Hypertension is defined as systolic blood pressure (SBP) of 140 mmHg or greater, diastolic blood pressure (DBP) of 90 mmHg or greater, or taking antihypertensive medication. VI JNC, 1997

Types of hypertension Essential hypertension Secondary hypertension 90% No underlying cause Secondary hypertension Underlying cause

Causes of Secondary Hypertension Renal Parenchymal Vascular Others Endocrine Neurogenic Miscellaneous Unknown

Hypertension: Predisposing factors Age > 60 years Sex (men and postmenopausal women) Family history of cardiovascular disease Smoking High cholesterol diet Co-existing disorders such as diabetes, obesity and hyperlipidaemia High intake of alcohol Sedentary life style

1999 WHO-ISH Guidelines : Definitions and Classifications of BP Levels SBP DBP Category* (mm Hg) (mm Hg) Optimal < 120 < 80 Normal < 130 < 85 High-normal 130-139 85-89 Grade 1 hypertension (mild) 140-159 90-99 Borderline subgroup 140-149 90-94 Grade 2 hypertension (moderate) 160-179 100-109 Grade 3 hypertension (severe) > 180 > 110 ISH > 140 < 90 Borderline subgroup 140-149 < 90 WHO-ISH Guidelines Subcommittee J Hypertens 1999; 17:151

1999 WHO-ISH Guidelines: Stratification of risk to Quantify Prognosis Degree of hypertension (mm Hg) Risk factors and Grade 1-mild Grade 2-moderate Grade3-severe disease history (SBP 140-159 (SBP 160-179 (SBP > 180 or DBP 90-99) or DBP 100-109) or DBP > 110) I No other risk Low risk Med risk High risk factors II 1-2 risk factors Med risk Med risk Very high risk III > 3 risk factors or High risk high risk Very high risk target organ disease or diabetes IV Associated Very high risk Very high risk Very high risk Clinical conditions WHO-ISH Guidelines Subcommittee J Hypertens 1999;17:151

Diseases Attributable to Hypertension Left Ventricular Hypertrophy Heart Failure Gangrene of the Lower Extremities Myocardial Infarction Hypertensive Encephalopathy Aortic Aneurym HYPERTENSION Coronary Heart Disease Blindness Cerebral Hemorrhage Chronic Kidney Failure Stroke Preeclampsia/Eclampsia Adapted from Dustan HP et al. Arch Intern Med. 1996; 156: 1926-1935

1999 WHO-ISH Guidelines: Desirable BP Treatment Goals Optimal or normal BP (< 130/85 mm Hg) for Young patients Middle-age patients Diabetic patients High-normal BP (< 140/90 mm Hg) desirable for elderly patients Aggressive BP lowering may be necessary in patients with nephropathy, chronic renal failure, particularly if proteinuria is < 1 g/d - 130/80 mm Hg > 1 g/d - 125/75 mm Hg

Significant benefits from intensive BP reduction in diabetic patients Major CV events / 100 patient-yr Lancet 1998, 351, 1755

Relative risks of specific types of clinical complications related to tight and less tight BP Control Patients with Absolute risk aggregate (events/1000 and points patients-yr) Tight Less tight Less RR for control control Tight tight tight control Clinical end point (n=758) (n=390) control control p (95% Cl) Any diabetes-related 259 170 50.9 67.4 0.0046 0.76 (0.62-0.92) end point Deaths related to 82 62 13.7 20.3 0.019 0.68 (0.49-0.94) diabetes All cause mortality 134 83 22.4 27.2 0.17 0.82 (0.63-1.08) Myocardial infarction 107 69 18.6 23.5 0.13 0.79 (0.59-1.07) Stroke 38 34 6.5 11.6 0.013 0.56 (0.35-0.89) Peripheral vascular 8 8 1.4 2.7 0.17 0.51 (0.19-1.37) disease Microvascular disease 68 54 12.0 19.2 0.0092 063 (0.44-0.89) Ref : UK Prospective Diabetes Study Group BMJ 1998; 317:703

Life style modifications Lose weight, if overweight Limit alcohol intake Increase physical activity Reduce salt intake Stop smoking Limit intake of foods rich in fats and cholesterol

Factors affecting choice of antihypertensive drug The cardiovascular risk profile of the patient Coexisting disorders Target organ damage Interactions with other drugs used for concomitant conditions Tolerability of the drug Cost of the drug

Drug therapy for hypertension Class of drug Example Initiating dose Usual maintenance dose Diuretics Hydrochlorothiazide 12.5 mg o.d. 12.5-25 mg o.d. -blockers Atenolol 25-50 mg o.d. 50-100 mg o.d. Calcium Amlodipine 2.5-5 mg o.d. 5-10 mg o.d. channel blockers -blockers Doxazosin 1 mg o.d. 1-8 mg o.d. ACE- inhibitors Lisinopril 2.5-5 mg o.d. 5-20 mg o.d. Angiotensin-II Losartan 25-50 mg o.d. 50-100 mg o.d. receptor blockers

Diuretics Example: Hydrochlorothiazide Act by decreasing blood volume and cardiac output Decrease peripheral resistance during chronic therapy Drugs of choice in elderly hypertensives Drawbacks Hypokalaemia Hyponatraemia Hyperlipidaemia Hyperuricaemia (hence contraindicated in gout) Hyperglycaemia (hence not safe in diabetes) Not safe in renal and hepatic insufficiency

Beta blockers Example: Atenolol Block b1 receptors on the heart Block b2 receptors on kidney and inhibit release of renin Decrease rate and force of contraction and thus reduce cardiac output Drugs of choice in patients with co-existent coronary heart disease Drawbacks Adverse effects: lethargy, impotency, bradycardia Not safe in patients with co-existing asthma and diabetes Have an adverse effect on the lipid profile

Calcium channel blockers Example: Amlodipine Block entry of calcium through calcium channels Cause vasodilation and reduce peripheral resistance Drugs of choice in elderly hypertensives and those with co-existing asthma Neutral effect on glucose and lipid levels Drawbacks Adverse effects: Flushing, headache, Pedal edema

ACE inhibitors Example: Lisinopril, Enalapril Inhibit ACE and formation of angiotensin II and block its effects Drugs of choice in co-existent diabetes mellitus Drawbacks Adverse effect: dry cough, hypotension, angioedema

Angiotensin II receptor blockers Example: Losartan Block the angiotensin II receptor and inhibit effects of angiotensin II Drugs of choice in patients with co-existing diabetes mellitus Drawbacks Adverse effect: dry cough, hypotension, angioedema

Alpha blockers Example: Doxazosin Block a-1 receptors and cause vasodilation Reduce peripheral resistance and venous return Exert beneficial effects on lipids and insulin sensitivity Drugs of choice in patients with co-existing hyperlipidaemia, diabetes mellitus and BPH Drawbacks Adverse effects: Postural hypotension

Antihypertensive therapy: Side-effects and Contraindications Class of drugs Main side-effects Contraindications/ Special Precautions Diuretics Electrolyte imbalance, Hypersensitivity, Anuria (e.g. Hydrochloro- ­ total and LDL cholesterol thiazide) levels, ¯ HDL cholesterol levels, ­ glucose levels, ­ uric acid levels b-blockers Impotence, Bradycardia, Hypersensitivity, (e.g. Atenolol) Fatigue Bradycardia, Conduction disturbances, Diabetes, Asthma, Severe cardiac failure

Antihypertensive therapy: Side-effects and Contraindications (Contd.) Class of drug Main side-effects Contraindications/ Special Precautions Calcium channel blockers Pedal edema, Headache Non-dihydropyridine (e.g. Amlodipine, CCBs (e.g diltiazem)– Diltiazem) Hypersensitivity, Bradycardia, Conduction disturbances, Congestive heart failure, Left ventricular dysfunction. Dihydropyridine CCBs– Hypersensitivity a-blockers Postural hypotension Hypersensitivity (e.g. Doxazosin) ACE-inhibitors Cough, Hypertension, Hypersensitivity, Pregnancy, (e.g. Lisinopril) Angioneurotic edema Bilateral renal artery stenosis Angiotensin-II receptor Headache, Dizziness Hypersensitivity, Pregnancy, blockers (e.g. Losartan) Bilateral renal artery stenosis

Choosing the right antihypertensive Condition Preferred drugs Other drugs Drugs to be that can be used avoided Asthma Calcium channel a-blockers/Angiotensin-II b-blockers blockers receptor blockers/Diuretics/ ACE-inhibitors Diabetes a-blockers/ACE Calcium channel blockers Diuretics/ mellitus inhibitors/ b-blockers Angiotensin-II receptor blockers High cholesterol a-blockers ACE inhibitors/ Angiotensin-II b-blockers/ levels receptor blockers/ Calcium Diuretics channel blockers Elderly patients Calcium channel -blockers/ACE- (above 60 years) blockers/Diuretics inhibitors/Angiotensin-II receptor blockers/- blockers BPH a-blockers b-blockers/ ACE inhibitors/ Angiotensin-II receptor blockers/ Diuretics/ Calcium channel blockers

Limitations on use of antihypertensives in patients with coexisting disorders Coexisting Diuretic b-blocker ACE All CCB a1-blocker Disorder inhibitor antagonist Diabetes Caution/x Caution/x     Dyslipidaemia x x     CHD       Heart failure  3/Caution   Caution  Asthma/COPD  x  /Caution    Peripheral  Caution Caution Caution   vascular disease Renal artery   x x   stenosis

Effect of various antihypertensives on coexisting disorders Total LDL- HDL- Serum Glucose Insulin cholesterol cholesterol cholesterol triglycerides tolerance sensitivity Diuretic ­ ­ ¯ ­­ ¯ ¯ b-blockers - ­ ¯¯ ­­­ - - ACE inhibitors - - - - ­ ­ All antagonists - - - - ­ ­ CCBs - - - - - - a-blockers ¯ ¯ ­ ¯ ­ ­

(Combination therapy) Combination therapy for hypertension – Recommended by JNC-VI guidelines and 1999 WHO-ISH guidelines With any single drug, not more than 25–50% of hypertensives achieve adequate blood pressure control J Hum. Hypertens 1995; 9:S33–S36 For patients not responding adequately to low doses of monotherapy Increase the dose of drug. This, however, may lead to increased side effects Substitute with another drug from a different class Add a second drug from a different class (Combination therapy) If inadequate response obtained Add second drug from different class (Combination therapy)

Advantages of fixed-dose combination therapy Better blood pressure control Lesser incidence of individual drug’s side-effects Neutralisation of side-effects Increased patient compliance Lesser cost of therapy

Fixed-dose combinations as recommended by JNC-VI (1997) guidelines and 1999 WHO-ISH guidelines Calcium channel blocker and b-blocker (e.g. Amlodipine and Atenolol) Calcium channel blocker and ACE-inhibitor (e.g. Amlodipine and Lisinopril) ACE-inhibitor and Diuretic (e.g. Lisinopril and Hydrochlorothiazide) b-blocker and Diuretic (e.g. Atenolol and Hydrochlorothiazide)

Reduces BP effectively Efficacy and Tolerability of a fixed-dose combination of amlodipine and atenolol (Amlopres-AT) in Indian Hypertensives (n=369) Reduces BP effectively 80.5% 175.4+19.4 143.8 + 13.2 Blood Pressure (mm Hg) 106.8 + 10.5 % responders 88.2 + 7.6 Safe and well tolerated Adverse events were reported in 7.9% of patients Common side effects included edema, fatigue and headache Indian Practitioner 1997; 50: 683-688.

Reduces BP effectively Efficacy and Tolerability of combined amlodipine and lisinopril (Amlopres-L) in Indian hypertensives (n=330) Reduces BP effectively 77.65 175.4+19.4 143.8 + 13.2 Blood Pressure (mm Hg) 106.8 + 10.5 % responders 88.2 + 7.6 Safe and well tolerated Adverse events were reported in 9.7% of patients Side effects commonly reported included cough and edema Only 1.76% of patients withdrew from the study. Indian Practitioner 1998; 51: 441-447.

Drugs in special conditions Pregnancy Coronary heart disease Congestive heart failure Preferred Drugs Nifedipine, labetalol, hydralazine, beta-blockers, methyldopa, prazosin Beta-blockers, ACE inhibitors, Calcium channel blockers ACE inhibitors, beta-blockers 1999 WHO-ISH guidelines

Summary Hypertension is a major cause of morbidity and mortality, and needs to be treated It is an extremely common condition; however it is still underdiagnosed and undertreated Hypertension is not controlled with monotherapy in at least 50% of patients; in these patients combination therapy is required