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BP = CO x TPR
CO = HR x SV
Dr. Ishac
Antihypertensive Agents
3. Pharmacotherapy:
1.
3.
5.
7.
9.
11.
Diuretics
Calcium antagonists
Alpha-antagonists
Vasodilators
Renin inhibitor
10.
Reduce NE release
2.
Renin / A-II system (ACEI, ARBs)
4.
Beta-receptor antagonists
6.
Potassium-sparing diuretics
8.
Central acting alpha2-agonists
Dopamine agonist
12.
Ganglionic blockers
4. Drugs which lower blood pressure act through three General Mechanisms:
1. Alter sympathetic activity
2. Relax vascular smooth muscle
3. Alter sodium and water balance
5.1. Diuretics
A. Thiazides (Frontline, 1st of equals): Hydrochlorothiazide, Metolazone
- early distal tubule, inhibit Na-Cl cotransporter 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, effective, retain effectiveness with elderly
Mechanism of action:
Initial:
Chronic:
Dr. Ishac
Antihypertensive Agents
Adverse effects:
- hypokalemia, hypercalcemia
- uric acid retention gout
- can cause hyperglycemia/glucose intolerance; caution in diabetes
- photosensitivity
- 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
C. Loop Diuretics: Generally not used in hypertension pharmacotherapy
- mainly used to decrease edema
Dr. Ishac
Antihypertensive Agents
Figure 5B.
Dr. Ishac
Antihypertensive Agents
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, category D)
- contraindicated in bilateral renal artery stenosis
- drug interaction with K-sparing diuretics (K+), NSAIDs ( effect)
B. Angiotensin II Type 1 Receptor Blockers (ARBs): Losartan, Valsartan, Irbesartan
[-sartan]
- competitive antagonists of Angiotensin II Type I receptors
- Type I receptors mediate: aldosterone, ADH, TPR, sympathetic NS
- Type II receptors mediate: vasodilation (TPR), NO
- use increasing, no generic, used if cannot tolerate ACEI
- actions similar to ACEI but not associated with dry cough (no bradykinin)
- less likely to cause angioedema, glossitis, oral ulceration, rash
- also contraindicated in pregnancy and bilateral renal a. stenosis
- increasing use, most likely will overtake ACEIs with generic availability
C. Renin Inhibitor: Aliskiren
- newest agent, introduced 2005, expensive
- direct renin inhibitor production of angiotensin I
- actions similar to ACEI but not associated with dry cough (no bradykinin)
- less likely to cause angioedema, glossitis, oral ulceration, rash
- adverse effects and contraindications similar to ACEIs/ARBs
- used if cannot tolerate ACEIs or ARBs
- poor bioavailability < 5%, may [furosemide] (MOA unknown)
5.2.3. Calcium Channel Blockers
Non-dihydropyridines (non-DHPs): Verapamil, Diltiazem, Bepridil
Dihydropyridines (DHPs): Nifedipine, Amlodipine, Nicardipine, Felodipine [-dipine]
- important agents, frontline class, oral and generally well absorbed
- bind to L-type calcium channels in cardiac and vascular smooth muscle
- inhibition of calcium influx into cardiac and arterial smooth muscle cells
- only minimal effects on venous capacitance vessels.
- dilate arterioles TPR BP (less verapamil, more nifedipine)
- negative inotropic action on heart (more verapamil, less nifedipine)
- T: most 2-5 hrs, bepridil 42 hrs, amlodipine 30-50- hrs
Nifedipine:
Verapamil:
Diltiazem:
Dr. Ishac
Antihypertensive Agents
Myocardial contractility
Nodal conduction
Peripheral resistance
Verapamil
6
Nifedipine (DHPs)
(reflex)
or (reflex)
(reflex)
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-), phenoxybenzamine (irreversible)
Dr. Ishac
Antihypertensive Agents
Dr. Ishac
Antihypertensive Agents
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
Propranolol: - non-selective -receptor blocker,
- no partial agonist action (no ISA), membrane stabilizing action
Dr. Ishac
Antihypertensive Agents
Adverse effects:
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:
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
10
v. Fenoldopam
- peripheral dopamine-1A agonist TPR
- used for acute hypertensive crisis
vi. Vasodilators used to treat pulmonary arterial hypertension
a. Epoprostenol (Flolan) - prostacyclin
b. Treprostenol (Remodulin) prostacyclin analogue
c. Bosentan (Tracleer) competitive antagonist of endothelin-1
d. Sildenafil (Revatio) inhibit cGMP specific phosphodiesterase type 5 (PDE5)
vii. Reflex compensatory responses
Mediated by baroreceptors and the sympathetic NS and Renin, Angiotensin, Aldosterone
(RAA) systems, these responses include cardiac stimulation and counteract the
hypotensive effects of vasodilation. Use in combination with sympatholytics blocks the
increases in HR, contractility and renin levels. Diuretics are useful in preventing fluid
retention and plasma volume expansion. See figure below.
Dr. Ishac
Antihypertensive Agents
11
Dr. Ishac
Antihypertensive Agents
12
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 some agents: ie. diuretics, ACEI, beta-blockers
- Compliance important, treat patient not just BP, quality of life
- Lifestyle - important, smoking, overweight, exercise, alcohol intake
6.2. Hypertension and Pregnancy:
- HT in pregnancy is among the leading cause of maternal mortality
- about 1% of pregnancies are complicated by chronic HT, 5% by gestational HT
- important: ACEI/ARBs are contraindicated in pregnancy
- agents recommended for use in pregnancy include:
a. Alpha-methyl dopa
b. Nifedipine
c. Beta-blockers (not atenolol, CI) d. Labetalol
e. Prazosin
f. Hydralazine
6.3. Pharmacological Basis for Combination Pharmacotherapy:
Combinations of drugs with diuretic, beta-blocker, ACEI/ARB or CCB are rational:
a. Different mechanisms of action produce additive effect with side effect
b. Alpha receptor mediated functions are avoided to minimize postural HT
c. Beta-blockers counter the reflex cardiac stimulation by vasodilators
d. Thiazides counter the fluid retention by sympatholytics and vasodilators
e. ACEIs/ARBs/K-sparing agents counter hypokalemia by thiazides
f. Fixed combinations availability improves effect, cost & compliance
6.4. Fixed Combination Availability:
a. Thiazide diuretic and Beta-blocker
b. Thiazide diuretic and ACE inhibitor
c. Thiazide diuretic and Ca-blocker
d. Thiazide diuretic and Angiotensin II receptor blocker
e. Thiazide diuretic and K-sparing diuretic
f. ACE inhibitor and Ca-blocker
g. Thiazide diuretic and Sympathoyltic (other than beta-blocker)
- Thiazide and Alpha-methyl dopa
- Thiazide and Clonidine
- Thiazide and Prazosin
- Thiazide and Guanethidine
- Thiazide and Reserpine
6.5.
1. Thiazides (1st)
2. Ca-Blockers
2. ACEI/ARBs
4. Beta-blockers
Dr. Ishac
Antihypertensive Agents
13
6.6. Treatment strategy: Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)
Thiazide
X
Post MI
CAD Risk
Diabetes
Kidney Disease
Stroke Prevention
Recommended Drugs
B-blocker
ACEI
ARB
CCB
X
X
X
XX
K-sparing
X
X
XX
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
14
Figure 11.
8. References
Basic and Clinical Pharmacology, B.G. Katzung, 11th ed., 2009, pp. 167-189.
Goodman and Gilmans The Pharmacological Basis of Therapeutics, Hardman and
Limbird, 11th ed., 2005, pp. 789-932.