1. Hypertension Dept. of Pharmacology Faculty of Medicine & Health Sciences AIMST

2. Hypertension-How to block ? (contd.)-Lecture Outline Diuretics Mechanism of Action Thiazide Diuretics Side Effects Calcium Channel Blockers Salient Features Mechanism of Action Therapeutic Uses Adverse Effects

3. Hypertension-How to block ? (contd.)-Lecture Outline(contd.) Angiotensin Converting Enzyme(ACE) Inhibitors Renin Angiotensin Aldosterone System (RAAS)-Role in HT Mechanism of Action Therapeutic Uses Side Effects Angiotensin Receptor Blockers(ARBs) Mechanism of Action

4. Hypertension-How to block ? (contd.)-Lecture Outline(contd.) Treatment of HT in patients with concomitant disease Principles of therapy in HT

5. Diuretics-MOA in Hypertension Initially- Enhances excretion of Na+ and H20, →↓ bl vol →↓ CO →↓ BP Decreased body sodium causes relaxation of vascular smooth muscles ( due to Na+ depletion)=decrease in PVR =decrease in BP Direct vasodilatory effect- by opening K + channels

6. Diuretics-MOA in Hypertension Thiazides (hydrochlorothiazide)- act on early distal convoluted tubule ↓ Na + & Cl - cotransport Loop diuretics (furosemide)- act on loop of henle, ↓ Na + /K + /2Cl - cotransport K + sparing diuretics (spironolactone) acts on late distal convoluted tubule aldosterone antagonist

7. Thiazide Diuretics-Side Effects Hypokalemia Hyponatremia Hypomagnesemia Impaired glucose tolerance Hyperlipidemia Hyperuricemia Allergic reaction, weakness, fatigability

8. Calcium Channel Blockers Verapamil, Diltiazem, Dihydropyridines (Nifedipine, Amlodipine, Felodipine, Isradipine, Nicardipine, Nisoldipine) Block voltage gated L-type & T-type Ca +2 channel → Ca +2 influx into arterial sm. mus cells → dilate arterioles →↓ TPR ↓ BP Different effect on the heart & vessels

9. Calcium Channel Blockers Verapamil more cardioselective, DHP more vascular selective, Diltiazem is in between Elderly pts. respond well but people of African origin are less responsive They have ability to control BP but actually ↑ mortality, mechanism unknown

10. Calcium Channel Blockers- Therapeutic Uses Nifedipine- HT, angina, migraine, cardiomyopathy, Raynaud’s phenomenon Verapamil- HT, angina, migraine, cardiomyopathy, arrhythmias (PSVT & atrial tachycardias) Diltiazem – angina, HT, Raynaud’s phenomenon

11. Calcium Channel Blockers Adverse Effects Nifedipine – Dizziness, flushing, headache, palpitation, tremor, hypotension, skin rash, ankle edema, tachycardia Verapamil/Diltiazem- Bradycardia, hypotension, CHF, heart block, skin rash, constipation

12. ACE Inhibitors and ARB’s ACE Inhibitors Captopril/Enalapril/ Lisinopril / Fosinopril/Perindopril/Ramipril/ Spirapril/Trandolapril/Zofenopril/ Benazepril etc. Angiotensin Receptor Blockers (ARB’s) Losartan/Candesartan/Eprosartan/ Irbesartan/Telmisartan/ Valsartan, etc.

13. Renin-Angiotensin Aldosterone System- Role in HT

14. Bradykinin ACE ( kininase-2) also degrades bradykinin. Hence, ACE I will raise the levels of bradykinin. Bradykinin is a potent vasodilator, hence fall in PVR and fall BP.

15. Angiotensin Converting Enzyme Inhibitors- Therapeutic Uses Hypertension ↓ systemic vascular resistance ↓ systolic/diastolic/mean BP Left Ventricular Systolic Dysfunction Prevents/delays progression of HF ↓ incidence of sudden death/MI ↓ hospitalization ↑ Quality Of Life Unless contraindicated, ACE inhibitors should be given to all pts. with impaired LV systolic function

16. Angiotensin Converting Enzyme Inhibitors- Side Effects Hypotension Dry cough (in ~ 30% patients probably due to local bradykinin generation) Renal damage in occasional patients with preexisting renal vascular disease (although they protect the diabetic kidney) Hyperkalemia (especially when used simultaneously with K + sparing diuretics) Skin rashes Gastrointestinal upset Altered taste sensation (dysgeusia) Angioneurotic edema

17. Angiotensin Converting Enzyme Inhibitors- Side Effects (contd.) ABSOLUTELY CONTRAINDICATED in pregnancy (cause fetal renal damage) Bilateral Renal Artery Stenosis

18. Angiotensin Receptor Blockers Losartan Competitive antagonist of Angiotensin II Type 1 receptor -relaxation of vasuclar smooth muscles, rise in Na+ and water excretion, reduces blood volume….. No effect on bradykinin metabolism Same side effects except cough & angioedema Also contraindicated in pregnancy

19. Treatment of HT in Pts with concomitant Diseases Diseases Prefered Alternative Angina β bl/CCB’s ACEI/diuretics IDDM ACEI/CCB’s - Hyper- ACEI/CCB’s - lipidemia

20. Treatment of HT in Patients with concomitant diseases Diseases Preferred Alternative CHF ACEI/diuretics (avoid verapamil) H/O MI β bl/ACEI’s CCB’s/Diuretics CRF Diuretics/CCB’s β bl/ACEI’s Asthma Diuretics/CCB’s ACEI (avoid βbl)

21. Principles of therapy in HT Right diagnosis & grade of HT Nonpharmacological therapy Pharmacotherapy – 1. Monotherapy vs polytherapy 2. Individualized care approach (Blacks-use diuretics/CCB’s but not β bl, elderly- use diuretics/CCB’s/ACEI’s but not β bl/α bl) 3. HT with co-existing disease

22. Hypertension-How to block ? (contd.)-Lecture Summary Diuretics Mechanism of Action Thiazide Diuretics Side Effects Calcium Channel Blockers Salient Features Mechanism of Action Therapeutic Uses Adverse Effects

23. Hypertension-How to block ? (contd.)-Lecture Summary(contd.) Angiotensin Converting Enzyme(ACE) Inhibitors Renin Angiotensin Aldosterone System (RAAS)-Role in HT Mechanism of Action Therapeutic Uses Side Effects Angiotensin Receptor Blockers(ARBs) Mechanism of Action

24. Hypertension-How to block ? (contd.)-Lecture Summary(contd.) Treatment of HT in patients with concomitant disease Principles of therapy in HT

25. For Further Reading!.. Basic & Clinical Pharmacology by Bertram G. Katzung (7th Edition) (Chapter 11) Modern Pharmacology with Clinical Applications by Charles R Craig & Robert E Stitzel (6th Edition) (Chapter 20) Drugs for the Heart by Lionel H Opie & Bernard J Gersh (6th Edition) (Chapter 7)