Pharmacology of Anti-hypertensive Drugs.

This PPT of antihypertensive drugs, their MOA, and treatment. It also covers classification of antihypertensive drugs including diuretics, ACE inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers, and vasodilators. It provides details on how each drug class lowers blood pressure by reducing peripheral vascular resistance, cardiac output, or sodium retention. Common side effects and advantages are also summarized for each drug class. Guidelines for treating different stages of hypertension are presented, including recommendations to start with monotherapy or 2-drug combinations depending on severity, and to follow an A-B-C-D approach

1. Antihypertensive Drugs Dr. Nikhilkumar S Sakle Assistant Professor, Department of Pharmacology, Y. B. Chavan College of Pharmacy, Aurangabad.

2. Classification of Hypertension Primary (essential) Hypertension Secondary Hypertension Primary Hypertension: - The cause is not known. - Sympathetic and renin-angiotensin systems (RAS) may or may not be overactive.

3. Ranges of blood pressure (in mmHg): Normal blood pressure is below 120 systolic and below 80 diastolic Prehypertension is 120-139 systolic or 80-89 diastolic Stage 1 high blood pressure (hypertension) is 140-159 systolic or 90-99 diastolic Stage 2 high blood pressure (hypertension) is 160 or higher systolic or 100 or higher diastolic Hypertensive crisis (a medical emergency) is when blood pressure is above 180 systolic or above 110 diastolic.

4. CLASSIFICATION Diuretics ACE inhibitors Angiotensin (AT1 receptor) blockers Direct renin inhibitor Calcium channel blockers β Adrenergic blockers β + α Adrenergic blockers α Adrenergic blockers Central sympatholytics Vasodilators

5. Diuretics Thiazides : Hydrochlorothiazide, Chlorthalidone , Indapamide High ceiling : Furosemide , etc. K+ Sparing : Spironolactone , Amiloride

6. Mechanism of antihypertensive action Reduces plasma and e.c.f . volume by 5–15%, and this decreases c.o. Slowly developing reduction in t.p.r . Decrease in intracellular Na+ concentration in the vascular smooth muscle may reduce stiffness of vessel wall.

7. Antihypertensive action of diuretics is lost when salt intake is high. Thiazides are mild antihypertensives , average fall in mean arterial pressure is ~10 mm Hg. The JNC 7 recommends instituting low-dose (12.5–25 mg) thiazide therapy, preferably with added K + sparing diuretic, as a first choice treatment of essential hypertension

8. ACE inhibitors Captopril , Enalapril , Lisinopril , Perindopril , Ramipril , Fosinopril , Trandolapril  etc. First choice drugs in all grades of essential as well as renovascular hypertension. Require relatively lower doses

9. Used alone they control hypertension in ~50% patients, and addition of a diuretic/β blocker extends efficacy to ~90%. Dry persistent cough is the most common side effect requiring discontinuation of ACE inhibitors. They are the most appropriate antihypertensives in patients with diabetes, nephropathy (even nondiabetic ), left ventricular hypertrophy, CHF, angina and post MI cases.

10. Renin-angiotensin system

11. Mechanism of Action

12. ACE Inhibitors MOA

13. Angiotensin receptors and transducer mechanisms Specific Ang II receptors are expressed on the surface of target cells. Two subtypes : AT1 receptors and AT2 receptors. Both subtypes are GPCRs. All major effects of Ang II are mediated by AT1 receptors Ang III also activates AT1 and AT2 receptors (weaker agonist).

14. ACTIONS 1. CVS The most prominent action of Ang II is vasoconstriction 2. Smooth muscles Ang II contracts many visceral smooth muscles in vitro, but in vivo effects are insignificant. 3. Adrenal cortex They enhance synthesis and release of aldosterone which acts on distal tubule in kidney to promote Na+ reabsorption and K+/H+ excretion . 4. Kidney Ang II promotes Na+/H+ exchange in proximal tubule - increased Na+, Cl ¯ and HCO3 ¯ reabsorption . Further, Ang II reduces renal blood flow and GFR , and produces intrarenal haemodynamic effects which normally result in Na+ and water retention .

15. 5. CNS induce drinking behaviour and ADH release . Ang II also increases central sympathetic outflow , which contributes to the pressor response . 6. Peripheral sympathetic structures Ang II enhances sympathetic activity by peripheral action as well. It releases Adr from adrenal medulla , stimulates autonomic ganglia and increases the output of NA from adrenergic nerve endings.

16. Adverse effects Hypotension: Hyperkalaemia : Cough: (Persistent brassy cough) Rashes, urticaria : Angioedema : Dysgeusia : (loss or alteration of taste) Foetopathic : Headache, dizziness, nausea and bowel upset: Granulocytopenia and proteinuria : Acute renal failure:

17. Interactions Diuretics synergise with the hypotensive action of ACE inhibitors by depleting Na+ and raising renin levels. In diuretic treated patients, the starting dose of ACE inhibitors should be low. NSAIDs attenuate the hypotensive action by retaining salt and water. Hyperkalaemia can occur if K+ supplements/ K+ sparing diuretics are given with captopril . Antacids reduce bioavailability of captopril . ACE inhibitors reduce Li+ clearance and predispose to its toxicity.

18. Inhibition of renin-angiotensin system 1. Sympathetic blockers (  blockers, adrenergic neurone blockers, central sympatholytics )— decrease renin release. 2. Direct renin inhibitors (DRIs): block renin action—interfere with generation of Ang I from angiotensinogen (rate limiting step). 3. Angiotensin converting enzyme (ACE) inhibitors—prevent generation of the active principle Ang II. 4. Angiotensin receptor blockers (ARBs)— antagonise the action of Ang II on target cells. 5. Aldosterone antagonists —block mineralocorticoid receptors.

19. Angiotensin (AT1 receptor) blockers Losartan , Candesartan , Irbesartan , Valsartan , Telmisartan . Developed as alternatives to ACE inhibitors ARBs are remarkably free of side effects . Because they do not increase kinin levels , the ACE inhibitor related cough is not encountered.

20. Mechanism of Action

21. Direct renin inhibitor Aliskiren : Mechanism: - Aliskiren binds selectively to the catalytic site of renin and competitively blocks the access of angiotensinogen - Ang I is not produced and the chain of RAS is interrupted.

22. Antihypertensive efficacy of aliskiren is equivalent to that of ACE inhibitors or ARBs. At present, aliskiren is recommended as an alternative antihypertensive drug (for those who do not respond/do not tolerate 1st line drugs) and in combination with others for greater BP lowering.

23. Calcium channel blockers Verapamil , Diltiazem , Nifedipine , Felodipine , Amlodipine , Nitrendipine , Lacidipine , etc

24. They lower BP by decreasing peripheral resistance without compromising c.o. Despite vasodilatation, fluid retention is insignificant. The onset of antihypertensive action is quick. With the availability of long acting preparations. Monotherapy with CCBs is effective in ~ 50% Their action is independent of patient’s renin status. They are preferred in the elderly hypertensive.

25. Advantages of CCBs Do not compromise haemodynamics : no impairment of physical work capacity. No sedation or other CNS effects; cerebral perfusion is maintained. Not contraindicated in asthma, angina (especially variant) and PVD patients: may benefit these conditions. Do not impair renal perfusion. Do not affect male sexual function. No deleterious effect on plasma lipid profile, uric acid level and electrolyte balance. Shown to have no/minimal effect on quality of life. No adverse foetal effects; can be used during pregnancy (but can weaken uterine contractions during labour).

26. β Adrenergic blockers Propranolol , Metoprolol , Atenolol .

27. Do not significantly lower BP in normotensives Used alone they suffice in 30–40% patients—mostly stage I cases ( high blood pressure (hypertension) is 140-159 systolic or 90-99 diastolic ) . β blockers develops over 1–3 weeks- effect is sustained. Antihypertensive action of most β- blockers is maintained over 24 hr with a single daily dose. There are several contraindications to β blockers, including cardiac, pulmonary and peripheral vascular disease.

28. β blockers first choice drugs recommended by JNC 7 and WHO-ISH, especially for relatively young non-obese hypertensives , those prone to psychological stress or those with IHD. β blockers and ACE inhibitors are the most effective drugs for preventing sudden cardiac death in post infarction patients. β blockers are considered less effective and less suitable for the older hypertensive. Rebound hypertension has occurred on sudden discontinuation of β blockers; myocardial ischaemia may be aggravated and angina or MI may be precipitated .

29. β + α Adrenergic blockers Labetalol ( α and β blocker ) Carvedilol ( Nonselective β + weak selective α1 blocker ).

30. It is a combined α and β blocker; reduces t.p.r . and acts faster than pure β blockers. Labetalol has been used i.v . for rapid BP reduction in hyperadrenergic states, cheese reaction, clonidine withdrawal, eclampsia , etc. Restricted to moderately severe hypertension- side effects of both α blocker and β blocker occur with it.

31. α Adrenergic blockers Prazosin , Terazosin , Doxazosin ( α 1 blockers ) Phentolamine , Phenoxybenzamine ( Nonselective α blockers )

32. α - 1 blockers dilates both resistance and capacitance vessels (veins). There is little reflex cardiac stimulation and renin release during long-term therapy. Postural hypotension and fainting may occur in the beginning—called ‘first dose effect’, and with dose increments. An oral dose produces peak fall in BP after 4–5 hours and the effect lasts for nearly 12 hours. Terazosin , Doxazosin are long-acting Non- selectives are reserved for special situations

33. Adverse effects Prazosin is generally well tolerated at low doses. Apart from postural hypotension related symptoms (particularly in the beginning), other side effects are headache, drowsiness, dry mouth, weakness, palpitation, nasal blockade, blurred vision and rash. Ejaculation may be impaired in males: especially with higher doses. Fluid retention attending prazosin monotherapy may precipitate CHF.

34. Central sympatholytics Clonidine , Methyldopa

35. Clonidine is a partial agonist with high affinity and high intrinsic activity at α 2 receptors, especially α 2A subtype in brainstem. This decreases sympathetic out flow → fall in BP and bradycardia . Enhanced vagal tone contributes to bradycardia Plasma NA declines. Clonidine is a moderately potent antihypertensive 3 rd or 4 th choice drug in treatment-development of tolerance.

36. Adverse effects • Sedation, mental depression, disturbed sleep; dryness of mouth, nose and eyes (secretion is decreased by central action), constipation ( antisecretory effect on the intestines). • Impotence, salt and water retention, bradycardia . • Postural hypotension occurs, but is mostly asymptomatic. • Alarming rise in BP, in excess of pretreatment level, with tachycardia, restlessness, anxiety, sweating, headache, nausea and vomiting occur in some patients when doses of clonidine are missed for 1–2 days. The syndrome is very similar to that seen in pheochromocytoma : plasma catecholamine (CA) concentration is increased. This is due to: (a) Sudden removal of central sympathetic inhibition resulting in release of large quantities of stored CAs . (b) Supersensitivity of peripheral adrenergic structures to CAs that develops due to chronic reduction of sympathetic tone during clonidine therapy.

37. Interactions Tricyclic antidepressants and chlorpromazine abolish the antihypertensive action of clonidine , probably by blocking α receptors on which clonidine acts.

38. Other indications 1. Opioid withdrawal: Opioid and α 2 adrenergic systems converge on the same effectors in many systems; both activate the Gi regulatory protein. Clonidine suppresses sympathetic overactivity of opioid withdrawal syndrome and reduces craving to some extent. Clonidine has also facilitated alcohol withdrawal and smoking cessation. 2. Clonidine has analgesic activity. It has been used to substitute morphine for intrathecal /epidural surgical and postoperative analgesia. 3. Clonidine attenuates vasomotor symptoms of menopausal syndrome . 4. Clonidine has been used to control loose motions due to diabetic neuropathy. It may be acting by α 2 receptor mediated enhancement of salt absorption in gut mucosa.

39. Methyldopa : P recursor of dopamine (DA) and NA and first rationally designed antihypertensives . a selective α 2 agonist - decrease efferent sympathetic activity. Decreases t.p.r . more than HR or c.o. In large doses, methyldopa inhibits the enzyme dopa decarboxylase in brain and periphery → reduces NA synthesis and forms the false transmitter methyl-NA in periphery as well. Methyldopa is a moderate efficacy antihypertensive

40. Vasodilators Arteriolar: Hydralazine , Minoxidil , Diazoxide Arteriolar + venous: Sodium nitroprusside

41. TREATMENT OF HYPERTENSION Aim of antihypertensive therapy is to prevent morbidity and mortality. Both systolic and diastolic BP target organ damage (TOD) and complications such as: (a) Cerebrovascular disease, transient ischaemic attacks, stroke, encephalopathy. (b) Hypertensive heart disease—left ventricular hypertrophy, CHF. (c) Coronary artery disease (CAD), angina, myocardial infarction, sudden cardiac death. (d) Arteriosclerotic peripheral vascular disease, retinopathy. (e) Dissecting aneurysm of aorta. (f) Glomerulopathy , renal failure.

42. JNC 7 (2003) has reclassified BP readings 1. Normal <120 and <80 2. Prehypertension 120–139 or 80–89 3. Hypertension Stage I 140–159 or 90–99 4. Hypertension Stage II ≥ 160 or ≥ 100. If the cause of hypertension can be identified (hormonal, vascular abnormality, tumour, renal disease, drugs) all efforts should be made to remove it.

43. Nonpharmacological measures (life style modification— diet , Na+ restriction, aerobic activity or exercise, weight reduction, moderation in alcohol intake, mental relaxation, etc.) should be tried first and concurrently with drugs. A value of < 140 systolic and < 90 mmHg diastolic is considered adequate response, because it clearly reduces morbidity and mortality.

44. JNC7, WHO-ISH & British Hypertension Society* (BHS) 2004, Guidelines Except for stage II hypertension, start with a single most appropriate drug, which for majority of patients is a thiazide . The BHS (2004) recommended following the A B C D rule (A—ACE inhibitor/ARB; B—β blocker; C—CCB, D—diuretic). Initiate therapy at low dose; if needed increase dose moderately. Thiazide dose should be 12.5–25 mg/day hydrochlorothiazide or chlorthalidone .

45. If only partial response is obtained, add a drug from another complimentary class or change to low dose combination. If no response, change to a drug from another class, or low dose combination from other classes. Majority of stage II hypertensives are started on a 2 drug combination; one of which usually is a thiazide diuretic.