Cardiovascular Pharmacology - Antihypertensive Agents
Edward JN Ishac. Ph.D.
Professor, Dept. Pharmacology & Toxicology
Office: Smith Bldg, Room 742
Email: eishac@vcu.edu Tel: (804) 828 2127
Objectives:
Demonstrate an understanding of antihypertensive agents with respect to:
1. Subcategories (drug classes) and the specific mechanisms
2. Major pharmacokinetic characteristics of each drug class
3. Primary adverse effects of each drug class
4. Unique characteristics of individual agents
5. Similarities and differences in the hemodynamic effects of the drug classes
6. Differences among populations in response to drug classes
7. Advantages or disadvantages of using combinations from different drug classes
1. Blood Pressure Regulation: Physiology
Frank's formula, BP regulation:
BP = CO x TPR
CO = HR x SV
Baroreceptor reflex: oppose changes in BP, rapid, moment-to-moment BP adjustments
Renal system: Control of Na and H2O balance, responsible for long-term BP control
Figure 1. Regulation of blood pressure
2. Non-drug treatment (Life-style changes)
- ↓salt intake (2.5g/d → 1 g/d)
- ↓alcohol consumption
- ↓stress factors
- ↓calorie intake, weight loss
- ↑physical activity
- stop smoking, ↓caffeine intake
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Antihypertensive Agents
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3. Pharmacotherapy:
1.
3.
5.
7.
9.
11.
Diuretics
Calcium antagonists
Alpha-antagonists
Vasodilators
Renin inhibitor
Reduce NE release
2.
4.
6.
8.
10.
12.
Renin / A-II system (ACEI, ARBs)
Beta-receptor antagonists
Potassium-sparing diuretics
Central acting alpha2-agonists
Dopamine agonist
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:
 body store Na+   BV/PV   CO  BP (TPR, reflex)
CO unchanged,
 TPR,
 NE   [Ca++]i   TPR
Figure 3. Thiazide diuretics, hemodynamic changes
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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
Figure 4: Sites of action of diuretic agents.
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5.2. Renin Angiotensin (AT) - Aldosterone System:
A. Converting Enzyme Inhibitors (ACEI)
Captopril, Lisinopril, Enalapril (prodrug), Benazepril, Fosinopril [-pril]
- frontline class; preferred class with diabetes
- inhibition of ACE to decrease production of angiotensin II from angiotensin I
- Angiotensin II (AT-II): potent vasoconstrictor peptide, ↑ aldosterone production
Figure 5A. Renin Angiotensin Aldosterone System
Figure 5B.
Actions of Angiotensin-Converting Enzyme (ACE) Inhibitors
- decrease activity of sympathetic NS
-  TPR, CO unchanged, HR unchanged
- no reflex  HR, probably due to resetting () of baroreceptor reflex sensitivity
-  aldosterone production   Na/water retention
-  bradykinin level (inhibit metabolism)
- improves intrarenal hemodynamics
- less effective in elderly and Afro-Americans
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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)
- T½: most 2-5 hrs, bepridil 42 hrs, amlodipine 30-50- hrs
Nifedipine:
Verapamil:
Diltiazem:
- mainly arteriole vasodilation, little direct cardiac effect
- commonly cause reflex tachycardia, flushing, peripheral edema
- significant cardiac depression, bradycardia, constipation
- caution in digitalized patients ( digoxin levels)
- actions on cardiac & vascular beds, closer to verapamil action
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Antihypertensive Agents
Cardiovascular & renal actions:
Diltiazem
Heart rate

Myocardial contractility

Nodal conduction

Peripheral resistance

Renal blood flow

Verapamil





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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
5.2.4. Beta-Adrenoceptor Blocking Agents: [-olol], -?lol – unique, A-M – β1
- Frontline class, high clinical value as antihypertensive agents
- delayed hypotensive action
- actions diminished in elderly, Afro-Americans, smokers
- Multiple possible mechanisms of action:
i. CNS effect to decrease sympathetic NS tone
ii. inhibition of renin secretion: beta1-receptors mediate renin release
iii. block cardiac beta1-receptors:  HR   CO   BP
Features of beta-adrenoceptor antagonists
- Selective vs non-selective ie. atenolol (β1-) vs propranolol (no)
- Partial agonist activity (ISA) ie. pindolol (yes) vs propranolol (no)
- Membrane stabilizing action (LA-action) ie. metoprolol (yes) vs atenolol (no)
- Lipid solubility (CNS availability): atenolol (low), propranolol (high)
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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
Figure 7. Propranolol hemodynamic changes
Adverse effects:
- adverse effects are enhanced in elderly
-  myocardial reserve (blockade of cardiac 1-ARs)
- fatigue, dizziness
- asthma (blockade of bronchial beta2-ARs)
- peripheral vascular insufficiency
- diabetes (blockade of hepatic beta2-ARs)
- CNS: nightmares, mental depression, insomnia
- withdrawal syndrome (supersensitivity, rebound HT)
- may worsen Raynand’s syndrome
5.2.5 Alpha-Adrenoceptor Antagonists
Not frontline agents in chronic hypertension. Option for acute hypertensive crisis. Used
for unique circumstances (ie. pheochromocytoma, benign prostrate hypertrophy).
Phenoxybenzamine
- irreversible, non-competitive 1-receptor blocker (x5)
- reflex tachycardia effect, postural hypotension
- therapeutic value in pheochromocytoma treatment (acute & chronic)
Prazosin (most useful class, others Terazosin, Doxazosin) [-azosin]
- selective, competitive alpha1-receptor blocker (x1000)
- no reflex tachycardia (maintain functional alpha2-receptors)
- used to treat benign prostrate hypertrophy, primary HT
Phentolamine (non-selective -receptor blocker)
- reflex tachycardia effect, not used for primary hypertension
Dr. Ishac
Antihypertensive Agents
Adverse effects:
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- postural hypotension (all agents)
- impotence (phenoxybenzamine)
- salt and fluid retention
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
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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.
Figure 8. Consequences of hemodynamic changes to vasodilators
5.2.7. Centrally acting sympatholytic agents
Clonidine, -Methyldopa (prodrug, converted to -methyl-NE)
- good clinical value as antihypertensives, useful but not frontline
- no major metabolic side effects, do not interfere with exercise
- Agonist central 2-receptors   sympathetic outflow from Vasomotor center
- -Methyldopa is preferred agent for hypertension during pregnancy
- clonidine also used in opiate and nicotine withdrawal treatment (↓severity)
Adverse effects:
- dry mouth, drowsiness, lightheadedness, dizziness, impotence
- abrupt withdrawal effect (rebound HT, esp. clonidine)
Dr. Ishac
Antihypertensive Agents
5.2.8. Ganglion-Blocking Agents
- Earliest effective class used to treat hypertension
- competitively block ganglionic nicotinic receptors (SNS, PNS)
- rarely used, clinical value as antihypertensive drug is very low.
a. Trimethaphan
- i.v. injection, rapid effect, short half life (precise titration)
- hypertensive crisis, controlled hypotension, usually during surgery
b. Mecamylamine: orally active
Serious adverse effects (both agents):
sympathoplegia:
- excessive orthostatic hypotension
- sexual dysfunction
parasympathoplegia: - constipation, urinary retention
- glaucoma, blurred vision, dry mouth
5.2.8. Adrenergic Neuron-Blocking Agents
- Antihypertensive clinical value is low, effective but agents of last resort
Guanethidine, (Bretylium used as antidysrhythmic, saved ET)
- inhibits release of NE from nerve terminals → gradual depletion of NE stores
- neuronal uptake (uptake 1) is essential for action (TCAs or cocaine ↓ effect)
Adverse effects:
- marked postural hypotension,
- diarrhea, impaired ejaculation
Reserpine (significant adverse effects)
- Antihypertensive clinical value is low, effective but agent of last resort
- inhibit uptake of NE into storage vesicle (also DA, 5-HT)
- leads to depletion of transmitter stores (peripheral & CNS action)
Adverse effects:
- severe sedation, mental depression, Parkinsonism
- increases gastric acid secretion
Figure 9.
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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.
Front-line agents include:
1. Thiazides (1st)
2. Ca-Blockers
2. ACEI/ARBs
4. Beta-blockers
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6.6. Treatment strategy: Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)
Figure 10. Strategy of hypertension pharmacotherapy
6.7. Hypertension and Compelling Indication for Use:
High Risk Condition
Heart failure
Thiazide
X
Post MI
CAD Risk
X
Diabetes
X
Kidney Disease
Stroke Prevention
X
B-blocker
X
Recommended Drugs
ACEI
ARB
CCB
X
X
XX
X
X
X
K-sparing
X
X
X
XX
X
X
X
X
X
JNC VII: 2003. X: Indicates compelling indication for use; ARB: Angiotensin II Type 1
receptor blocker, CCB: Calcium channel blocker, CAD: Coronary artery disease
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7. Hypertension Pharmacotherapy Summary:
Figure 11.
NOTE: Beta-blockers used in the treatment of congestive heart failure. Contraindication
include: bronchospasm, significant bradycardia, decompensated heart failure and
depression.
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.