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This document discusses antihypertensive drugs. It begins by defining hypertension and describing the types and outcomes of hypertension. It then covers the normal blood pressure regulation mechanisms. The document classifies antihypertensive drugs into several categories including diuretics, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, and others. For each drug class, it provides examples, discusses the mechanism of action, desirable properties, and drawbacks. It concludes by discussing the current treatment approaches and guidelines for selecting antihypertensive drugs.

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ANTIHYPERTENSIVE DRUGS Dr. Divya G.Krishnan KMCT Medical College
Introduction  Hypertension is a very common disorder particularly past middle age.  Hypertension is defined as a BP more than 140mm Hg systolic and 90mm Hg diastolic. (JNC 7 guidelines).
Introduction Types of Hypertension Essential Secondary A disorder of unknown origin affecting the Blood Pressure regulating mechanisms Secondary to other disease processes
Introduction Outcomes of Hypertension :-  Atherosclerosis  Ischemic heart disease & cerebrovascular accidents (CVA)  Nephropathy  Congestive heart failure “Hence early detection &treatment of htn with antihypertensive drugs is very important”
Normal Blood Pressure Regulation 1. Blood Pressure = Cardiac output (CO) X TPR. Physiologically CO and PVR is maintained by arterioles , postcapillary venules & Heart . 2. Baroreflex : Baroreceptors regulate BP. Central sympathetic neurones in vasomotor area are tonically active. When there is stretch in the vessel wall brought about by rise in pressure, baroreceptor stimulation occurs and inhibits sympathetic discharge. When there is fall in BP, there is reduction in stretch leading to increased baroreceptor activity leading to increase in TPR and CO thereby restoring normal blood pressure. 3. Renin-angiotensin- aldosterone system (RAAS)(role of kidney) 4. Local agents like Nitric oxide  All antihypertensives act via interfering with one or more of the normal mechanisms
Expected Questions  Classification of antihypertensives. Write the Mechanism of antihypertensive action, desirable properties and drawbacks of use of Diuretics/ ACEI/ARBs/CCB/Beta blockers in HTN.  Drugs for HTN in pregnancy  Drugs for Hypertensive emergencies  Selection of first line antihypertensives
Classification of Antihypertensive Drugs 1. Diuretics:  Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide  High ceiling: Furosemide  K+ sparing: Spironolactone, Triamterene, Amiloride 2. Angiotensin-converting Enzyme (ACE) inhibitors:  Captopril, Lisinopril., Enalapril, Ramipril , Fosinopril 3. Angiotensin (AT1 receptor) blockers:  Losartan, Candesartan, Valsartan, Telmisartan 4. Direct renin inhibitor  Aliskiren
Classification of Antihypertensive Drugs 5. Calcium Channel Blockers (CCB):  Verapamil, Diltiazem, Nifedipine, Amlodipine, 6. ß-adrenergic blockers:  Non selective: Propranolol  Cardioselective: Metoprolol , atenolol 7. ß and α – adrenergic blockers:  Labetolol, carvedilol 8. α – adrenergic blockers:  Prazosin, terazosin, doxazosin, phenoxybenzamine , phentolamine 9. Centrally acting:  Clonidine, methyldopa
Classification of Antihypertensive Drugs 10. Vasodilators:  Arteriolar : Hydralazine, Minoxidil, Diazoxide  Arteriolar + venous: Sodium Nitroprusside Pnemonic : ABCD A (ACEI, ARBs, alpha blockers) B(beta blockers)C (CCB, centrally acting) D (Diuretics, direct renin inhibitors, dilators)
Each group of drugs will be discussed under the following headings  Examples of drugs under each group  Mechanism of antihypertensive action  Desirable properties as antihypertensives  Drawbacks as antihypertensives  Current status in treatment of hypertension
Diuretics Examples :  Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide  High ceiling: Furosemide  K+ sparing: Spironolactone, Triamterene, Amiloride
Diuretics  Mechanism of antihypertensive action: (Thiazides) Act on Kidneys to increase excretion of Na and H2O  decrease in blood volume decrease in COP & hence decrease in BP.  After 4 - 6 weeks, compensatory mechanisms operate to regain Na+ balance, plasma volume and Cardiac output but BP remains low. Why?  Answer: Even after the compensatory mechanisms, there exists a small deficit of Na+ in the vessel wall. This Na deficit reduces stiffness of vessel wall leading to vasodilation . This leads to decrease in TPR and fall in BP.  So, the initial fall in BP due to thiazides is due to fall in COP but fall in BP is sustained due to fall in TPR.
Diuretics Mechanism of antihypertensive action (high ceiling diuretics) Fall in BP is dependent only on reduction in plasma volume & Cardiac output (similar to the initial fall in BP due to thiazides) but unlike thiazides the Na deficit is not persistent due to short action of high ceiling diuretics . Hence no fall in t.p.r and no sustenance of BP fall.
Diuretics Desirable properties of Diuretics as antihypertensives - Once a day dosing - No fluid retention - No tolerance development to antihypertensive action - Low incidence of postural hypotension - Effective in isolated systemic hypertension - Less risk of fractures in elderly (hypocalciuric action of thiazides) - Low cost
Diuretics Drawbacks of Diuretics as antihypertensives  Hypokalaemia – muscle pain and fatigue  Hyperglycemia  Hyperlipidemia  Hyperuricaemia  Sudden cardiac death – tosades de pointes due to hypokalemia All the above adverse effects occurr at higher doses of thiazides (50 – 100 mg per day). These adverse effects are minimal with low doses (12.5 to 25 mg). So, low doses of Thiazides are used as antihypertensives now.
Diuretics Current status  Thiazides are mild antihypertensives, cause fall of abt 10mm Hg in BP. Alone they are used only in mild HTN (stage 1 HTN). Low dose of thiazide therapy is used preferably with a potassium sparing diuretic as first choice in elderly.  They prevent tolerance to other antihypertensives. Can be used as combination in any grade of HTN. Indapamide : modified thiazide with minimal side effects It has very mild diuretic action and is used mainly as antihypertensive and not as diuretic.
Diuretics Loop diuretics Cause more fluid & electrolyte imbalance. They are indicated in HTN only if it is complicated by:- - Chronic renal failure - Refractory CHF - Resistance to thiazides - Marked fluid retention. K+ sparing diuretics Used only in conjunction with Thiazides to prevent K+ loss & to supplement their antihypertensive action.
Angiotensin Converting Enzyme (ACE) Inhibitors Examples :- Captopril, Lisinopril., Enalapril, Ramipril , Fosinopril Mechanism of antihypertensive action Inhibit the Renin Angiotensin Aldosterone system (RAAS). WHAT IS RAAS??? Next slide
RAAS  Renin is produced by JG cells of kidney in response to  Fall in BP or blood volume  Decrease Na+ in macula densa  Renin acts on a plasma protein Angiotensinogen to convert it to Angiotensin-I  Angiotensin-I is rapidly converted to Angiotensin-II by ACE (present in luminal surface of vascular endothelium)  Angiotensin-II is degraded by peptidases to produce Angiotensin-III  Angiotensin II causes vasoconstriction (increased TPR) leading to rise in diastolic BP.  Both Angiotensin-II and Angiotensin-III stimulates Aldosterone secretion from Adrenal Cortex . Aldosterone promotes Na+ & water reabsorption by the kidneys leading to increased blood volume & increased COP & systolic BP.
RAAS - Diagram Vasoconstriction Na+ & water retention (Adrenal cortex) Kidney Increased Blood Vol. Rise in BP
ACE inhibitors MOA : Inhibit synthesis of Angiotensin II by inhibiting ACE –> decrease in (tpr) and blood volumefall in diastolic and systolic BP.
ACE inhibitors Desirable properties of ACEI as antihypertensives  No postural hypotension  Not much electrolyte imbalance  Renal perfusion well maintained  Reverses the ventricular hypertrophy  No hyperuricemia  No deleterious effect on plasma lipid profile  No rebound hypertension  Only minimal worsening of quality of life like general wellbeing, sleep and work performance.
ACE inhibitors Drawbacks/ adverse effects  Cough – persistent brassy cough due to inhibition of bradykinin breakdown in lungs  Hyperkalemia (in renal failure patients, those with K+ sparing diuretics, NSAID and beta blockers (routine check of K+ level))  First dose Hypotension – sharp fall may occur  Angioedema: swelling of lips, mouth, nose etc.  Rashes, urticaria  Dysgeusia: loss or alteration of taste  Foetopathic: hypoplasia of organs, growth retardation etc  Neutropenia  Proteinuria  Acute renal failure ( occurs in patients with bilateral renal artery stenosis)
ACE inhibitors Current status  1st line antihypertensive Drug  Used in relatively young patients  Most appropriate antihypertensives in patients with:- Diabetes, Chronic kidney disease, CHF Left ventricular hypertrophy, Angina, post MI, stroke Dyslipidemia, Gout Avoid in : Pregnancy, bilateral renal artery stenosis, hypersensitivity , hyperkalaemia , Preexisting dry cough
ACE inhibitors (2 important ones) Captopril  Sulfhydryl containing dipeptide.  Not a prodrug. Has drawbacks mentioned earlier  Half life: 2 Hrs, multiple doses Enalapril  Prodrug – converted to enalaprilate  Advantages over captopril:  More potent  Longer duration of action-once daily dose  Absorption not affected by food  Rash and loss of taste are less frequent  Slower onset of action, hence first dose hypotension
ACE inhibitors – other uses (to be discussed under ACE inhibitors chapter)  Congestive Heart Failure  Myocardial Infarction  Prophylaxis of high CVS risk subjects  Diabetic Nephropathy  Schleroderma crisis
Angiotensin Receptor Blockers (ARBs) Examples Losartan, Candesartan, Valsartan,Telmisartan Mechanism of antihypertensive action Angiotensin Receptors (AT1 & AT2) are present on target cells. Most of the physiological actions of angiotensin are mediated via AT1 receptor.  ARBs are competitive antagonists and inverse agonist of AT1 receptor. Blocks all the actions of A-II mediated by AT1 like vasoconstriction, aldosterone release and renal actions of salt & water reabsorption.
ARBs Current status of ARBs Similar to ACEI BUT theoretical superiority over ACEIs is claimed due to following reasons:  Cough is rare – no interference with bradykinin degradation.  Complete inhibition of AT1 & action of angiotensin II is fully blocked– (In case of ACEI, Angiotensin II formed by other mechanisms not involving ACE can act on AT1 reeptor & produce the effects)  AT1 blockade results in indirect activation of AT2 – vasodilatation (additional benefit)  Rare 1st dose hypotension  Low dysgeusia & angioedema Fetopathic like ACEI & hence should not be used in pregnancy.
Direct renin inhibitor-Aliskiren  Inhibits production of Angiotensin I & II.  Equally effective as ACEI & ARBs.  Since experience with it is limited, so it is used only as a second line antihypertensive when more established ACEI & ARBs cannot be used.
Beta blockers Examples - Non selective: Propranolol - Cardioselective: Metoprolol ,Atenolol Mechanism of antihypertensive action - Decreases heart rate, contractility, conduction velocity, cardiac output (inverse agonist on β1 ). Total peripheral resistance increases initially. - Initial phase : COP decreases (systolic BP decreases), t.p.r increases (diastolic BP increases) overall little BP change. - With prolonged use resistance vessels adapt to decreased COP so that t.p.r decreases both systolic & diastolic BP decrease
Beta blockers Desirable properties as antihypertensives  No postural hypotension  No salt and water retention  Low incidence of side effects  Low cost  Once a day regime Drawbacks of non selective beta blockers:-  Fatigue, lethargy (low CO?)– decreased work capacity  Bradycardia  Loss of libido – impotence  Cognitive defects – forgetfulness  Worsening of carbohydrate tolerance, lipid profile, PVD, asthma.  Sudden withdrawal—chance of rebound HTN, precipitation of MI or angina
Beta blockers Advantages of cardio-selective beta blockers over non- selective beta blockers:  Safer in asthmatics (no bronchoconstriction)  Safer in diabetes (no interference with hypoglycemia induced glycogenolysis)  Less worsening of PVD  Lipid profile-less deterioration
Beta blockers Current status:  As first line drugs cardioselective beta blockers alone in mild/moderate HTN - Action maintained over 24hrs  Preferred in:- - Young non-obese hypertensives those with coexisting anxiety, migraine, tachycardia & those with IHD - For preventing sudden cardiac death in Post MI patients - In stable heart failure along with ACEI  Not preferred in old
Αlpha blockers  Examples Non selective alpha blockers (Phenoxybenzamine, Phentolamine) not used in chronic essential hypertension but used in Pheochromocytoma. Specific alpha-1 blockers like prazosin, terazosin and doxazosine are used in HTN treatment  Mechanism of antihypertensive action Blockade of vasoconstrictor α receptors - pooling of blood in capacitance vesselsdecreased venous return & decreased COP fall in BP
Αlpha blockers  Adverse effects:  postural hypotension  salt and water retention  Nasal stuffiness  Miosis  failure of ejaculation in males  Current status:  But not used as first line agent,  May be added to diuretics + beta blockers if target bp is not achieved with their use alone.
Alpha + beta blockers  Labetalol used IV for rapid BP reduction. Orally used for severe HTN.  Carvedilol used as antihypertensive as well as in CHF.
Calcium Channel Blockers - Classification
Calcium Channel Blockers Mechanism of antihypertensive action  Three types of Ca+ channels in smooth muscles – Voltage sensitive, receptor operated and leak channel  Voltage sensitive are again 3 types – L-Type, T-Type and N- Type  Normally, L-Type of channels admit Ca+ and causes depolarization – excitation-contraction coupling through phosphorylation of myosin light chain – contraction of vascular smooth muscle –vasoconstriction-- elevation of BP  CCBs block L-Type channel resulting in :- - Smooth Muscle relaxation - Negative chronotropic, ionotropic effects on heart.  DHPs have highest smooth muscle relaxation and vasodilator action followed by verapamil and diltiazem. Hence DHPs are the CCBs used in HTN.
Calcium Channel Blockers Desirable properties  Do not compromise haemodynamics – no impairment of work capacity  No deleterious effect on lipid profile, uric acid or electrolyte balance.  Can be given to asthma, angina and PVD patients  No renal and male sexual function impairment  No adverse fetal effects and can be given in pregnancy  Minimal effect on quality of life
Calcium Channel Blockers Drawbacks - Worsen GERD - Negative chronotropic effect can worsen Conduction defects - Worsen BHP & bladder voiding difficulty in males
Calcium Channel Blockers Current status  Used as 1st line by many because of excellent tolerability and high efficacy.  Preferred in elderly/asthma/COPD/PVD/ stroke/DM/pregnant/isolated systolic HTN  To be avoided in:-  Myocardial inadequacy, CHF  Conduction defects  Receiving beta blockers  IHD, post MI cases.  Enlarged prostate  GERD
Assignment  Contrast Nifedipine and Amlodipine
Vasodilators Hydralazine  Directly acting vasodilator  MOA: hydralazine causes NO release – relaxation of vascular smooth muscle – fall in BP.  Uses: 1) Moderate hypertension when 1st line fails 2) Hypertension in Pregnancy Minoxidil Relaxes smooth muscle & relaxes arterioles. Used only in life threatening HTN & topically in alopecia
Sodium Nitroprusside  Rapidly acting vasodilator (both arteriolar & venous)  MOA: RBCs convert nitroprusside to NO (enzymatically) & non enzymatically by glutathione to NO & CN- –..>NO causes vasodilation of both resistance (arterioles) and capacitance vessels (veins) and reduces t.p.r and CO (decrease in venous return)  Uses: Hypertensive Emergencies  Adverse effects: Palpitation, pain abdomen, disorientation, psychosis, weakness and lactic acidosis.  Psychosis is due to CN- formation
Centrally acting Drugs  Alpha-Methyl dopa: (Alpha methyl analogue of DOPA) - a prodrug  MOA:Gets converted to alpha methyl Noradrenaline. which acts on alpha-2 receptors in brain and causes inhibition of adrenergic discharge – fall in BP  Only used therapeutically now in Hypertension during pregnancy.  Clonidine: Agonist of central alpha-2 receptor  Not frequently used now because of tolerance and withdrawal hypertension
Some important points Antihypertensives preferred in a patient with coexisting DM:- - ACEI, ARBs, CCBs, Diuretics(less prefererred as compared to other 3 due to hyperglycemia) Antihypertensives preferred in a patient with coexisting asthma/copd – CCBs, ARBs Antihypertensives preferred in a patient with coexisting CAD:- Diuretics, ACEI, ARBs, cardioselective beta blockers Antihypertensives preferred in a patient with coexisting stroke – diuretics, ACEI, ARBs, CCBs
Drugs for Hypertension in pregnancy Drugs found safe for treating HTN in pregnancy - Alpha methyl Dopa - CCBs like Nifedipine (BUT they should be stopped before labour as they weaken uterine contractions) - Cardioselective beta blockers & those with ISA (atenolol, Metoprolol) used only if no other choice available - Prazosin, Clonidine - Hydralazine
Drugs for Hypertension in pregnancy  Drugs to be avoided - ACEI : fetopathic - Diuretics : reduce uteroplacental circulation increased risk of fetal death - Non selective beta blockers : causes low birth weight, neonatal bradycardia and hypoglycemia. - Sodium nitroprusside
Drugs for Hypertensive Emergencies  Hypertensive emergencies : Systolic BP > 220 or diastolic BP > 120 mm Hg with evidence of active end organ damage.  Hypertensive urgency : Systolic BP > 220 or diastolic BP > 120 mm Hg without overt signs of endorgan damage.  Controlled reduction of BP is required to prevent :- 1. Cerebrovascular accident (haemorrhage) 2. Hypertensive encephalopathy 3. Hypertensive acute LVF and pulmonary edema. 4. Unstable angina or MI with raised BP. 5. Dissecting aortic aneurysm. 6. Acute renal failure with raised BP.
Drugs for Hypertensive Emergencies  Oral therapy (not recommended due to problems) - Nifedipine (causes abrupt fall in BP and precipitates MI or stroke, or may be fatal). - Captopril (response is variable and it carries risk of excessive hypotension). - Clonidine (produces sedation and rebound rise in BP on stopping the drug).
Drugs for Hypertensive Emergencies Parenteral therapy - Sodium nitroprusside : DOC for emergencies due to its instantaneous, balanced arteriovenous vasodilatory action & lack of development of tolerance. - GTN : Acts in 2–5 min and has brief titratable action, but is a less potent hypotensive. Its predominant venodilator action makes it particularly suitable for lowering BP in acute LVF, MI, unstable angina. - Hydralazine : is less predictable, and not a first line drug. Used in eclampsia. - Esmolol : Useful when cardiac contractility and work is to be reduced, such as in aortic dissection.
Drugs for Hypertensive Emergencies - Phentolamine : Drug of choice for hyperadrenergic states, e.g. hypertensive episodes in pheochromocytoma, cheese reaction or clonidine withdrawal. - Labetalol : Can be an alternative in pheochromocytoma, etc. Also used to lower BP in MI, unstable angina, eclampsia. - Furosemide : as an adjunct with any of the above drugs if there is volume overload (acute LVF, pulmonary edema, CHF)
Principles of HTN treatment NON PHARMACOLOGICAL MEASURES  Diet  Salt restriction in diet  Aerobic activity or exercise  Weight reduction  Reduce alcohol intake  Mental relaxation
Principles of HTN treatment  Stage I HTN treatment - Start with a single appropriate drug. A B C D rule (A—ACE inhibitor/ARB; B—β blocker; C—CCB, D—diuretic). A & B are preferred in younger patients (<55 years), C & D are preferred in the older (> 55 years) for step 1 treatment. - Initiate therapy at low dose; if needed increase dose moderately. - If only partial response is obtained, add a drug from another complimentary class.(step 2).
Principles of HTN treatment Stage II HTN treatment  Started on a 2 drug combination; one of which usually is a thiazide diuretic.(directly step 2)  Rationale for combination therapy : Since BP is regulated by several interrelated factors, an attempt to block one of them tends to increase compensatory activity of the others. Hence drugs with different mechanisms of action are combined. Eg: Drugs which increase plasma renin activity— diuretics, vasodilators, CCBs, ACE inhibitors may be combined with drugs which lower plasma renin activity—β blockers, clonidine, methyldopa.
Steps of therapy  In step 2 when two drugs are to be used, combine one out of A or B with one out of C or D.  When 2 drugs are inadequate in achieving target BP lowering, 3 drug regimen is prescribed. Both C and D are combined with A or B  Patients who fail to reach the goal BP with 3 drugs are labelled as ‘resistant hypertension’. In them even 4 drug therapy (step 4 )may have to be given to achieve the target BP.
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