability of about 2.5%. Peak plasma concentrations are reached about 1 to 3 hours after anoral dose. Absorption is reduced when aliskiren is taken with a high-fat meal. Aliskiren is about 50% boundto plasma proteins. It is excreted mainly in the faeces,possibly via the bile; about 25% of the absorbed doseis excreted in the urine as unchanged drug. Aliskiren is a substrate for the cytochrome P450 isoenzymeCYP3A4 but metabolism appears to be minimal. The elimination half-life is about 24 to 40 hours, and steady-state concentrations are reached in about 7 to 8days.

Aliskiren directly inhibits the enzyme renin, which is secreted by granular cells of the juxtaglomerular apparatus. Renin inhibition reduces theconversion of the hepatically secreted polypeptide angiotensinogen to angiotensin I.Its effect on the RAS is therefore `upstream' of ACEIs and ARAs and it does not cause bradykinin accumulation.

DRIs have the same potential to cause renal dysfunction and electrolyte disturbances as ACEIs and ARAs. It should therefore be used with caution in patients with renal impairment or renovascular hypertension. Patients withsodium or volume depletion (for example those receiving high-dose diuretics) may experience symptomatic hypotension on starting aliskiren and treatment shouldbegin under close medical supervision.Diarrhea is aspecific side-effect to higher doses of DRIs. Aliskiren may have a larger role in the management ofhypertension in future, possibly in combination with other drugs. Aliskiren should be avoided in pregnancy since drugsacting on the renin-angiotensin system have been associated with fetal and neonatal morbidity and mortality.

Use of aliskiren with other antihypertensives or drugsthat cause hypotension may have an additive effect.Renal function and electrolytes should be monitored indiabetic patients taking aliskiren and ACE inhibitorssince there is an increased risk of hyperkalaemia andrenal impairment.Aliskiren is metabolised to a small extent by the cytochrome P450 isoenzyme CYP3A4 but few significant interactions have been reported. Plasma-aliskiren concentrations may be reduced by irbesartan and increasedby atorvastatin and ketoconazole but the clinical relevance is not clear. Aliskiren has caused significant decreases in furosemide concentrations.

â-Blockers are not used as first-line antihypertensives unless there are otherindications, for example, after myocardial infarction, or in tachyarrhythmias such as atrial fibrillation. Theirdiverse indications include stable heart failure, thyrotoxicosis, oesophageal varices, anxiety, and glaucoma.

â-Blockers antagonize catecholamines at â-adrenoceptors.
These Gs type G-protein-coupled receptors are classified as â1, present mainly within the heart and kidneys; and â2, present throughout the body in lungs, blood vessels, and muscle. The reduction in arterial pressure achieved by â-blockers is attributable
to their effects upon multiple pathways. Block of â1 receptors in
the sinoatrial node reduces heart rate and block of myocardial receptors reduces contractility (reduced chronotropy and inotropy, respectively). They also reduce sympathetic nervous system activity, while block of receptors in the juxtaglomerular apparatus reduces renin secretion.

Propranolol hydrochloride is usually given orally. Inhypertension it is given in initial doses of 40 to 80 mgtwice daily increased as required to a usual range of 160 to 320 mg daily; some patients may require up to640 mg daily.

Propranolol is almost completely absorbed from thegastrointestinal tract, but is subject to considerablehepatic-tissue binding and first-pass metabolism. Peakplasma concentrations occur about 1 to 2 hours after anoral dose. Plasma concentrations vary greatly between individuals. Propranolol has high lipid solubility. Itcrosses the blood-brain barrier and the placenta, and is distributed into breast milk. Propranolol is about 90% bound to plasma proteins. It is metabolised in the liverand at least one of its metabolites (4-hydroxypropranolol) is considered to be active, but the contribution of metabolites to its overall activity is uncertain.The metabolites and small amounts of unchanged drug are excreted in the urine. The plasma half-life of propranolol is about 3 to 6 hours.

Propranolol is a non-cardioselective â-blocker. Propranolol also blocks sodium channels andhave membrane stabilizing activity and is thus classed as Vaughan-Williams class 2 antiarrhythmic with other â-blockers. In addition to their antihypertensive effect, propranolol improves the myocardial oxygen supply:demand ratio and help reduce myocardial ischemiaby prolonging the period of diastole.

While â-blockers are used instable heart failure, they have the potential to worsen symptomsin some patients by reducing cardiac output. Poor peripheralcirculation and Raynaud's phenomenon may be precipitatedboth by reduced cardiac output and block of peripheral â2 receptors. Bronchospasm caused by â2 block may be a significantrespiratory side-effect in susceptible individuals, for example,asthmatics. Central nervous system effects include malaise,tiredness, and vivid dreams, particularly with lipid-solubledrugs. Ininsulin-dependent diabetic patients, the symptoms ofhypoglycaemia may be suppressed by sympathetic block.

á-Blockers are used to treat hypertension in patients resistantto, or intolerant of, other treatments. Specific indications fortheir use in secondary hypertension include labetalol for preeclampsia and phentolamine in the perioperative management of phaeochromocytoma. á-blockers are also commonly used to improve urinary flow in benign prostatic hyperplasia, for
example, tamsulosin.

Prazosin is given orally as the hydrochloride, but dosesare usually expressed in terms of the base. Prazosin hydrochloride 1.1 mg is equivalent to about 1 mg of prazosin.In hypertension, the usual initial dose is500 micrograms two or three times daily for 3 to 7days; if tolerated the dose may then be increased to1 mg two or three times daily for a further 3 to 7 days,and thereafter gradually increased, according to the patient's response, to a usual maximum of 20 mg daily individed doses.

Prazosin is readily absorbed from the gastrointestinaltract with peak plasma concentrations occurring 1 to 3hours after an oral dose. The bioavailability is variableand a range of 43 to 85% has been reported. Prazosinis highly bound to plasma proteins. It is extensivelymetabolised in the liver and some of the metabolites are reported to have hypotensive activity. It is excretedas the metabolites and 5 to 11% as unchanged prazosinmainly in the faeces via the bile. Less than 10% is excreted in the urine. Small amounts are distributed intobreast milk. Its duration of action is longer than wouldbe predicted from its relatively short plasma half-life ofabout 2 to 4 hours. Half-life is reported to be increasedto about 7 hours in patients with heart failure.

Prazosin is an alpha blocker that acts by selective blockade of alpha1-adrenoceptors.Prazosin produces peripheral dilatation of both arterioles and veins and reduction of peripheral resistance,usually without reflex tachycardia. It reduces bothstanding and supine blood pressure with a greater effect on the diastolic pressure.

Treatment with prazosin should be introduced cautiously because of the risk of sudden collapse following the initial dose. Extra caution is necessary in patients with hepatic or renal impairment and in theelderly.Prazosin is not recommended for the treatment of heart failure caused by mechanical obstruction, for exampleaortic or mitral valve stenosis, pulmonary embolism,and restrictive pericardial disease. It should be used with caution in patients with angina pectoris. Prazosinmay cause drowsiness or dizziness; patients so affected should not drive or operate machinery.The hypotensive effects of prazosin may be enhancedby use with diuretics and other antihypertensives, andby alcohol and other drugs that cause hypotension. Therisk of first-dose hypotension may be particularly increased in patients receiving beta blockers or calcium-channel blockers.

CCBs are first-line treatment for primary hypertension in patients over the age of 55 and black patients of African orCaribbean family origin. Rate-controlling CCBs (diltiazem, verapamil) are also used to manage tachyarrhythmias and angina,where their negative inotropic and chronotropic effects improvethe myocardial oxygen supply. Some CCBs havespecific non-cardiac indications, for example, nimodipine inneurosurgery to reduce cerebralvasospasm in patients afterspontaneous subarachnoid hemorrhage, and verapamil inneurology to treat cluster headache.

Amlodipine is given orally as the besilate, but doses are usually expressed in terms of the base; amlodipine besilate 6.9 mg is equivalent to about 5 mg of amlodipine. The camsilate, maleate, and mesilate are alsoused.In hypertension the usual initial dose is 5 mg once daily, increased, if necessary, to 10 mg once daily.

Amlodipine is well absorbed after oral doses with peakblood concentrations occurring after 6 to 12 hours. Thebioavailability varies but is usually about 60 to 65%.Amlodipine is reported to be about 97.5% bound toplasma proteins. It has a prolonged terminal elimination half-life of 35 to 50 hours and steady-state plasmaconcentrations are not achieved until after 7 to 8 daysof use. Amlodipine is extensively metabolized in theliver; metabolites are mostly excreted in urine togetherwith less than 10% of a dose as unchanged drug.

Amlodipine as well as other dihydropyridines act on L-type calcium channels present in vascularsmooth muscle and in myocardial and nodal tissues. The variable affinity of the different CCBs to these different tissues determines their effects.

Cardiovascular side-effects include reflex tachycardia which may potentiate myocardial ischemia, disturbance of the peripheral microcirculation leading to swelling of the hands and feet, flushing, and headache. Rate-limiting agents prolongatrioventricular conduction and cause bradycardia; the negativeinotropic and chronotropic effects may worsen heart failure. Amlodipine may enhance the antihypertensive effects ofother antihypertensive drugs such as beta blockers although the combination is generally well tolerated. Enhanced antihypertensive effects may also be seen ifused with drugs such as aldesleukin and antipsychotics that cause hypotension. Amlodipine may modify insulinand glucose responses and therefore diabetic patientsmay need to adjust their antidiabetic treatment when receiving amlodipine. Amlodipine is extensively metabolized in the liver by the cytochrome P450 isoenzymeCYP3A4, and interactions may occur with other drugs,such as quinidine, sharing the same metabolic pathway, and with enzyme inducers, such as carbamazepine, phenytoin, and rifampicin, and enzymeinhibitors, such as cimetidine, erythromycin, and HIVprotease inhibitors.

Thiazide (bendroflumethiazide, hydrochlorothiazide) and thiazide-like (chlortalidone, indapamide) diuretics are the most commonly prescribed diuretic agents used to treat hypertension.They are used in patients intolerant of CCBs and in patients with heart failure, or at risk of heart failure. They are also usedas `add on' drugs in patients who have not responded to firstand second-line antihypertensive treatments.

Thiazides are usuallygiven in the morning so that sleep is not interrupted by diuresis.Hydrochlorothiazide is given orally.In the treatment of hypertension an initial dose of12.5 mg may be sufficient, increasing to 25 to 50 mgdaily if necessary, either alone or with other antihypertensives. Doses of up to 100 mg have been suggestedbut are rarely necessary.

Hydrochlorothiazide is fairly rapidly absorbed fromthe gastrointestinal tract. It is reported to have a bioavailability of about 65 to 70%. It has been estimated tohave a plasma half-life of between about 5 and 15hours and appears to be preferentially bound to redblood cells. It is excreted mainly unchanged in theurine. Hydrochlorothiazide crosses the placental barrier and is distributed into breast milk.

Thiazides are moderately potent diuretics and exerttheir diuretic effect by reducing the reabsorption ofelectrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water. They act mainly at the beginning ofthe distal tubules. The excretion of other electrolytes,notably potassium and magnesium, is also increased.The excretion of calcium is reduced. They also reduce carbonic-anhydrase activity so that bicarbonate excretion is increased, but this effect is generally small compared with the effect on chloride excretion and does notappreciably alter the pH of the urine. They may also reduce the glomerular filtration rate.Their hypotensive effect is probably partly due to a reduction in peripheral resistance; they also enhance theeffects of other antihypertensives. Paradoxically, thiazides have an antidiuretic effect in patients with diabetes insipidus.

Thiazide diuretics have many clinically relevant biochemicalside-effects including hypokalaemia, hypercalcaemia, hyponatraemia, hypomagnesaemia, hyperglycaemia, hyperuricaemia, hypercholesterolaemia, and hypochloraemic alkalosis. Plasma volume loss may precipitate dehydration and acute kidney injury. Less common side-effects include skin rashes, photosensitivity reactions, and blood dyscrasias including thrombocytopaenia.
Many of the interactions of hydrochlorothiazide andother thiazides are due to their effects on fluid and electrolyte balance. Diuretic-induced hypokalaemia mayenhance the toxicity of digitalis glycosides and mayalso increase the risk of arrhythmias with drugs that prolong the QT interval, such as astemizole, terfenadine, halofantrine, pimozide, and sotalol. Thiazidesmay enhance the neuromuscular blocking action of competitive neuromuscular blockers, such as atracurium, probably by their hypokalaemic effect. The potassium-depleting effect of diuretics may be enhanced bycorticosteroids, corticotropin, beta2 agonists such as salbutamol, carbenoxolone, amphotericin B, or reboxetine.

Diuretics may enhance the effect of other antihypertensives, particularly the first-dose hypotension that occurs with alpha blockers or ACE inhibitors. Orthostatichypotension associated with diuretics may be enhanced by alcohol, barbiturates, or opioids. The antihypertensive effects of diuretics may be antagonised bydrugs that cause fluid retention, such as corticosteroids,NSAIDs, or carbenoxolone; diuretics may enhance the nephrotoxicity of NSAIDs. Thiazides have been reported to diminish the response to pressor amines, suchas noradrenaline, but the clinical significance of this effect is uncertain.Thiazides should not usually be used with lithium sincethe association may lead to toxic blood concentrations of lithium. Other drugs for which increased toxicity hasbeen reported when given with thiazides include allopurinol and tetracyclines. Thiazides may alter the requirements for hypoglycaemics in diabetic patients.

Other diuretics include aldosterone antagonists, for example, spironolactone, are recommended as fourth-line treatment of primary hypertension. The use of these drugs carries a risk of hyperkalaemia, particularly in patients with impaired renal function or who are taking other potassium-sparing agents. Loop diuretics are indicated for resistant hypertension in patients with heart failure, chronic kidney disease, and in those at risk of hyperkalaemia.

Directly acting vasodilators, for example, hydralazine andminoxidil, are seldom used due to their side-effect profiles.Hydralazine is used in hypertension secondary to pre-eclampsia. In addition to its antihypertensive effects, minoxidil is used topically as a treatment for male pattern baldness.

In the treatment of hypertension minoxidil is givenwith a beta blocker, or with methyldopa, to diminishthe cardiac-accelerating effects, and with a diuretic,usually a loop diuretic, to control oedema.An initial dose of 5 mg of minoxidil daily(or 2.5 mg daily in the elderly) is gradually increased atintervals of not less than 3 days to 40 or 50 mg dailyaccording to response; in exceptional circumstances up to 100 mg daily has been given.

In the treatment ofalopecia androgenetica (male-pattern baldness) 1 ml of a 2% or 5% solution of minoxidil is applied twice daily to the scalp. The 5% solutionis not recommended for women.

About 90% of an oral dose of minoxidil is absorbedfrom the gastrointestinal tract. The plasma half-life isabout 4.2 hours although the haemodynamic effectmay persist for up to 75 hours, presumably due to accumulation at its site ofaction. Minoxidil is not boundto plasma proteins. It is distributed into breast milk.Minoxidil is extensively metabolised by the liver. It requires sulfation to become active, but the major metabolite is a glucuronide conjugate. Minoxidil is excretedpredominantly in the urine mainly in the form ofmetabolites. Minoxidil and its metabolites are dialysable, although the pharmacological effect is not reversed. About 0.3 to 4.5% of a topical dose of minoxidil is absorbed from intact scalp.

Vasodilators cause relaxation of vascular smooth muscle in resistance (arteriolar) vessels. Minoxidil achieves this via adenosine triphosphate-dependent potassium channels on smoothmuscle cell membranes.Vasodilatation provokes reflex cardiac stimulation (which may precipitate cardiac ischemia) and RAS activation. These compensatory responses may be offset by â-blockersor diuretics.

Vasodilator drugs are poorly tolerated. Side-effects includeheadache, fluid retention, and edema. Other specific side effects include left ventricular hypertrophy, pericardial and
pleural effusions, hypertrichosis and coarsening of featureswith minoxidil, while peripheral neuropathy, blood dyscrasias,and a lupus-like reaction can occur with hydralazine.The antihypertensive effect of minoxidil may be enhanced by use of other hypotensive drugs. Severeorthostatic hypotension may occur if minoxidil andsympathetic blocking drugs such as guanethidine aregiven concurrently.Topical minoxidil should not be used with other topicalagents known to enhance absorption, such as corticosteroids, retinoids, or occlusive ointment bases.

Centrally acting agents include clonidine (á2 adrenoceptor agonist), methyldopa (precursor of an á2 adrenoceptor agonist), and moxonidine (agonist at imidazoline binding sites). Their use inprimary hypertension is limited to difficult to treat cases, while methyldopa is used to treat hypertension in pregnancy. The evidence base for the use of centrally acting drugs in hypertension is limited and adverse effects are common. Clonidine is an analgesic and sedative drug which reduces the minimumalveolarconcentration of inhalation anestheticagents. Both of these drugs cause side-effects including drymouth and sedation. Methyldopa has immunological side effects, including pyrexia, hemolytic anemia, and hepatitis.Cessation of treatment with clonidine can cause reboundhypertension.

Methyldopa is given orally as the sesquihydrate, butdoses are usually expressed in terms of anhydrousmethyldopa. Methyldopa sesquihydrate 1.13 g isequivalent to about 1 g of anhydrous methyldopa. Forhypertensive crises, methyldopa has been given intravenously as methyldopate hydrochloride.In hypertension, the usual initial adult oral dose is250 mg of methyldopa two or three times daily for 2days; this is then adjusted, not more frequently than every 2 days according to response, up to a usual maximum dose of 3 g daily. The usual maintenance dosage is 0.5 to 2 g of methyldopa daily. In the elderly an initial dose of 125 mg twice daily has been used; this dosemay be increased gradually if necessary, but should not exceed 2 g daily

After oral use methyldopa is variably and incompletelyabsorbed, apparently by an amino-acid active transportsystem. The mean bioavailability has been reported to be about 50%. It is extensively metabolised and is excreted in urine mainly as unchanged drug and the Osulfate conjugate. It crosses the blood-brain barrier andis decarboxylated in the CNS to active alpha-methylnoradrenaline.The elimination is biphasic with a half-life of about 1.7 hours in the initial phase; the second phase is more prolonged. Clearance is decreased and half-life prolongedin renal impairment. Plasma protein binding is reported to be minimal. Methyldopa crosses the placenta; smallamounts are distributed into breast milk.

Methyldopa is an antihypertensive that is thought tohave a mainly central action. It is decarboxylated in theCNS to alpha-methylnoradrenaline, which is thoughtto stimulate alpha2 adrenoceptors resulting in a reduction in sympathetic tone and a fall in blood pressure. Itmay also act as a false neurotransmitter, and have some inhibitory actions on plasma renin activity. Methyldopa reduces the tissue concentrations of dopamine,noradrenaline, adrenaline, and serotonin.

Methyldopa should be used with caution in the elderly,and in patients with hepatic or renal impairment or witha history of haemolytic anaemia, liver disease, or depression. Care is also advisable in patients with Parkinsonism. It should not be given to patients with active liver disease or depression and it is not recommendedfor phaeochromocytoma.It is advisable to make periodic blood counts and toperform liver function tests at intervals during the first6 to 12 weeks of treatment or if the patient develops anunexplained fever. Patients taking methyldopa mayproduce a positive response to a direct Coombs' test; if blood transfusion is required, prior knowledge of apositive direct Coombs' test reaction will aid crossmatching. Methyldopa may cause sedation; if affected, patients should not drive or operate machinery. The hypotensive effects ofmethyldopa are potentiatedby diuretics, other antihypertensives, and drugs withhypotensive effects. However, there have been reportsof paradoxical antagonism of the hypotensive effectsby tricyclic antidepressants, antipsychotics, and betablockers. Sympathomimetics may also antagonise the hypotensive effects.There may be an interaction between methyldopa andMAOIs and care is required if they are given together.Caution is also needed with catechol-O-methyltransferase inhibitors, such as entacapone, since they might reduce the metabolism of methyldopa.

Ganglion blockers, such as trimetaphan, antagonize acetylcholine at nicotinic receptors, including those at the adrenal cortex. Trimetaphan causes vasodilatation with a consequent rapid reduction in arterial pressure. Although ganglion blockers may be
used to manage hypertensive crises or to provide hypotensive anesthesia, their use is increasingly rare.

The drug regimenmay include drugs with differing pharmacological actions; the antihypertensive mechanism is not fully understood in all cases. Historically, thiazide diuretics and beta blockers have been the mainstay of drug therapy for hypertension, but CCBs, ACEI, ARAs, and alpha blockers are now also widely used[3].

Studies such as the TOMHS[75] (comparing chlortalidone, acebutolol, amlodipine, enalapril, and doxazosin), and a similar study[76] (comparing hydrochlorothiazide, atenolol, diltiazem, captopril, prazosin, and clonidine), have shown that the main types of antihypertensive drug reduce blood pressure to a similar extent and in a similar proportion of patients, although the response may also depend on individual factors such as age[77] and race[78,79]. ARAs also effectively reduceblood pressure. However, it is now generally acknowledgedthat a single drug is unlikely to control blood pressureadequately and most patients will require more thanone drug to reach their treatment target. Tolerance of thedrug groups is also similar, although there has been concernabout the metabolic effects of thiazides and betablockers. Alpha blockers (specifically doxazosin[80]) havebeen associated with an increased risk of heart failure,which may limit their use. The safety of short-acting dihydropyridine CCBs has also been questioned,and they are no longer generally recommended forhypertension[3]; long-acting dihydropyridines,however, are of established benefit[81]. Diuretics(particularly thiazides) and beta blockers were the firstdrugs to demonstrate an effect on mortality in long-termoutcome studies and have therefore been preferred for initialtherapy[3]. However, long-term studies with other druggroups have now been performed, and have generallyshown comparable effects on mortality and morbidity. Ameta-analysis concluded that there was little differencein overall cardiovascular outcomes for regimens based on ACEIs, ARAs, CCBs, beta blockers, or diuretics, suggestingthe major benefit of treatment related to reduction of blood pressure rather than to specific properties of the individualdrugs[82]. In general, guidelines acknowledge that lowering bloodpressure appears to be more important than which drug ischosen for initial therapy, and that most patients will requirea combination of drugs, making the initial choice lessimportant[3]. Thiazide diuretics, ACEIs, ARAs, or CCBs mayall be used, and choice should take into account individualpatient characteristics, including age, ethnicity, contra-indicationsor compelling indications for specific drugs, adverseeffects, and relative cost-effectiveness[40,59-61]. Strictguidance is therefore not generally given, although foruncomplicated patients WHO guidelines[59]recommend thiazide diureticsas first-line, whereas in theUK[81] diuretics or CCBsare recommendedfor older patients (55 years or over) and black patients,while in younger, non-black patients ACEIs or ARAsare preferred. Compellingindications in all the guidelines include the use of ACEIs or ARAs in patientswith nephropathy, diuretics or CCBs in elderly patients, and beta blockers in patientswho have had a myocardial infarction.

Having decided what drug to use, treatment is started at thelowest recommended dose. If this is ineffective or onlypartially effective the dose may be increased (except in thecase of thiazide diuretics where there is generally no additionalbenefit, but more adverse effects); alternativelyanother first-line drug may either be substituted (sequential therapy) or added (combination therapy). Two-drugcombinations will control blood pressure in a higher proportionof patients and may be necessary in most patientsto achieve optimal levels, although the effects of the twodrugs may not be fully additive. Combination therapy alsoallows lower doses of the individual drugs to be used witha consequent reduction in adverse effects. Initial treatmentwith a low-dose combination may be considered in somepatients[40,61].

The most effective combinations involve drugsthat act on different physiological systems. Appropriatecombinations therefore include[3]:

Alpha blockersmay be used with any of the other classesbut are usually reserved for third-line therapy unless specificallyindicated for another reason. A 3-drug combinationis often required, especially in severe hypertension. Inpatients who maintain an elevated diastolic blood pressuredespite triple therapy the possibility of secondary hypertensionshould be considered, although factors such as non-compliance, NSAID use, or alcohol abuse may contributeto resistance[83,84].

Other classesof antihypertensive drugs that are sometimesused include: centrally acting drugs such as clonidine,methyldopa, and the less sedating moxonidine; direct-actingvasodilators such as hydralazine and minoxidil; the aldosteroneantagonist, eplerenone; and the DRI,aliskiren[3]. Endopeptidase inhibitors and endothelinantagonists are among various drug groups thatare under investigation.

It has been standard teachingthat drug treatment for hypertension is continued indefinitely,but there have been some reports of successfulwithdrawal in selected patients[85,86]. If this is attempted,blood pressure must be closely monitored and lifestylemeasures should be continued indefinitely[40,81].

The mainobjective of hypertension management is to achieve BP control through changes in lifestyle andappropriate therapeutic measures[1,3]. In the recent years,a growing number of patients seem to present resistanceto the antihypertensive treatment[87]. Non-adherence has important economic implications: itdecreases the cost-effectiveness of interventions, leading topoor clinical results with increased costs for public health[88].

Different methods to measure therapeutic adherence areavailable; all have favourable and unfavourable aspects andthere currently is no gold standard[10]. These methods canbe classified as direct or indirect: interviews and questionnairesadministered to patients (one of the most used isMorisky's scale), diaries, pill count, electronic monitoringof orally administered drugs, rates of prescriptions' refillingthrough pharmacies' databases and direct dosage ofdrug levels in biological fluids[10].At the present time therapeutic drug monitoring (TDM)is available for most antihypertensive drugs and severalstudies have demonstrated its efficacy in the evaluation ofadherence[89,90].

Therapeutic adherence describes the extent to which patients actively take medications as prescribed by their health care providers based on a therapeutic alliance or contract established between them; it differs from the term compliance, withwhich it is often confused[10]. The term compliance suggests apassive attitude when the patient follows the physician'sinstructions and treatment plan, without a real therapeuticalliance[10].In any case, these two terms do not allow to differentiatepatients who systematically fail to follow the recommendationsfrom those who occasionally forget a pill or reducethe dose of the drug[91].

Several conditions could affect therapeutic adherence:type of prescribed therapy, patient socio-cultural level,frequency of clinical controls[92]. The WHO hasidentified five different conditions[23] correlated with pooradherence: social and economic factors, condition-relatedfactors, therapy-related factors, patient-related factors andhealth care system/health care team-related factors. Moreover,frequently patients start the prescribed therapy, butadherence is progressively reduced because they do notpersist[23].

Different methods to measure therapeutic adherence areavailable. Indirect methods are less invasive andless expensive. Indirect methods for evaluating drug adherence include: patient interview, diaries, questionnaires,pill count, review of prescriptions, electronic monitoring[15,21].Conversely, direct methods are more invasive, expensiveand include the direct observation of the patient duringthe administration of therapy and the measurement of thedrug or of its metabolites in blood or urine[93]. Nonetheless, only a limited number of drugs can be monitored in this way because the bioavailability and completenessof absorption of various drugs, as well as the rate of metabolismand excretion, are factors that make it difficult tocorrelate drug concentrations in blood or urine with adherence[15].

In clinical practice, each method has advantages anddisadvantages and not all can be easily used in all settings;it is often not possible to accurately determine the realdegree of adherence.

The patient interview is one of the simplest and lessexpensive methods, but its efficacy is strongly influenced bythe ability of the interviewer and by the way in which thequestions are asked; it also heavily relies on a strongdoctor-patient relationship. Interviews may allow a pharmacist to show concern for the patient andprovide immediate feedback. Typical questions include askingthe patient to report the name, the dosage and the timeof drug intake. Alternatively, the doctor may ask the patienthow often they forget to take the pills during a week or amonth; according to the answers the physician can theninfer the degree of adherence.The patient interview can also be targeted to encouragebehavioural changes and to improve therapeutic adherence.

A drawback of this method isthat it can overestimate adherence, and its accuracy dependson the patient's cognitive abilities and the honesty of replies,as well as the interviewer's correct interpretation of responses.

The questionnaires are simple and economical methods toevaluate adherence. They are usually composed of a limitednumber of questions that the patient is asked to answer.A potential disadvantage is represented by the difficultysome subjects may have understanding the questions incase of low level of education.One of the most frequently used questionnaire is theMorisky 8 items MMAS-8 (Eight-Item Morisky MedicationAdherence Scale), which has a higher specificity(93%) compared to the original 4-item questionnaire.The MMAS-8 consists of seven binary questions (YES/NO) and one last multiple choice question. A clearlimitation of this instrument is represented by patients whomight answer the questions untruthfully. Similarly to thepatient interview, questionnaires are useful to evaluateunintentional poor adherence.

Counting pills is a simple and cost-effectiveness method toevaluate therapeutic adherence, but it is characterized byseveral limitations[94]. Among these, the most relevantlimitation is represented by the fact that patients canmislead the doctor, throwing away the pills before the visit.Furthermore, this method does not provide accurateinformation on daily adherence[10].The accuracy of the pill count method is adequate when compliance is excellent because there is nothing to return; however, in cases of low compliance, the pill count is not accurate.

An effective but at the same time more complex andexpensive method is electronic monitoring, in which thepill count is performed automatically and continuously by adevice at the patients' home[96].

There are different electronic monitoring systems, usuallyvery expensive and invasive. However, in view of theirhigh efficacy they can be considered as the gold standardfor assessing drug adherence.One of the less invasive options is the medication events monitoring system (MEMS), which uses a device to recordthe time and the date in which medications are taken fromthe box. In the last years, a more invasive system was validated: the ingestible sensor technology. In thiscase the sensor is inside the pill, so it becomes possible toaccurately document each time a pill is ingested.

The most accurate direct method for evaluating therapeuticadherence is the measurement of the drug concentration (orthe concentration of its metabolites) in body fluids (bloodor urine)[94]. For this purpose, liquid chromatography-massspectrometry analysis can be used[93].In the recent years, several studies used TDM to evaluatetherapeutic adherence, especially in patients withsuspected resistant hypertension[89,90]. Chung et al.[98]have recently demonstrated that TDM is a cost-effectivemethod to assess adherence in the workup of resistanthypertension, independently by sex and age. TDM wouldallow a substantial economic advantage when comparedwith previous cost-effectiveness analyses of invasive proceduresfor the treatment of resistant hypertension[99,100].

TDM, however, has some limitations: it provides resultswithout giving information about the causes of non-adherence;it is very intrusive for the patient; it can induce thephenomenon of white-coat adherence; antihypertensivedrugs can present an altered metabolism when taken withother drugs. An ethical problem should also be considered:such measurements need to be done with the informedconsent of patients and thus tend to induce white-coatadherence[94]. Despite these limitations, TDM, used inselected cases, may provide a way to decrease health costs, by reducing the number of visits in patients who intentionallydo not take drugs and by identifying those patientswho would undergo unnecessary and sometimes invasiveprocedures.

Properly identify patients who do not take prescribedtherapy has important consequences, such as execution ofunnecessary medical visits or diagnostic tests, as well asscreening evaluation for secondary forms of hypertension.For this reason it is important to improve therapeuticadherence in all patients with hypertension, mostly in thosewith difficult to treat or resistant hypertension. Although itis a difficult task, physician should help individual patientto get better therapeutic compliance.

There are different strategies for improving long termtherapeutic adherence: simplifying medical regime withfixed associations of drugs when available, giving patientsinstructional material, counselling about therapy, remindingfor medications and appointments, cuing medications todaily events and explicitly acknowledging patient's effortto adhere.Therefore, treating physician should establish a goodrelationship with each individual patient to address andresolve poor therapeutic adherence.

In a cross-sectional study carried out by Lin et al. in 1995 in Tainan City, the medication adherence rate found was 57.6%. Subjects taking 80% or more of their prescribed medicines were considered adherent[102]. The factors associated significantly with poor adherence included: more than once daily dose frequency, no health check-up in the previous year, disbelief in the efficacy of antihypertensives, and presence of adverse drug reactions in the past 6 months.

In a cross-sectional study by Hashmi et al. in 2005 in Pakistan, 77% of their cases were adherent. Univariate analyses showed that decreasing age, poor awareness and decreasing number of pills prescribed significantly promoted poor adherence[103].

In Bangladesh, Hussain et al. found in 2006 that 85% of the study population were non-adherent to treatment. The reasons pointed out were low levels of education, low family income, duration of diagnosis, insufficient knowledge of the disease, lack of accompanying person to go to the physician/hospital, and deficiencies in information from the service provider[104].

In a cohort study carried out in Italy involving 18,806 newly diagnosed hypertensive patients =35 years of age, Mazzaglia et al. in 2009 found varying adherence rates. 6 months after index diagnosis, the authors found rates of 8.1%, 40.5%, and 51.4% corresponding to high, intermediate, and low adherence levels, respectively. The authors also found thatthe risk of being a poor adherer increased in the absence of concurrent treatment[105].

In a descriptive exploratory study conducted by Demoner et al. in 2011 in Brazil, 64% of patients in the study were nonadherent to antihypertensive therapy. Adherence level was assessed using the Morisky-Green Test. Poor adherence was significantly associated with participants who were: in the youngest age group, working, lack of understanding of the health team recommendations and presenting with overweight or obesity[106].The younger patients (18-40 years) presented lowerlevels of adherence compared to those in older agegroups. This may be related to the fact that HTN is asilent disease and, thus, leads to a certain nonchalance inyounger individuals regarding the control of the disease,who only give importance to adequate treatment whenthere is a worsening of symptoms, increasing risks ofserious complications and mortality for stroke and MI.

In a cross-sectional study carried out in 2014 in Iran, Behnood-Rod et al. found that about half of the sample population (49.6%) showed low adherence (8-item Morisky Medication Adherence Scale <6). In addition the authors also found that overweight/obesity, previous history of admission to emergency services due to hypertensive crisis, and getting medication directly from drugstore without refill prescription in hand were factors recognized to have statistically significant association with the 8-item Morisky Medication Adherence Scale score[107].

In a retrospective cohort study including 5025 Swedish adult patients in 2015, Hedna et al. found that non-adherence to any antihypertensive medication was higher among persons < 65 years (17.5%) and with the lowest income (12.8%). Also the authors found that, non-adherence to the full AHT regimen was higher among new users (44.2%), persons using specialized healthcare (38.3%) and having multiple antihypertensive medications (54.3%). Finally, the authors noted that non-adherence to any antihypertensive medication a month prior to healthcare visit wasassociated with elevated BP[108].

In cross-sectional correlational study by Lo et al. in Hong Kong in 2016, more than half of the respondents (55.9%) acknowledged some degree of medication nonadherence. Older age, living alone, and perception related to treatment control were independently associated with increased odds of medication non-adherence[109].

In a cross sectional study carried out in Northwest Ethiopia in 2011, Ambaw et al. found that more than half (64.6%) of the study participants were found to be adherent to their treatment. Male gender, insufficient knowledge about hypertension and its treatment, distance from the hospital and presence of comorbidity were found to be significantly associated with poor treatment adherence[7].

In 2013, Okwuonu et al. found in a cross-sectional study carried out in Nigeria that BP control was optimal in 33%, good knowledge of hypertension was found in 52% and only 31.8% were adherent to prescribed medications. The authors also added that the duration ofhypertension from time of diagnosis, systolic and diastolic blood pressures andtotal number of pills swallowed per time were found to independently correlatewith medication adherence, albeit negatively[110].

In a multicenter cross-sectional study conducted in 2013 by Boima et al., medication non-adherence was found in 66.7% of the study population. Medication non-adherence showed correlation with depression, concern about medications, and knowledge of hypertension. Adherence was associated with formal education and use of herbal preparation. Poor BP control was observed in 69.7% and there was significant association between medication non-adherence and poor BP control[111].

Tufon et al. found in a cross-sectional study carried out at the Mankon Sub-Divisional Health Center in 2014 that level of adherence was found to be low (80.0%) with smoking (85%) and alcohol intake (55%) identified as associated factors. Moderate level of knowledge (77.5%) was found as opposed to a high level of adherence (80.0%) and the authors found no significant relationship between the level of knowledge and level of adherence[18].

Essomba et al. reported in 2015 in a cross-sectional and analytical study, that 26.2% of their study population had good adherence to antihypertensive treatment. At the same time, 25.7% were bad adherers. Reasons for non-adherence included: forgetfulness, medication cost and poor knowledge of the disease[19].

Akoko et al. in 2015 reported that antihypertensive compliance rate was 43.9% in their cross-sectional study. Independent predictors of noncompliance were forgetfulness, lack of motivation due to the incurable nature of the disease, and lack of symptoms of the disease[20].

Mbouemboue et al. reported in 2016 that, 12.9% of patients enrolled in the study in the Medico-Social Centre of the National Social Insurance Fund in Garouafollowed up their treatment correctly, 52.9% had minor observance problems, and 34.3% had a poor therapeutic adherence to antihypertensive drugs. Therapeutic adherence was evaluated on the basis of the Girerd X observance test. The determining factors of poor adherence were the presence of complications of high BP, the presence of a handicap, and a low level of education[16].

CHAPTER III: MATERIALS AND METHOD

This study was conducted at the external consultation service of the cardiology unit of the Yaounde General Hospital (YGH) which is located in Yaounde, the capital city of Cameroon.YGH serves as a teaching centre, and is a reference hospital for other hospitals in the Centre region.

YGH is a state-owned hospital made up of several units: internal medicine, surgery, obstetrics, gynaecology and paediatrics. It covers an area of 20,301 square metres and as of 2001 had 302 beds. Inhabitants from Yaounde and beyond come to this reference health institution to seek for general and specialized health services.

This study was carried out over a period of seven months (November 2017 - May 2018).

Hypertensive patients receivingantihypertensive treatment as outpatients at the YGH.

Ø Outpatients diagnosed with HBP and on antihypertensive drug treatment for at least 6 months prior to recruitment period;

The following assumptions were made:previous data indicated an adherence rate of 12.9% in Garoua[16]. So proportion was taken as 12.9%(p = 0.129), 95% confidence interval, and 5% margin of error(d = 0.05).

Therefore, from the above formula a minimum sample size of 173 patients was required for the study.

Ø A laptop with Microsoft^®Office Tools 2013 for data entry and Epi-info^TMsoftware Version 3.5.4 for data analysis.

In accordance with research ethics, ethical clearance was obtained from the Institutional Review Board of the Faculty of Medicine and Biomedical Sciences of the University of Yaounde I(APPENDIX 1A), as well as authorization from the Director of the YGH before the recruitment of patients for the study (APPENDIX 1B). The study was explained to the patients and informed consent by signature was obtained prior to their enrolment into the study (APPENDIX 2). During the study, the case report forms (APPENDIX 3) were kept secret by the investigator from people not involved in the study, in order to respect patient confidentiality.

The patients admitted into this study were selected consecutively at the external consultation service of the cardiology unit. Patients that met our inclusion criteria were selected during consultations and interviewed immediately after. After obtaining their written consent, we proceeded by measuring their resting BP. Two sitting BP measurements were taken on both arms with a pretested electronic sphygmomanometer approximately 2 minutes apart. Another 2 minutes later, a third measurement was taken on the arm with the highest BP reading. Then an average of the last two readings was eventually used to determine the BP level during the visit. After recording the BP reading, we proceeded with an interview of the patients in order to fill the pretested questionnaires. BP measurements and interview were carried out in private in a consultation box. The 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults[113] was used to evaluate the level of control of patient BP:

v Hypertensive patients aged 60 years and above were considered to have a controlled hypertension if their average BP reading was<150/90 mmHgduring the last 3 months and if they presented with no diabetes nor chronic kidney disease.

v Hypertensive patients aged 60 years and above were equally considered to have a controlled hypertension if their average BP reading was<140/90 mmHg during the last 3 monthsif they presented with diabetes or chronic kidney disease.

v Also, patients aged under 60 were considered to have a controlled hypertension if their average BP reading was<140/90 mmHgduring the last 3 months and if they presented with or without other comorbidities (diabetes and chronic kidney disease).

Ø Sociodemographic data (independent variables): Age, sex, zone of residence, marital status, trip duration to the hospital, level of education, and profession.

Ø Socioeconomic data (independent variables):Socioeconomic status (which is an adapted classification from theRevised Kuppuswamy's socio-economic status scale- January 2015[114](see APPENDIX 3) where the projected family income was estimated from the Gross National Income (GNI) per capital; health insurance; monthly drug costs. A score of <5 was considered low; between 5 and 10 was considered middle; and >10 was considered high socioeconomic status.

Ø Clinical characteristics of respondents(independent variables):Comorbidities present (if any); blood pressure readings; handicap present (if any).

Classification of BP:SBP <120mmHg and DBP <80mmHg was considered optimal; SBP [120-129]mmHg and/or DBP [80-84]mmHg was considered normal; SBP [130-139]mmHg and/or DBP [85-89]mmHg was considered High Normal; SBP [140-159]mmHg and/or DBP [90-99]mmHg was considered Grade I hypertension; SBP [160-179]mmHg and/or DBP [100-109]mmHg was considered Grade II hypertension; SBP=180mmHg and/or DBP =110mmHg was considered Grade III hypertension; SBP =140mmHg and DBP <90mmHg was considered isolated systolic hypertension.

Definition of heart failure:Inability of the heart to ensure blood flow necessary for the metabolic and functional needs of body organs. Clinical signs include edema, tachycardia, and rales with low ejection fraction (EF<43%).

Diagnostic criteria for diabetes: A1C =6.5% or Fasting Plasma Glucose =126 mg/dl (7.0 mmol/l) or 2-h plasma glucose =200 mg/dl (11.1 mmol/l) during an Oral Glucose Tolerance Test or in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose =200 mg/dl (11.1 mmol/l).

Definition of gout:Inflammatory microcrystalline arthropathy associated with intense pain and related to a disruption of the metabolism ofuric acid.Hyperuricemia is generally above 390 umol/L (6.5 mg/dL).

Diagnostic criteria for arthritis:Prolonged morning stiffness, swollen joints, and painful/inflamed joints.

Diagnostic criteria for gastritis: Nausea, abdominal pain, bloating, vomiting, indigestion, and burning feeling in the epigastric region.

Diagnostic criteria for hyperthyroidism: Nervousness, mood swings, muscle weakness, heat intolerance, insomnia, hand tremors, tachycardia, diarrhea, weight loss, enlarged thyroid gland, and elevated thyroid stimulating hormone, free thyroxine and total triiodothyronine levels.

Definition of epilepsy: Presence or history of recurrent convulsions which are involuntary, violent, and spasmodic or prolonged contraction of skeletal muscles.

Definition of anemia: Decrease in hemoglobin per unit of blood volume below physiological values i.e. 13 g / dL in men; 12 g / dL in women and children.

Diagnostic criteria for benign prostate hypertrophy: Presence of enlarged prostate, high prostate specific antigen levels, polyuria, weak stream and/or urinary incontinence.

Diagnostic criteria for depression: Presence of psychological symptoms (low mood, low self-esteem, feeling irritable, no interest in things, anxiety, suicidal thoughts); and physical symptoms (changes in weight, constipation, unexplained pains, loss of libido, changes in menstrual cycle).

Definition of glaucoma: Intraocular pressure above an upper normal value of 21 mmHg.

Diagnostic criteria for hemorrhoids: Presence of bleeding with or without defecation, mucous discharge, pruritus, incomplete evacuation, distal rectal mass upon digital exam, and presence of fissures after anoscopy.

Diagnostic criteria for deep venous thrombosis: Presence of pain, swelling and tenderness in legs, warm skin in the area of the clot upon palpation, positive D-dimer test, detection of clots with Doppler ultrasound.

Definition of physical handicap: Presence of physical defects, including upper or lower limb loss or poor manual dexterity.

Definition of sensory handicap: Presence of visual impairment or blindness, hearing loss or deafness.

Ø Therapeutic characteristics of respondents(independent variables): Type of therapy; molecule(s) prescribed;Drugs prescribed (pioneer or generic); Antihypertensive drug groups prescribed; number of drugs used per day; Dosage schedule; Presence of side effects (if any); Duration onantihypertensive treatment.

Ø Adherence profile (dependent variable):The Eight-Item Medication Adherence Scale (Table VI) was used to assess therapeutic adherence[95].

We assessed the adherence level of the study population by using the validated MMAS-8. The scale is based on patients` self-response.Patients with a score of 8 on the scale were termed highly adherent, medium adherers were those with a score of 6 to <8, and those classified as lowadherers were those with a score of <6.This medication adherence scale has the advantage of beingrelatively simple and practical to use in clinical settings. The instrument was used to identify patients with adherence problems, and could also be used to monitor adherence over the course of the treatment. One important feature of the scale is that treatment-related attitudinal and behavioral problems thatthe patient may be facing can be immediately identified and health care providers may provide reinforcement and advice such that the patient can take positive steps early on to address these issues. Patients were considered to have a poor adherence if they had <8 and good adherence if they scored 8 on the MMAS-8 (Table VII).

Data concerning patients' knowledge of hypertension (i.e. causes, treatment, and complications) was also collected on the pretested questionnaires (APPENDIX 3). Knowledge scores for individuals were calculated and summed up to give a total knowledge score. The scoring range isfrom 0 (minimum) to 16 (maximum). A cut-off score of <8 was considered as poor knowledge, ascore of [8-12] was considered knowledgeable and a score of [13-16] was considered good knowledge.

Data entry and analysis was undertaken using the statistical software Epi Info version 3.5.4. Data cleaning was performed to check for accuracy, consistency and that there were no missed values during entry. Frequencies, proportions and summary statistics were equally generated to describe the study population in relation to the relevant variables.Bivariate analysis using the chi2test was carried out to assess associations of each independent variable with thedependent variable. Variables with P-value< 0.05 in bivariate analysis were selected as candidate variables for multivariate analysis with logistic regression. Odds ratio and 95% confidence interval were used to identify the presence andstrength of association. Statistical significance was considered at P-value < 0.05.

CHAPTER IV: RESULTS

In this study, 181 potential participants were identified during consultations. Of the 6 patients not included 3 did not have time to participate in the study and 3 gave incomplete information. 175 patients were finally retained for the study as they complied with the stated inclusion criteria.

I- SOCIODEMOGRAPHIC AND SOCIOECONOMIC CHARACTERISTICS OF THE STUDY POPULATION

Of the 175 patients recruited into the study, 54.90% were men and 45.10% were women with a sex ratio of 1.2.

The mean age of the study participants was 60.1 #177; 11.1 years with extremes from 33 to 88 years and with the age group =60 years being the most represented (48%; n =48).

The majority of the participants lived in an urban setting (88.60%), while 11.40% of them lived in rural communities.

Among the 175 participants, 51.43% had a non-liberal profession and 21.14% were unemployed. The non-liberal class was represented in majority by public servants.

Of the 175 participants, 66.30% of participants lived as a couple either legally married or not while 33.7% were single (either divorced, never married or widowed).

Most participants in our study (40%) had a higher education. 2.3% never went to a formal system of education.

Among the 175 participants, 84.60% spent less than 1 hour to reach the YGH. The mean trip duration was 38.6 #177; 30.8 minutes with extremes between 5 minutes and 3 hours.

Three sociodemographic factors were found to be significantly associated with poor therapeutic adherence: single marital status (OR = 4.66; CI₉₅=2.07 - 11.28 ; p <0.001); 1^st cycle secondary education (OR = 3.03; CI₉₅=1.22 - 8.42 ; p <0.001); and more than 1 hour trip duration (OR = 7.39; CI₉₅=1.93 - 47.51; p <0.001).

Urban place of residence (OR = 0; CI₉₅=0 - 0.29 ; p <0.001); living as a couple (OR = 0.21; CI₉₅= 0.09 - 0.48 ; p <0.001) and <1 hour trip duration (OR = 0.14; CI₉₅=0.02 - 0.52; p <0.001) were significantly associated with good adherence.

	Poor adherence	Good adherence	Total	P-value*	P_A**
Sociodemographic variables	n (%)	n (%)	n (%)
Gender
Male	66 (68.8)	30 (31.3)	96 (54.9)	0.400
Female	52 (65.8)	27 (34.2)	79 (45.1)	0.400
Age (years)
<40	4 (80)	1 (20)	5 (2.9)	0.470
[40-50[	18 (75)	6 (25)	24 (13.7)	0.270
[50-60[	43 (70.5)	18 (29.5)	61 (34.9)	0.320
=60	53 (62.4)	32 (37.6)	85 (48.6)	0.110
Place of residence
Urban	98 (63.2)	57 (36.8)	155 (88.6)	*<0.001*
Rural	20 (100)	0 (0)	20 (11.4)	0.000
Profession
Liberal	28 (58.3)	20 (41.7)	48 (27.4)	0.080
Non-Liberal	61 (67.8)	29 (32.2)	90 (51.4)	0.520
Unemployed	29 (78.4)	8 (21.6)	37 (21.1)	0.080
Marital status
Single	51 (86.4)	8 (13.6)	59 (33.7)	*<0.001*	*0.0003*
Couple	67 (57.8)	49 (42.2)	116 (66.3)	*<0.001*
Level of education
Never gone to school	3 (75)	1 (25)	4 (2.3)	0.610
Primary	19 (70.4)	8 (29.6)	27 (15.4)	0.460
Secondary-1^st cycle	31 (83.8)	6 (16.2)	37 (21.1)	*0.010*	*0.0209*
Secondary-2^ndcycle	22 (59.5)	15 (40.5)	37 (21.1)	0.170
Higher education	43 (61.4)	27 (38.6)	70 (40)	0.110
Trip duration (hour)
<1	93 (62.8)	55 (37.2)	148 (84.6)	*<0.001*
=1	25 (92.6)	2 (7.4)	27 (15.4)	*<0.001*	*0.008*

*p-value from Chi-square test; **P_Ais p-value adjusted for significant factors obtained from logistic regression analysis using variables with P < 0.05 in bivariate analysis as candidate variables.

Figure 9 shows the distribution of participants according to socioeconomic status. The high socioeconomic status group was greatly represented (60%) in our study followed middle socioeconomic status group (39.40%).Middle socioeconomic status was found to be significantly associated to poor therapeutic adherence (OR = 2.68; CI₉₅ = 1.33-5.53; p < 0.001).

Figure 10 shows the distribution of participants according to possession of health insurance. Only 11.00% of our study population had a health insurance.

Figure 11 shows the BP distribution of the study participants. The High Normal BP group was the most represented (n=43; 24.60%). Only 4.60% had a Grade III hypertension.

Figure 12 shows the distribution of participants according to BP status. 57.70% of the study population had a controlled BP and 42.30% were uncontrolled.

Figure 13 illustrates the distribution of comorbidities of the study population. The most frequently associated pathology to HBP was heart failure (24.57%) followed by hypercholesterolemia (20.00%).

*Other comorbidities encountered in the study included : gout, arthritis, gastritis, hyperthyroidism, epilepsy, anemia, asthma, benign prostate hypertrophy, depression, glaucoma, haemorrhoids, and deep venous thrombosis

Figure 14 shows the distribution of participants according to type of handicap.32 participants had a form of handicap. 16.57% of the study population had a motor handicap and 1.71% had a sensory handicap. Presence of handicap was found to be significantly associated to poor therapeutic adherence (OR = 4.12; CI₉₅ = 1.45-14.34; p < 0.001).

Table IX shows the different classes screened in the study. Calcium channel blockers was the most encountered (31.90%) monotherapy drug class in our study. ACE inhibitors/thiazide diuretics was the most encountered fixed-dose combination bitherapy (40.96%). ACE inhibitors/Thiazide diuretics/CCBs was the most frequent fixed-dose combination tritherapy encountered (81.80%).

Table IX: Distribution according to class of antihypertensive used by the study population on enrolment

***ACE: Angiotensin Converting Enzyme; ****ARA2: Angiotensin 2 Receptor Antagonist; **BB: Beta Blocker; *CCB: Calcium Channel Blocker

In this study, 81.10% of participants had less than 3 different antihypertensives at the moment of enrolment.

Of the 175 participants, 46.30% had a monthly medication cost between 10000FCFA and 20000FCFA followed by 33.10% whose monthly drug cost was <10000FCFA. Only 5.10% had a monthly drug cost of =30000FCFA. The mean monthly drug cost was 14543 #177; 8613 FCFA with extremes between 800FCFA and 50000FCFA.

Among the 175 participants, 98.30% were on a once daily medication schedule and 92.60% took their medication(s) in the morning with breakfast. In this study, 65.70% were on monotherapy and 88.60% were on a specialty drug. Of the 175 participants, 38.30% experienced side effects with respect to ongoing treatment.

Among the 175 participants, 55.40% were on treatment for less than 10 years. Mean duration on treatment was 9.4 #177; 7.3 years with extremes from 7 months to 36 years.

3 therapeutic variables were found to be significantly associated with poor adherence; monotherapy (OR = 2.07; CI₉₅=1.07 - 4; p = 0.020); drug taking in the evening (OR = 2.55; CI₉₅=1.07-6.62; p = 0.030); presence of side effects (OR = 11.51; CI₉₅=4.47-34.2; p = 0.000).

<10000FCFA monthly treatment cost was found to be significantly associated with good therapeutic adherence(OR = 0.5; CI₉₅=0.26-0.97; p = 0.030).

	Poor adherence		Good adherence		Total		P-value*		P_A**
Therapeutic variables	n (%)		n (%)		n (%)
Antihypertensive taken
<3	92 (64.8)		50 (35.2)		142 (81.1)		0.090
=3	26 (78.8)		7 (21.2)		33 (18.9)		0.090
Therapy type
Monotherapy	84 (73)		31 (27)		115 (65.7)		*0.020*		*0.0295*
Bitherapy	55 (66.3)		28 (33.7)		83 (47.4)		0.440
Tritherapy	5 (45.5)		6 (54.5)		11 (6.3)		0.100
Posology
Once daily	116 (67.4)		56 (32.6)		172 (98.3)		0.700
Twice daily	22 (78.6)		6 (21.4)		28 (16)		0.120
Thrice daily	1 (100)		0 (0)		1 (0.6)		0.670
Moment the drug was taken
Morning	109 (67.3)		53 (32.7)		162 (92.6)		0.580
Afternoon	6 (60)		4 (40)		10 (5.7)		0.420
Evening	31 (81.6)		7 (18.4)		38 (21.7)		*0.030*		*0.0399*
Morning, evening	22 (81.5)		5 (18.5)		27 (15.4)		0.070
Morning, afternoon, evening	1 (100)		0 (0)		1 (0.6)		0.670
Side-effects
Yes	62 (92.5)		5 (7.5)		67 (38.3)		*<0.001*		*<0.001*
No	56 (51.9)		52 (48.1)		108 (61.7)
Type of medication taken
Specialty	106 (68.4)		49 (31.6)		155 (88.6)		0.300
Generic	44 (71)		18 (29)		62 (35.4)		0.290
Monthly drug cost (FCFA)
<10000		33 (56.9)		25 (43.1)		58 (33.1)		*0.030*
[10000-20000[		59 (72.8)		22 (27.2)		81 (46.3)		0.100
[20000-30000[		20 (74.1)		7 (25.9)		27 (15.4)		0.290
=30000		6 (66.7)		3 (33.3)		9 (5.1)		0.610
Duration on treatment (years)
<10		66 (68)		31 (32)		97 (55.4)		0.423
[10-20[		37 (71.2)		15 (28.8)		52 (29.7)		0.252
=20		15 (57.7)		11 (42.3)		26 (14.9)		0.132
p-value from Chi-square test; *PA is p-value adjusted for significant factors obtained from logistic regression analysis using variables with P < 0.05 in bivariate analysis as candidate variables.

Of the 175 participants, 32.60% were high adherers; 40.60% of participants were medium adherers; and 26.90% were low adherers. Table XIshows the adherence profiles of the study population while figure 15 illustrates the level of adherence.

Table XII shows the distribution according to BP status and good adherence. 36.57% of the study participants who had a poor adherence to medication equally had an uncontrolled BP. Of the 74 participants having an uncontrolled BP, 86.49% had poor therapeutic adherence.

Uncontrolled (OR = 5.57; CI_{95 =}2.6-12.48; p = 0.000) BP was found to be significantly associated with poor therapeutic adherence.

A controlled BP status (OR = 0.18; CI_{95 =}0.08-0.38; p = 0.000) was found to be significantly associated to good therapeutic adherence.

Table XII: Distribution according to blood pressure status and good adherence

Figure 16 shows the distribution according to level of knowledge on hypertension. Of the 175 participants, 54.30% were knowledgeable about hypertension and 37.7 % had good knowledge.

After multivariate analysis with logistic regression 9 predictive factors of poor therapeutic drug adherence were identified (Table XIII): 1^st cycle secondary education(p=0.0209; OR = 3.0287); Single marital status (p = 0.0003; OR = 4.6623); trip duration of= 1 hour away from the hospital (p = 0.008; OR = 7.3925); middle socioeconomic status (p = 0.006; OR = 2.6814);uncontrolled BP status(p = 0; OR = 5.5704); presence of handicap(p = 0.0117; OR = 4.1222); Monotherapy(p = 0.0295; OR = 2.0721); presence of side effects(p = 0; OR = 11.5143);and taking medication in the evening (p = 0.0399; OR = 2.5452).

CHAPTER V:DISCUSSION

Ensuring patient adherence to antihypertensive medications in order to prevent complications remains a major challenge to public health in many developing countries. Poor adherence to treatment is the single most important reason for uncontrolled hypertension, serious complications and wastage of health care resources [7].

Our main objective was to assess adherence level and its associated factors to antihypertensive treatment among adult hypertensive patients followed-up at the YGH. All five specific objectives were achieved by the end of this study. However some technical difficulties were witnessed which included: lack of an adequate secluded area at certain times to carry out interviews privately, incomplete or missing information on patient medical records, dealing with some patients presenting with comorbidities affecting their quality of life like stroke, heart failure, gout or diabetic neuropathy and making participant understand each item of the questionnaires. The study as a whole has the following limits:

1) The study was carried out in the YGH and so the results obtained cannot be used to generalize the adherence levels in the Centre region. More data has to be collected from various hospitals and clinics in order to bring out a general trend in adherence levels.

2) The research did not investigate adherence levels in patients suffering from a mental handicap or disease.

Our study sample comprised 175 participants whose average age was 60.1 #177; 11.1 years. The 60 years and above age group was the most represented (48%; n = 48). Our results are in line with the previous literature[1,106-108]. However, in Ethiopia, Ambaw et al. found in 2012 that the ]40-60[ years age group was predominant at 51.70%[7].Mbouemboue et al. had a similar finding where the most represented age group was between ]45-65] years old at 57.10%[16]. Nonetheless, what these studies have in common is that there is a general incremental trend in the prevalence of hypertension in adults aged 25 and above.

The sex ratio was 1.2 in favor of males (54.90%). Several authors have reported a similar finding[1,101,102,110].In a 2012 study carried out in Cameroon on 2,120 persons, Dzudie et al. reported that HBP was more frequent in the male population (50.10%) than in the female population (44.60%)[28].However other authors reported a female predominance: Ambaw et al. in 2012 in Ethiopia at63%[7]; Mbouemboue et al. in 2016 inCameroonat 54.76%[16]; Akoko et al. in 2017 in Cameroon at 55.70%[20]; andEssomba et al. in 2017 in Cameroon at64.60%[19] and the latter author suggested that a possible reason for this female predominance is that women take their health issues more seriously compared to men.

The majority of the participants lived in an urban setting (88.60%). The YGH is located in the heart of the capital city of Cameroon and therefore patients who go there for consultations are mostly city dwellers.Ambaw et al. in 2012 in Ethiopia had a similar finding at 76.60%[7]; and Behnood-Rod et al. in 2016 in Iran had 97.50%[107].

Most participants in our study went through secondary education (42.29%). Our results were in line with the previous literature [16,19,20,103,110,111]. This research was undertaken in an urban setting where basic education is promoted and secondary education institutions are very much present. Other authors reported lower levels of education.Tufon et al. in 2014 in Cameroon had 65% of participants whohad primary level of education possibly because the study site was conducted in a rural setting[18]; Hussain et al. in 2011 in Bangladesh had 51.70% with primary level of education or below[104].

The majority of our study population (84.60%) spent less than 1 hour to the reach the YGH. The reason for this was that most patients lived in neighboring quarters. Ambaw et al. in 2012 in Ethiopia had a similar result where 39.30% spent 30 minutes to reach the hospital and 60.70% spent more than 30 minutes[7].

Only 10.90% of our study population had a health insurance. A similar result is observed in a study by Mbouemboue et al. in 2016 in Cameroon who had 8.60%[16]. Thiscould be primarily because of the fact that health insurance isnot mandatory in the current health-care system, and in partbecause of the lack of awareness on the benefits of healthinsurance. On the contrary,Behnood-Rod et al. in 2016 in Iran had 87.80% of participants with health insurance[107]. A reason for this high record could be that health insurance is fully integrated into Iranian healthcare systems and thus easy access to health services.

Our study revealed that 57.70% of the study population had a controlled BP. This was higher than what was reported in previous literature. Mbouemboue et al. in 2016 in Cameroon had 48.57%[16]; Akoko et al. in 2017 in Cameroon had 42.1%[20]; Behnood et al. in 2016 in Iran had 43.6%[107]; Okwuonu et al. in 2015 in Nigeria had 33%[110]. A reason for the high level of BP control in our study is that patients are given regular appointments especially upon treatment initiation in order to appreciate therapeutic efficiency. Physicians comply with treatment guidelines to change or intensify antihypertensive therapy if BP remains uncontrolled with pharmacotherapy.

The most frequently associated pathology to HBP was heart failure at 24.57%. Essomba et al. in 2017 in Cameroon had diabetes at 86.60%[19]; Behnood-Rod et al. in 2016 in Iran had ischaemic heart disease at 10%[107]; Boima et al. in 2015 in Ghana and Nigeria had diabetes or renal comorbidities at 27.73%[111]; Hedna et al. in 2015 in Sweden had ischaemic heart disease at 16.4%.

The majority of drugs screened in this study were CCBs (31.90%) present as fixed-dose monotherapy. Hedna et al. in 2015 in Sweden had 62.10% drugs acting on the renin-angiotensin system in their study[108]. The reasons for this is that CCBs are first-line treatment for primary hypertension in patients over the age of 55and black patients of African[3,68,71,74]. CCBs are also readily available locally mainly as generics thus facilitating a wider access of antihypertensives.

The mean monthly drug cost of participants was 14,543FCFA.Mbouemboue et al. in 2016 in Cameroon had a lower average monthly cost of9,811FCFA per patient per month. The average drug cost was higher in our study because the majority of drugs prescribed were specialty medications (88.60%) which are more expensive than their generic counterparts.

Our study revealed that 32.60% were high adherers; 40.60% of participants were medium adherers; and 26.90% were low adherers according the Morisky medication adherence scale.Mbouemboue et al. and Akoko et al.reported dissimilar figures in their respective studies [16,20].High adherers were low in a similar study by Behnood-Rod et al. where 49.60% showed low adherence to antihypertensives, 33.90% had moderate adherence and 16.40% showed high adherence [107].These figures varied mainly because of the different methodologies used in assessing adherence.The ultimate goal of health care intervention is to encourage good adherence of patients to their antihypertensive drugs. This will have the effect of controlling their BP thence preventing complications.

After bivariate analysis 10 variables were found to be significantly associated with poor adherence (living singly, first cycle secondary education, trip duration of one hour or more, medium socioeconomic status, uncontrolled BP status, presence of handicap, monotherapy, taking medications in the evening, presence of side effects, and knowledgeable about hypertension). 9 variables persisted after multivariate analysis with logistic regression (first cycle secondary education, living singly, trip duration of one hour or more, middle socioeconomic status, uncontrolled BP status, presence of handicap, monotherapy, presence of side effects, and taking medications in the evening.

Patients who had a 1^st cycle secondary education were more associated with a poor level of adherence compared to those who had other educational levels (p=0.0209; OR=3.0287). This was similar to findings by Mbouemboue et al. in 2016 in Cameroon[16];Hussain et al. in 2006 in Bangladesh[104]; and Boima et al. in 2013 in Nigeria and Ghana also reported insufficient levels of education[111]. Patients with insufficient background of the disease will have the tendency to neglect medication adherence and thus be subject to high BP setbacks.

We noted that 66.30% of participants lived as a couple either legally married or not. Other authors reported similar results [7,16,18-20,103,106,110,111].Patients who were single were more associated with a poor level of adherence(p=0.0003; OR=4.6623). Lo et al. reported in 2016 in China reported a similar finding[109]. Living singly could encourage forgetfulness about drug taking and neglect of appointments with physicians as opposed to patients living as couples.

Patients who lived 1 hour or more away from the hospital were more associated with poor therapeutic adherence(p=0.008; OR=7.3925). A similar finding was gotten from Ambaw et al. in 2012 in Ethiopia[7]. Patients living far away from health centres have the tendency of absenting from their medical appointments. This can create a breach in patient follow-up, foster poor adherence and lead to uncontrolled BPs.

Middle socioeconomic status was more associated with a poor level of adherencecompared to the low and high statuses(p=0.006; OR=2.6814). Patients in this socioeconomic class usually have difficulties purchasing their medications which were predominantly specialties and therefore expensive.In this light, health care providers should promote the prescription of generic drugs which are affordable and accessible.

Of the 74 participants having an uncontrolled BP, 86.49% had poor therapeutic adherence.Patients with an uncontrolled BP were more associated with poor therapeutic adherence than those with a controlled BP(p<0.001; OR=5.5704). Boima et al. had a similar finding [111].This association therefore confirms that poor adherence to antihypertensive medication is responsible for the increasing prevalence of hypertension.

In our study, 18.29% had a form of handicap of which 16.57% were physical handicaps. A similar finding was obtained by Mbouemboue et al. in 2016 in Cameroon (18.1%) but with only sensory handicap[16].Patients with a handicap were more associated with poor therapeutic adherence compared to those without(p=0.0117; OR=4.1222). Mbouemboue et al. had a similar finding[16]. Any form of handicap affects a person's quality of life and also normal medication taking. Patients with a handicap go through extra challenges in order to correctly take their medications as prescribed. They therefore need assistance from family and friends to improve adherence.

Patients who experienced side effects were more associated with poor therapeutic adherence compared to those who did not experience it (p<0.0001; odds ratio=11.5143). Lin et al. reported a similar finding[102]. It is important for physicians to address medication side effects in patients promptly. This will prevent therapeutic gaps which are likely to occur in the presence of these side effects. Drug changes or dosages are therefore imperative in this case.

Patients who took their medications in the evening were more associated with poor therapeutic adherence compared to those who took their drugs at other times(p=0.0399; odds ratio=2.5452). Patients are more likely to forget when told to take drugs in the evening before bedtime. Daily duties associated with physical and mental stress deter patients from medication taking thus constituting a hindrance to good adherence.

CHAPTER VI: CONCLUSION AND RECOMMENDATIONS

At the end of this study, we could say our different objectives have been attained and the following points should be retained:

Sex ratio of participants was 1.2 with male predominance of 54.90%. The mean age was 60.1 #177; 11.1 years with extremes from 33 to 88 with the 60 years and more, age group highly represented (48.60%). Most participants (88.60%) lived in urban areas and 51.43% had a non-liberal profession,the majority (66.30%) lived as couples and 40.00% had a higher level of education. Trip duration to the hospital was less than one hour for 84.60% of participants. The high socioeconomic status was greatly represented in this study (60%) and 10.9% of participants had a health insurance.

The High Normal BP group was most represented (24.60%) and 57.70% had a controlled BP. The most frequently encountered comorbidity was heart failure (24.57%). Only 18.29% of participants had a handicap.

Calcium channel blockers were the most encountered monotherapy (31.90%). The majority of participants took less than 3 different antihypertensive. The mean treatment cost was 14543 #177; 8613FCFA and most participants were in the 10000-20000FCFA monthly drug cost range. More than 90% of participants were on a once daily posology 65.70% were on monotherapy. Specialty medications were prescribed in most cases (88.60%) and 38.30% experienced side effects due to medication.

Poor adherence was observed in 32.60% of study participants.After multivariate analysis with logistic regression, 9 variables were significantly associated with poor adherence: first cycle secondary education, living singly, trip duration of one hour or more, middle socioeconomic status, uncontrolled BP status, presence of handicap, monotherapy, presence of side effects, and taking medications in the evening.

Of the 74 patients with uncontrolled BP, 86.49% had poor adherence. Patients with uncontrolled BP were associated with poor therapeutic adherence.

1- To reinforce information, education and communication in the whole country on non-communicable diseases especially hypertension, so that patients should know the importance of adhering to antihypertensive treatments prescribed.

2- To accelerate the implementation of the universal insurance coverage in Cameroon so that patients could easily purchase their antihypertensive drug prescribed.

1. Reinforce sensitization of patients with hypertension on the need to adhere to their treatments which is lifelong in order to avoid comorbidities and complications.

2. Insist on the need to prescribe generic drugs which are less expensive in order to increase access and improve treatment adherence.

3. To opt for antihypertensive drugswhich have less side effects and which are taken once daily to facilitate adherence.

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CHAPTER VIII: APPENDIX

Title of study: Adherence to antihypertensive treatment and its associated factors in hypertensive patients followed-up at the Yaounde General Hospital

Background:You are invited to take part in a research study. Before you decide to participate in this study, it is important you understand why the research is being done and what it will involve. Please feel free to read through the following piece of information and enquire from the investigator if there is anything ambiguous or if you need more information.

Study aim: To assess the adherence level and its associated factors to antihypertensive therapy among adult hypertensive patients on follow-up in the Yaounde General Hospital.

Study procedure: Patients admitted into this study shall be randomly and consecutively selected at the external consultation cardiology service. After obtaining a written consent, we shall proceed by measuring the resting blood pressure of each patient. Afterwards, during an interview carried out in private, the investigator shall fill the pretested questionnaires. Then, the questionnaires will eventually be collected and safely stored to data analysis.

Benefits: By accepting to participate in this study, you will directly help your healthcare providers to identify your adherence issues. By so doing, adequate advice and support shall be provided to you so that you adopt the right attitudes directed towards reducing your high blood pressure.

Risks/Discomfort:There are virtually no risks in participating in this study. A momentary discomfort could however be felt while taking the blood pressure (i.e. when the cuff is inflated).

Participation: Participation in this research study is voluntary. You have the right to withdraw at any time or refuse to participate entirely without prejudice to the health care offered by the hospital.

Ethics:Information you will provide will be used for this study only and will not be shared for any other purposes or projects.

Consent:I have read, understood, and received a copy of the above consent form. I desire on my own free will to participate in this study.

Titre de l'étude: Observance au traitement antihypertenseur et ses facteurs associés chez les patients hypertendus suivis à l'Hôpital Général de Yaoundé

Contexte: Vous êtes invité à participer à un travail de recherche. Avant de décider de participer à cette étude, il est important que vous compreniez pourquoi la recherche a lieu d'être et ce qu'elle impliquera. N'hésitez pas à lire l'information suivante et à vous renseigner auprès de l'enquêteur s'il y a quelque chose d'ambigu ou si vous avez besoin de plus d'information.

But de l'étude: Évaluer le taux d'observance et ses facteurs associés au traitement antihypertenseur chez les patients adultes hypertendus suivis à l'Hôpital Général de Yaoundé.

Procédure: Les patients admis dans cette étude seront sélectionnés de manière aléatoire et consécutive dans les services externes de consultation cardiologiques. Après avoir obtenu un consentement écrit, nous procéderons en mesurant la pression artérielle au repos de chaque patient. Ensuite, lors d'un échange en privé, l'enquêteur remplira les questionnaires pré-testés. Les questionnaires seront éventuellement collectés et rangés en lieu sûr par l'investigateur pour l'analyse ultérieure des données.

Avantages: En acceptant de participer à cette étude, vous aiderez directement vos fournisseurs en soins de santé à identifier vos problèmes d'observance. Ce faisant, des conseils et un soutien adéquats vous seront fournis afin que vous adoptiez les bonnes attitudes visant à réduire votre tension artérielle élevée.

Risques/inconfort: Il n'y a pratiquement aucun risque à participer à cette étude. Un inconfort momentané peut toutefois être ressenti lors de la prise de la pression sanguine (c'est-à-dire lorsque le brassard est gonflé).

Participation: La participation à ce travail de recherche est volontaire. Vous avez le droit de vous retirer à tout moment ou de refuser de participer entièrement sans préjudice des soins de santé offerts par l'hôpital.

Éthique: Les informations que vous fournirez ne seront utilisées que pour cette étude et ne seront pas partagées à d'autres fins ou projets.

Consentement: J'ai lu, compris et reçu une copie du formulaire de consentement ci-dessus. Je désire de mon plein gré participer à cette étude.