Antihypertensives Pharmacology PDF

Pharmacology of AntiHypertensives Rekha Yesudas, MPhil, Ph.D. PCOM Pharmacology, 2024 Copyright © 2024, This presentation is intended for students use only. No part of this presentation may be distributed, reproduced or uploaded/po...

Pharmacology of AntiHypertensives Rekha Yesudas, MPhil, Ph.D. PCOM Pharmacology, 2024 Copyright © 2024, This presentation is intended for students use only. No part of this presentation may be distributed, reproduced or uploaded/posted on any Internet websites without the expressed written consent from the author. 1  Learning Objectives Identify examples of drugs in each class of antihypertensive agents. List major antihypertensive drugs & their clinical indications. Explain the mechanism of action of major antihypertensive drugs. Discuss the major pharmacokinetics and drug interactions of antihypertensive drugs. Describe the common and severe adverse effects of commonly used antihypertensive drugs. Summarize the major contraindications of antihypertensive drugs. 2 Renin-Angiotensin-Aldosterone System Regulation of BP, Na & water balance Cardiovascular & renal Angiotensinogen →Angiotensi → Angiotensin homeostasis. n ⇧I II ⇧ AD Reni AC AT1R H n E Aldosteron e  Angiotensin Receptors AT1R subtype is the best elucidated Ang II receptor. G-protein coupled receptor embedded in plasma membrane of Ang II target cells (vascular smooth muscle, renal vasculature, mesangial, adrenal gland and brain cells). ⇡ BP ⇣BP  BP regulation Eg: β-blockers ⇣CO, Thiazide diuretics ⇣peripheral vascular resistance. Fight or flight response 5  Drugs Relevant to Hypertension Diuretics Loop Thiaz K+ ide CA I (intracranial, sparing intraocular) RAAS InhibitorsReni ACE I nI ARB s Ca channel blockers Cardio- Vaso-selective selective Sympatholytics Nitrates Β-blockers ⍺1 blockers, sparing agonists 6  ABCDs of Antihypertensives ACE inhibitors: ‘pril’ Can be 1st choice ARBs: ‘sartan’ Alpha blockers: ‘osin’ Beta blockers: ‘lol’ Ca channel blockers: ‘dipine’ Diuretics, Dilators Can be 1st choice Pregnancy CI: ACE & ARBs. Absolute contraindications. ⍺-Methyldopa, vasodilators or Labetalol, β-B are safe. 7  Multifactorial disease Primary/essential Hypertension (Htn): doesn’t have known cause. ~93% of adult Htn. ~ genetic or environmental factors. Risk factors include smoking, stress, poor diet, obese, family history, sedentary lifestyle etc. Secondary Htn: Caused by another medical condition. Many treatment for primary helps with secondary Htn. Causes may be renovascular or adrenal or thyroid diseases, drug-alcohol induced Htn (steroids, contraceptives), obstructive sleep apnea, tightening of aorta etc. (7%) Whitecoat Htn: Abnormal in doctor’s office, due to anxiety or stress. Masked Htn: Normal at doctor's office. Malignant Htn or Htn emergency: target organ damage - retina, nephron. 8  Htn Emergencies Sudden, life-threatening elevation of BP Acute end organ damage Intravenous vasoactive drips such as labetalol, esmolol, nicardipine, and nitroglycerin are typically effective options Oral medications, such as clonidine and nifedipine, play no role in the immediate management of a hypertensive emergency. 9  Pregnancy Treatment of choice is usually Labetalol. Hydralazine or ⍺–methyldopa can be useful β-blockers & Ca channel blockers are ok. Do not use RAAS inhibitors or Diuretics during pregnancy. CI: ACE I, ARBs 10  Patient with Asthma Treatment of choice is usually: Low dose diuretics ARBs Ca channel blockers CI: β-blockers, αβ-blockers Recommendations: β-blockers and αβ-blockers must not be used as antihypertensive drugs in patients with bronchial asthma or chronic obstructive pulmonary disease. ACE inhibitors are not recommended [not contraindicated either] because they may cause dry cough as an adverse effect and increase airway sensitivity. Ca channel blockers, ARBs, and a low dose of diuretics may be used. 11  Renin inhibitors High-renin hypertension- ~ 15% :prevalent among young males. Blocks the synthesis of all angiotensin peptides. Eg: Aliskiren Blocks the catalytic activity of renin. x ☝️ renin ☝️ aliskiren  Aliskiren I: hypertension MOA: Direct renin inhibitor. Ultimately blocks conversion of Angiotensinogen. PK: combination drugs Eg: Aliskiren+ HydroChloroThiazide High fat meal reduce absorption, AE: GI symptoms CI: pregnancy, ACEI, ARBs 13 I. ACE inhibitors Beneficial in diabetes, heart failure, chronic renal disease, hyperuricemia. 14 Angiotensin Converting Enzyme (ACE) ACE is another central component of RAAS. Secreted by alveolar capillary endothelial cells. Rich in pulmonary circulation. ACE converts the inactive Ang I into Ang II. It is a zinc-metalloenzyme (Thus ACE can be inhibited by metal-chelating agents). ACE also degrades bradykinin required for the synthesis of major vasodilator NO 15  ACE Inhibitors Drugs inhibiting the action of ACE1 To reduce circulating & local levels of Ang II Also decrease aldosterone & ADH secretion. Zinc-containing metalloprotease:’pril’ drugs. carboxypeptidase A & carboxyl group (lisinopril, ramipril etc), Phosphoryl group (fosinopril). I: hypertensive patients with evidence of renal disease (DM, microalbuminuria) Captop ril 👉 x  Capoten® Captopril I: Hypertension (normal/impaired renal function) Monotherapy or combination. MOA: Inhibits the conversion of Ang1 to II Keep vessels dilated. Prevent aldosterone secretion. Maintain safe BP PK: renal elimination. Twice daily administration.Captopril has sulfhydryl group, causes proteinuria, skin rashes, altered taste. Can cause Neutropenia and can worsen proteinuria. 17 ACE Dry cough: AE – Due to elevated bradykinin. Angioedema. (severe, life-threatening) – swelling under the skin or in mucous membranes (lips, tongue, face, larynx, abdomen, or arms and legs) due to fluid leaking from small blood vessels. – 0.1 to 0.7% patients that take ACE inhibitors (but 20-30% of all angioedema presentations to x the Emergency Department). – Bradykinin overload: hinders the degradation of bradykinin and can lead to idiosyncratic angioedema. – Risk high in AA/black population Mnemonics: Pril 18 Lips  ACE inhibitor-induced cough is a dry, nonproductive, hacking cough that usually begins within months of initiating therapy and resolves within 1 to 4 weeks after discontinuing. ACE inhibitor-induced angioedema can occur anytime during therapy but most commonly occurs within the first 3 months of treatment. This adverse reaction is secondary to elevated bradykinin levels by inhibiting ACE, causing vasodilatation and extravasation of plasma into the submucosal tissue, leading to angioedema. 19  Osmitrol® Lisinopril PK: Longer ½ life. Hydrophilic, does not bind to albumin or other proteins. Not broken down by liver. Excreted unchanged in urine. Enalapril Enalaprilat: IV formulation 20  II. ARBs Patient: Hypertension, patient cannot tolerate ACE I 21  Angiotensin Receptor Blockers: MOA Act by blocking Ang II action at the receptor level. x Reduce BP by decreasing systemic vascular resistance. Inhibition of vasoconstriction. Reduced sympathetic NS activity. Reduced extracellular volume (inhibits PCT Na absorption +inhibits aldosterone secretion). ARBs (‘tan’ drugs: losartan, valsartan, candesartan etc) I: patients who cannot tolerate ACEIs. No effect on bradykinin metabolism.  Cozaar® Losartan Most common ARB I: Htn Works well with low dose hydrochlorothiazide. MOA: Angiotensin II Receptor Blocker (ATI receptor blocker) [Angiotensin II binds on to the receptor called AT1 Rr, to contract vessels. By blocking these receptors, losartan relaxes the vessels]. PK: oral, once a day. Extensively metabolized by liver. No dose adjustment in renal insufficiency. AE: upper respiratory tract infection (~8%), dizziness, hyperkalemia (with spironolactone) CI: fetal toxicity- pregnancy 23  Sacubitril-Valsartan 1st agent approved in a new class: Angiotensin receptor neprilysin inhibitor (ARNI). This is instead of ACEI or ARBs. Combine with standard β-blocker or Aldosterone antagonist. Also approved in pediatric patients with heart failure. I: HF patients with reduced ejection fraction (