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Ishac M2 Cardio Antihypertensives 2010
Ishac M2 Cardio Antihypertensives 2010
5.2.1. Diuretics
A. Thiazides (Frontline, 1st of equals): Hydrochlorothiazide, Metolazone
- early distal tubule, inhibit Na-Cl symporter to inhibit water/Na + reabsorption
- BP by depletion body of Na+ → ↓ blood volume (BV)/plasma volume (PV)
- also some vasodilator action via K+-channel opening
- high clinical value as antihypertensive & combination therapy, inexpensive
- inexpensive, effective, retain effectiveness with elderly
Mechanism of action:
Initial: body store Na+ BV/PV CO BP (TPR, reflex)
Chronic: CO unchanged, TPR, NE [Ca++]i TPR
- hypokalemia, hypercalcemia
- ↑ uric acid retention → gout
- can cause hyperglycemia/glucose intolerance; caution in diabetes
- excreted unchanged; caution with decreased renal function (need >30ml/min)
B. K+-Sparing:
- aldosterone antagonists: Spironolactone, Eplerenone
- epithelial sodium channel blockers: Amiloride, Triamterene
- used as adjunct therapy (usually with thiazide & loop), least potent
- act at late distal & collecting tube, can cause hyperkalemia
- used also in heart failure
Figure 5B.
Adverse effects:
- severe hypotension in hypovolemic patients
- angioedema, hyperkalemia
- dry cough (associated with bradykinin)
- glossitis, oral ulceration, rash
- altered sense of taste (loss of zinc)
- contraindicated in pregnancy (tetrogenic)
- contraindicated in renal artery stenosis
- drug interaction with K-sparing diuretics (K+), NSAIDs ( effect)
Adverse effects:
- constipation (more likely with non-DHPs)
- non-DHPs: cardiac depression, bradycardia, AV block
- non-DHPs are contraindicated with beta-blockers
- mostly DHPs: hypotension, reflex tachycardia, flushing, headache, edema
- hypotension (more likely with DHPs)
- can cause gingival hyperplasia (more likely with nifedipine, 10%)
- non-DHPs contraindicated in CHF, DHPs not recommended
- CYP3A4 inhibitors: grapefruit, verapamil, diltiazem
- CYP3A4 substrates: amlodipine, verapamil
Figure 6. Calcium blockers and nitrates
Vasodilators:
A. Ca channel blockers: Inhibit movement of Ca through L-type channels (ie. Verapamil)
B. Open K-channels: Minoxidil (Rogaine), Diazoxide (acute HT)
C. Direct vasodilator: mainly arterioles, Hydralazine, may inhibit calcium release
D. Coupled to NO/cGMP: dilate veins also, sodium nitroprusside, nitroglycerin, nitrates
E. Dopamine agonist: Fenoldopam (Dopamine-1A subtype) for acute hypertension
F. Alpha-antagonists: Prazosin (alpha1-)
Dr. Ishac Antihypertensive Agents 8
Labetalol, Carvedilol
- mixed alpha and beta-receptor blockers
- uses: hypertension (acute & chronic), CHF Carvedilol)
- beta/alpha = 3:1 (better beta-blockers)
- HR generally unchanged, CO unchanged, TPR BP
5.2.6. Vasodilators
- all vasodilators relax arteriolar smooth muscle, some also relax veins
- various MOA: NO/cGMP, direct relaxation or opening of K-channel
- relax smooth muscle of arterioles TPR reflex HR
- general adverse effects of vasodilators include: headache, nausea,
palpitations, sweating, flushing, fluid retention
- good clinical value (in combinations and hypertensive emergencies)
i. Hydralazine
- direct muscle relaxation (probably involve ↓ Ca++ release)
- dilate arterioles but not veins
- TPR reflex tachycardia
- bioavailability: 25% (slow and rapid acetylators)
Adverse effects: - reflex tachycardia, HR can provoke angina
- headache, nausea, palpitations
- sweating, flushing, fluid retention
- lupus reaction (mainly in slow acetylators)
ii. Minoxidil (Rogaine)
- opens K+-channels in smooth muscle membranes
- stabilization of membrane at its resting potential, contraction less likely.
- dilates arterioles but not veins
Adverse effects: - reflex sympathetic stimulation (use with -blocker)
- fluid retention (usually combo-therapy with diuretic)
- hypertrichosis (OTC, topical application as Rogaine)
iii. Sodium Nitroprusside
- used for acute emergency hypertension and congestive heart failure
- used i.v., (cyanide toxicity via oral administration)
- activation of guanylyl cyclase (direct and/or via release of NO cGMP)
- dilates both arterial ( TPR) and venous vessels
- venous return to the heart is decreased, reflex tachycardia
Adverse effects: - cyanide liberation cyanide toxicity
- reflex HR (arrhytmias), severe hypotension
- methhemoglobinemia, metabolic acidosis
iv. Diazoxide
- used for acute hypertensive crisis
- opens K+-channels - stabilizes membrane potential
- dilates arteriolar vessels TPR reflex HR CO
- inhibits insulin release (via opening K+-channels on beta cell membrane)
- similar structure as thiazide diuretics but no diuretic effect
Dr. Ishac Antihypertensive Agents 11
v. Fenoldopam
- peripheral dopamine-1A agonist TPR
- used for acute hypertensive crisis
6. Treatment of Hypertension
6.1. General considerations
- Age – Beta-blocker and ACEI/ARB efficacy may decrease with age (>70 yrs)
- Race - Beta-blockers and ACEI/ARBs less effective in blacks than whites
- Renin – Patients with ↑renin may respond better with beta-blocker, ACEI/ARBs
- Smokers – Beta-blockers less effective
- Diabetes – ACEI/ARBs improve renal function
- Chronic NSAIDs – ↓response of some agents: ie. diuretics, ACEI, beta-
blockers
- Compliance – important, treat patient not just BP, quality of life
- Lifestyle - important, smoking, overweight, exercise, alcohol intake
2. Ca-Blockers 4. Beta-
blockers
Dr. Ishac Antihypertensive Agents 15
JNC VII: 2003. X: Indicates compelling indication for use; ARB: Angiotensin II Type 1
receptor blocker, CCB: Calcium channel blocker, CAD: Coronary artery disease
Dr. Ishac Antihypertensive Agents 16
Figure 11.
8. References
Basic and Clinical Pharmacology, B.G. Katzung, 11th ed., 2009, pp. 167-189.
Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Hardman and
Limbird, 11th ed., 2005, pp. 789-932.