Antihypertensive Drugs Flashcards
Drugs Used to Treat Hypertension
Diuretics (reduce blood volume)
Thiazide diuretics, Loop diuretics, Potassium-sparing diuretics
Vasodilators (reduce peripheral resistance)
Inhibitors of angiotensin (ACE inhibitors, ARBs, renin inhibitors), Calcium-channel blockers, Alpha-adrenoceptor antagonists, Direct vasodilators
Cardioinhibitory drugs (reduce heart rate and contractility)
Beta-blockers, Calcium-channel blockers
Centrally acting sympatholytics (reduce systemic vascular resistance & cardiac output)
Central Alpha-2 agonists
Diuretics
Clinical Applications
Thiazide diuretics (eg, hydrochlorothiazide) are the preferred type of diuretic for treating mild-moderate hypertension in patients with normal renal and cardiac function. Thiazides (along with calcium-channel blockers) are a preferred choice of first-line drug in black/elderly patients who may not respond as well to treatment with either ACEI’s or ARB’s.
Loop diuretics (eg, furosemide) are infrequently used for the treatment of mild- moderate hypertension and are usually prescribed to patients who do not respond well to thiazide diuretics. However, they are preferable to thiazides in certain clinical situations such as severe hypertension and hypertension in patients with advanced chronic kidney disease. Current guidelines for management of hypertension in chronic kidney disease recommend replacing thiazide diuretics with loop diuretics once a patient’s GFR falls below 30ml/min/1.73m2.
K+-sparing diuretics (amiloride, triamterene) are less efficacious than thiazide and loop diuretics, and are used primarily in combination with other diuretics to attenuate or correct drug-induced K+ excretion and the resultant hypokalemia.
Aldosterone antagonists (spironolactone, eplerenone) are also K+-sparing diuretics but are more potent antihypertensives than either amiloride or triamterene and are often combined with first-line drugs for this property as well as for their K+-sparing property. This may be because aldosterone excess can contribute to resistant hypertension. Aldosterone antagonists are also very useful in the treatment of secondary hypertension caused by hyperaldosteronism. In addition, spironolactone has recently become part of standard treatment for heart failure.
Mechanism of Action
Acutely, diuretics lower blood pressure by causing diuresis. The reduction in plasma volume and stroke volume associated with diuresis decreases cardiac output and, consequently, blood pressure (both pre- and afterload are decreased by diuretics). However, the decrease in cardiac output stimulates the renin-angiotensin system, which leads to volume retention and an increase in peripheral vascular resistance. Chronically (after 6-8 weeks of treatment), the extracellular fluid volume and plasma volume return to almost pretreatment levels, and peripheral vascular resistance falls below its pretreatment baseline. The reduction in peripheral vascular resistance is responsible for the long-term hypotensive effects. Thiazides lower blood pressure by mobilizing sodium and water from arteriolar walls, which may contribute to the decreased peripheral vascular resistance.
Pharmacokinetics
Thiazide and K+-sparing diuretics have a long duration of action (~24 h) and are especially useful in the treatment of chronic hypertension.
Loop diuretics have a relatively short duration of action (4-6 h) and are much more efficiacous diuretics, thus are less useful for chronic administration.
Adverse Effects
In the treatment of hypertension, the most common adverse effect of diuretics is hypokalemia (except for the K+-sparing diuretics, which can cause hyperkalemia).
Captopril, Enalapril, Lisinopril
Clinical Applications
Angiotensin Converting Enzyme (ACE) Inhibitors
Clinical Applications
Hypertension: ACE inhibitors are first-line agents in the treatment of primary hypertension and hypertension caused by unilateral renal artery stenosis, which causes renin-dependent hypertension owing to the increased release of renin by the kidneys.
Black and/or elderly (>60 y) patients do not respond as well as other races to monotherapy with ACE inhibitors or ARBs (possibly due to the renin-angiotensin system being less active in black and/or elderly patients); the differences however, are eliminated with adequate diuretic dosing. In black and/or elderly patients, a thiazide or calcium channel blocker is preferred as a first-line agent over an ACEI or ARB.
Most current guidelines agree that ACE inhibitors (or ARBs) should be part of initial antihypertensive therapy for patients with hypertension and diabetes or patients with hypertension and chronic kidney disease, as they have been shown to slow the development and progression of the associated nephropathy.
Additionally, current guidelines recommend ACE inhibitors (or ARBs) for the treatment of nonpregnant patients with albuminuria. Treatment of moderate albuminuria with ACEI’s (or ARBs) has been shown to reduce the risk of progression to severe albuminuria.
Heart Failure: ACE inhibitors have proven to be very effective in the treatment of chronic heart failure.
Myocardial Infarction: ACE inhibitors have been shown to be effective in patients following myocardial infarction because they help to reduce deleterious remodeling that occurs post-infarction and are given as a standard of care 24 h after an MI.
Captopril, Enalapril, Lisinopril
Mechanism of Action and Pharmacokinetics
Mechanism of Action
ACE inhibitors block the conversion of angiotensin I to angiotensin II. ACE inhibitors thus reduce angiotensin II mediated vasoconstriction and aldosterone secretion, resulting in a reduction in blood pressure (without eliciting a reflex tachycardia). The attenuation of aldosterone secretion also influences K+ homeostasis. ACE inhibitors cause a small and clinically unimportant rise in serum K+ in patients with normal renal function. However, substantial K+ retention can occur in patients with renal insufficiency.
ACE inhibitors can also cause a small increase in serum creatinine (by as much as 30%), due to decreased vasoconstriction of the efferent arteriole in the kidney. This results in a small decrease in GFR that leads to a small increase in serum creatinine. This is a reversible change in function and is not harmful.
ACE inhibitors also block the degradation of bradykinin (which is mediated by the angiotensin converting enzyme, and is a vasodilator and produces a cough!!!) and stimulate the secretion of other vasodilating substances such as prostaglandin E2 and prostacyclin.
In addition, the action of angiotensin II on the AT1 receptors activates a negative feedback loop resulting in a decrease in the release of renin. In the presence of an ACE inhibitor, this feedback loop is not fully activated thus renin levels will increase along with angiotensin I levels.
ACE inhibitors have a particularly useful role in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function.
Pharmacokinetics
All ACE inhibitors are approved for once-daily dosing for hypertension except captopril, which is usually dosed two or three times daily.
Captopril, Enalapril, Lisinopril
Adverse Effects and Contraindications
Adverse Effects
Hypotension: May occur at onset of therapy, especially in patients who are sodium- or volume-depleted, in heart failure exacerbation, very elderly, or on concurrent vasodilators or diuretics.
Hyperkalemia: Due to the reduction in aldosterone secretion. It is rarely clinically important but can be serious in patients with chronic kidney disease or diabetes and in those also taking ARBs, NSAIDs, potassium supplements, or potassium-sparing diuretics.
Acute Renal Failure: ACEI’s are contraindicated in patients with bilateral renal artery stenosis due to the risk of renal failure. The elevated circulating and intrarenal angiotensin II in this condition constricts the efferent arteriole more than the afferent arteriole within the kidney, which helps to maintain glomerular capillary pressure and filtration. By blocking ACE, ACEI’s remove this constriction and can cause an abrupt fall in GFR. This does not usually occur in unilateral renal artery stenosis because the unaffected kidney can maintain sufficient filtration (and ACEI’s are still recommended as first-line drugs in these patients); however, with bilateral renal artery stenosis it is especially important to ensure that renal function is not compromised.
Dry Cough: Due to the rise in bradykinin levels. Occurs in up to 20% patients.
Angioedema: Occurs in < 1% patients. Drug withdrawal necessary for all patients with angioedema. Thought to be due to the increase in bradykinin levels.
Other Effects: Altered sense of taste, skin rashes, drug fever.
Contraindications
Pregnancy: Due to possible major congenital malformations associated with exposure in the first trimester and serious neonatal problems, including renal failure and death in the infant, from exposure during the second and third trimesters. (First trimester = Cat C; second and third trimesters = Cat D).
Bilateral renal artery stenosis
Hyperkalemia
Losartan and Valsartan Clinical Applications and Mechanism of Action
Angiotensin Receptor Blockers (ARBs)
Clinical Applications
ARBs are used in the treatment of hypertension and heart failure in a similar manner as ACE inhibitors. Both ACE inhibitors and ARBs have the same beneficial effects in patients with left ventricular failure or with diabetic nephropathy.
A combination of an ACEI and ARB is not recommended; each of these drug types is beneficial in patients with kidney disease, but in combination they may actually have adverse effects on kidney function.
They are often used as a good alternative to ACE inhibitors in patients who experience the bradykinin-mediated cough.
Like ACEI’s, they tend to work better in white, Asian and/ or young than in black and/or elderly patients, but, when combined with either calcium channel blockers or diuretics, they become equally effective in all patient groups.
Mechanism of Action
Angiotensin receptor blockers (ARBs) directly block the angiotensin type I receptor that mediate the effects of angiotensin II. Therefore, they block angiotensin II-mediated vasoconstriction and aldosterone secretion. Unlike ACE inhibitors, ARBs do not block the breakdown of bradykinin which contributes both to the vasodilation produced by ACE inhibitors and adverse effects such as the dry cough and angioedema risk.
ARBS have the potential for more complete inhibition of angiotensin II activity as there are enzymes other than ACE capable of generating angiotensin II.
In addition, the action of angiotensin II on the AT1 receptors activates a negative feedback loop resulting in a decrease in the release of renin. In the presence of an ARB, this feedback loop is not fully activated thus renin levels will be expected to increase along with angiotensin I and angiotensin II levels.
Losartan and Valsartan Adverse Effects and Contraindications
Pharmacokinetics
All drugs in this class have similar antihypertensive efficacy.
Adverse Effects
ARBs appear to have the lowest incidence of side effects compared with other antihypertensive agents. The adverse effects are similar to those of ACE inhibitors. However, because they do not affect bradykinin, they do not cause a dry cough.
Adverse effects include:
Hypotension
Hyperkalemia
Acute Renal Failure: Rare, but serious side effect. Bilateral renal artery stenosis or unilateral stenosis of a solitary functioning kidney renders patients dependent on the vasoconstrictive effect of angiotensin II on efferent arterioles, making these patients particularly susceptible to acute renal failure.
Angioedema: Less likely to occur than with ACE inhibitors (no increase in bradykinin levels), but cross-reactivity has been reported.
Contraindications
Pregnancy: Due to possible major congenital malformations associated with exposure in the first trimester and serious neonatal problems, including renal failure and death in the infant, from exposure during the second and third trimesters. (First trimester = Cat C; second and third trimesters = Cat D).
Bilateral renal artery stenosis
Hyperkalemia
Aliskiren
Renin Inhibitors
Clinical Applications
Aliskiren is approved for monotherapy and in combination with other drugs for the treatment of hypertension. At this time, aliskiren should only be used as an alternative therapy (ie, not a first-line drug) because of the lack of long-term studies evaluating CV event reduction.
Adding aliskiren to an ACEI or ARB might increase cardiovascular and renal events in patients with diabetes and should be avoided until more is known.
Mechanism of Action
Aliskiren blocks the renin-angiotensin-aldosterone system at its point of activation, which results in reduced plasma renin activity, vasodilation and a decrease in blood pressure.
Pharmacokinetics
Aliskiren is an orally active nonpeptide drug with a half-life of about 24 hours, and is dosed once daily.
Adverse Effects
Aliskiren, like ACE inhibitors and ARBs, has a relatively low incidence of side effects and is well-tolerated. The incidence of cough is much lower in patients taking aliskiren than those taking ACE inhibitors.
Hypotension
Hyperkalemia
Acute Renal Failure: Rare, but serious side effect. Bilateral renal artery stenosis or unilateral stenosis of a solitary functioning kidney renders patients dependent on the vasoconstrictive effect of angiotensin II on efferent arterioles, making these patients particularly susceptible to acute renal failure.
Angioedema: Is less likely to occur than with ACE inhibitors, but cross-reactivity has been reported.
Other Effects: GI effects (eg, diarrhea)
Contraindications
Pregnancy: Due to possible major congenital malformations associated with exposure in the first trimester and serious neonatal problems, including renal failure and death in the infant, from exposure during the second and third trimesters. (First trimester = Cat C; second and third trimesters = Cat D).
Bilateral renal artery stenosis
Hyperkalemia
What 4 drugs are Calcium Channel Blockers (CCB)?
Verapamil (diphenalkylamine)
Diltiazem (benzothiazepine)
Nifedipine (dihydropyridine)
Amlodipine (dihydropyridine)
Clinical Applications and Mechanism of Action of Calcium Channel Blockers
Clinical Applications
CCBs are used to treat hypertension, angina and arrhythmias.
Alongside thiazide diureteics, the calcium channel blockers are a preferred choice of first-line drug in black and/or elderly patients who may not respond as well to treatment with either ACEIs or ARBs.
The dihydropyridine, but not the nondihydropyridine agents can be safely combined with Beta-blockers due to their cardio-depressant effects.
Mechanism of Action
CCBs block voltage-sensitive calcium channels (L-type) located on vascular smooth muscle, cardiac myocytes and cardiac nodal tissue thereby reducing calcium entry into these cells. As a result CCBs cause vascular smooth muscle relaxation (vasodilation), decreased myocardial force generation and decreased heart rate.
CCBs lower blood pressure by decreasing peripheral vascular resistance. As a consequence, dihydropyridine (only act on vascular smooth muscle) CCBs may evoke a reflex tachycardia.
Factors Affecting the Choice of Calcium Channel Blockers (CCB)
Choice of CCB
Hemodynamic difference among CCBs may influence the choice of a particular agent. The dihydropyridines (nifedipine and amlodipine) are more selective for vascular smooth muscle and have less effect on cardiac muscle than the nondihydropyridines (verapamil and diltiazem). The dihydropyridines are thus more likely to evoke a reflex tachycardia. Verapamil has the greatest depressant effect on the heart and can decrease heart rate and cardiac output.
Dihydropyridines - due to their high selectivity for vascular smooth muscle the dihydropyridines are primarily used for the treatment of hypertension
Verapamil – has effects on both the myocardium and vascular smooth muscle with slightly more selectivity towards the myocardium. It is more commonly used for the treatment of angina and cardiac arrhythmias, but can still be used in the management of hypertension.
Diltiazem – is intermediate between verapamil and the dihydropyridines in its selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, diltiazem is able to reduce arterial pressure without producing the same degree of reflex tachycardia caused by the dihydropyridines. Diltiazem is indicated in the treatment of hypertension, angina and arrhythmias.
Pharmacokinetics, Adverse Effects and Contraindications of CCB’s
PHARMACOKINETICS
Orally administered. Only the sustained-release preparations of the dihydropyridines are approved for the treatment of hypertension due to evidence suggesting an increase in mortality (due to reflex tachycardia) with the use of immediate-release preparations.
ADVERSE EFFECTS - Dihydropyridines
Reflex tachycardia
Peripheral Edema
Other effects: Dizziness, flushing, headache, gingival hyperplasia
ADVERSE EFFECTS – Verapamil and Diltiazem
Cardiac conduction abnormalities: Bradycardia, AV block and heart failure
Other effects: Anorexia, nausea, peripheral edema, and hypotension
Constipation: Verapamil causes constipation in ~7% of patients
CONTRAINDICATIONS
Patients with bradycardia, conduction defects or heart failure should not be given CCBs, especially verapamil and diltiazem.
Doxazosin
Alpha1-Adrenoceptor Antagonists; Prazosin and Doxazosin
Clinical Applications
α1-adrenoceptor antagonists, are used in the treatment of primary hypertension, although their use is not as widespread as other antihypertensive drugs. To be maximally effective, they should usually be combined with a diuretic.
Studies have shown that doxazosin when used as monotherapy increases the risk for developing congestive heart failure. Because of this information all -adrenoceptor antagonists should be reserved as alternative agents for unique situations, such as men with benign prostatic hyperplasia. If used to lower BP, they should only be used in combination with first-line antihypertensive agents.
Non-selective -adrenoceptor antagonists (eg, phenoxybenzamine, phentolamine) are not used in the long-term treatment of hypertension but are indicated for the treatment of hypertensive emergencies due to pheochromocytoma.
Mechanism of Action
Prazosin and doxazosin are all 1-selective adrenoceptor antagonists. By blocking 1 receptors in arterioles and venules these drugs are able to reduce vasoconstriction and peripheral vascular resistance, resulting in a decrease in blood pressure. 1-receptor selectivity allows norepinephrine to exert unopposed negative feedback on its own release via 2 receptors, this results in less reflex tachycardia than the non-selective antagonists (which occurs due to enhanced release of norepinephrine binding to 1- receptors).
Alpha1-receptor antagonists dilate both arteries and veins because both vessel types are innervated by sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the arterial resistance vessels
Pharmacokinetics
Although long-term treatment causes very little postural hypotension, a precipitous drop in standing blood pressure develops in some patients after the first dose. For this reason, the first dose should be small and should be administered at bedtime.
Adverse Effects
Aside from the first dose phenomenon, the reported toxicities of the 1-adrenoceptor antagonists are relatively infrequent and mild.
First dose phenomenon: Characterized by orthostatic hypotension accompanied by transient dizziness or faintness, palpitations, and even syncope within 1-3 h of first dose or after a large dose increase.
Na+ and H20 retention: Can occur with chronic administration. Administer with a diuretic to minimize potential edema.
Other effects: Dizziness, drowsiness, headache, lack of energy, nausea, and palpitations.
Hydralazine and Minoxidil
Clinical Applications
Direct Vasodilators
Clinical Applications
Hydralazine is used in the treatment of moderate-severe hypertension and heart failure. It is not first-line therapy for hypertension as it has a relatively short half-life, which necessitates frequent dosing and also it precipitates a ‘strong’ reflex tachycardic response. Because of the prolonged and unpredictable antihypertensive effects of hydralazine and the inability to effectively titrate its hypotensive effect, it is best avoided in the management of hypertensive crises. Its current use as an antihypertensive is primarily limited to treatment of hypertensive crisis in pregnant women with eclampsia, because it is safe and generally effective for this indication.
Hydralazine also has a role in the management of heart failure because of its ability to reduce afterload and thereby enhance stroke volume and ejection fraction. When used in heart failure, it is given along with a diuretic and often with a nitrodilator.
Minoxidil is used in the management of severe hypertension and also for the treatment of alopecia androgenetica in males and females.
Because these agents often cause fluid retention and reflex tachycardia, they are most effective in reducing blood pressure when combined with diuretics and - blockers. For this reason, they are now usually used only as 4th-line or later additions to treatment regimens for the chronic treatment of hypertension.
Mechanism of Action and Adverse Effects of Hydralazine and Minoxidil
Mechanism of Action
Minoxidil and hydralazine are arterial vasodilators.
Minoxidil is a K+ channel opener that hyperpolarizes vascular smooth muscle cells and thereby attenuates the cellular response to depolarizing stimuli.
Hydralazine is less potent than minoxidil and has an uncertain mechanism of action.
Compensatory activation of baroreceptor reflexes in response to the vasodilation results in a reflex tachycardia as well as an increase in renin release (leading to Na+ and H20 retention).
Pharmacokinetics
Both are orally active. IV hydralazine is indicated when treating severe hypertension due to preeclampsia/eclampsia.
Adverse Effects – Hydralazine
Hypotension
Reflex tachycardia and Na+ & H20 retention: Both tachycardia and edema can be severe. Usually administered with -blocker and thiazide diuretic to combat these effects.
REVERSIBLE LUPUS-LIKE SYNDROME: More common in slow acetylators.
Other effects: Dermatitis, drug fever, peripheral neuropathy, hepatitis, vascular headaches, nausea, flushing
Adverse Effects – Minoxidil
Hypotension
Reflex tachycardia, renin release and Na+ retention effects are more dramatic than with hydralazine: Severe Na+ and H20 retention may precipitate congestive heart failure. Usually administered with a loop diuretic and -blocker to combat these severe effects.
Other effects: Reversible trichosis on face, arms, back and chest.
Beta-Adrenoceptor Antagonists (B-blockers): 5 drugs?
Clinical Applications
CARDIOINHIBITORY DRUGS
Propranolol, Metoprolol, Atenolol, Pindolol, Labetalol
Clinical Applications
B-blockers are used in the treatment of hypertension, angina, myocardial infarction, arrhythmias and heart failure.
Hypertension: B-blockers are now only considered first-line for patients with coronary heart disease, heart failure or post-MI where they have strong clinical outcome benefits. In primary prevention patients, they should only be used as second-line therapy in combination with first-line agents. They also are less effective in reducing blood pressure in black patients than in patients of other ethnicities.
Hypertensive Emergencies: Labetalol is an alternative for the treatment of hypertensive emergencies in patients without second- or third-degree AV block, bronchospastic disease or bradycardia.
Mechanisms of Action, Pharmacodynamics, and Pharmacokinetics of Beta-Adrenergic Antagonists
Mechanism of Action
By antagonizing receptors, -blockers are able to decrease blood pressure by several different mechanisms:
(1) decrease myocardial contractility, heart rate and cardiac output (by blocking cardiac 1 receptors);
(2) reduce renin secretion thus decrease circulating angiotensin II levels (by blocking 1 receptors on juxtaglomerular cells)
There is no reflex tachycardia evoked by -blockers due to their negative inotropic/chronotropic actions.
Pharmacodynamics
Propranolol – a non-selective -blocker
Metoprolol & atenolol – cardioselective -blockers (selective for 1 receptors). Less likely to cause bronchospasm and vasoconstriction and may be safer in patients with asthma, COPD, and diabetes. Most commonly used -blockers in treatment of hypertension.
Pindolol – partial agonist; cardioinhibitory effects appear to be less than with other - blockers thus may be beneficial for use in patients with bradyarrhythmias or peripheral vascular disease. Unfortunately, it does not reduce CV events as well as other - blockers and may increase risk after MI. It is the preferred -blocker for use in pregnancy.
Labetalol - Labetalol is able to block both and receptors. It is substantially more potent as a -antagonist than as a -antagonist. Blood pressure is lowered by a reduction in peripheral vascular resistance (via blockade) without significant alteration in heart rate or cardiac output (as -receptors are also blocked). Labetalol is useful in the treatment of hypertensive emergencies.
Pharmacokinetics
Propranolol – oral admin. Extensive first-pass metabolism.
Metoprolol & atenolol – oral admin. Metoprolol = extensive first-pass metabolism
Pindolol – oral admin.
Labetalol – oral and parenteral admin.
Full antihypertensive effects to all -blockers (except labetalol) may take several weeks to develop.
Adverse Effects and Contraindications of Beta-Adrenergic Antagonists
Adverse Effects
Drug withdrawal: Abrupt cessation of -blocker therapy may produce unstable angina, MI or even death in patients with coronary disease. In patients without heart disease, abrupt discontinuation of -blockers may be associated with tachycardia, sweating, and generalized malaise in addition to increased blood pressure. These effects are likely due to upregulation of -receptors during blockade. For these reasons, it is always important to taper the dose gradually over 1-2 weeks before discontinuation.
Cardiovascular effects: Bradycardia, reduced exercise capacity, heart failure, hypotension, AV block.
Disturb lipid metabolism: Increase serum triglyceride levels and decrease HDL cholesterol levels slightly. Increase is usually transient and not clinically important. Labetalol and pindolol do not affect lipid levels.
Hypoglycemia: Hypoglycemia can occur with -blockade because 2-adrenoceptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic release of glucagon, which work together to increase plasma glucose. Therefore, blocking B2- adrenoceptors lowers plasma glucose. B1-blockers have fewer metabolic side effects in diabetic patients; however, the tachycardia which serves as a warning sign for insulin- induced hypoglycemia may be masked. Therefore, B-blockers should be used cautiously in diabetics.
Bronchoconstriction: Occurs with non-selective blockers due to effects on 2 receptors located on airway smooth muscle.
CNS effects: Reduced sexual function & fatigue
Contraindications
Reactive airway disease (asthma, COPD): Non-selective B-blockers (propranolol) should be avoided.
Patients with sinus bradycardia and partial AV block: Symptoms will be exacerbated by -blocking effects
Clonidine and Methyldopa
CENTRALLY ACTING SYMPATHOLYTICS
Central Alpha- 2 agonists
Clinical Applications
Centrally acting α2-adrenoceptor agonists are used both in the chronic treatment of hypertension and in the treatment of hypertensive crises. However, they are generally not considered first-line therapy because of side effects that are associated with their actions within the brain. Treatment with a clonidine skin patch causes fewer side effects than the oral agent, but the patch is not always available and can be more costly than the tablets.
Methyldopa is the drug of choice for the treatment of pregnancy-induced hypertension.
Mechanism of Action
Blood pressure is lowered by stimulating 2-adrenergic receptors in the brain, which reduces sympathetic outflow from the vasomotor center and increases vagal tone. Stimulation of presynaptic 2-receptors peripherally may also contribute to the reduction in sympathetic tone. Consequently, there may be decreases in heart rate, cardiac output, total peripheral resistance and plasma renin activity.
Clonidine - partial 2 agonist
Methyldopa - converted to alpha-methyldopamine and alpha-methylnorepinephrine. Alpha-methylnorepinephrine is thought to activate the 2-receptors and produce the effects.
Pharmacokinetics
Clonidine – oral admin., also available as transdermal patch.
Methyldopa – oral & parenteral admin.
Adverse Effects
Rebound Hypertension: Abrupt cessation can lead to rebound hypertension, which is though to result from a compensatory increase in norepinephrine release that follows discontinuation of presynaptic -receptor stimulation
Na+ and H20 retention: Can occur with chronic use.
Other effects: Orthostatic hypotension, dizziness and anticholinergic effects occur commonly. Depression, nightmares and vertigo occur more infrequently.
Hemolytic anemia: A Coombs-positive hemolytic anemia occurs in less than 1% of patients receiving methyldopa, although 20% exhibit a positive direct Coombs test without anemia.
Hepatitis: Methyldopa can cause a transient elevation in hepatic transaminases that is clinically unimportant. However, if elevations persist drug should be discontinued.
Which Two Drugs are Used in Pulmonary Hypertension?
Pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries. Two drugs that are used specifically in the treatment of pulmonary hypertension are bosentan and epoprostenol.
Bosentan
Mechanism of Action
Bosentan acts as an antagonist at the endothelin receptors located on vascular endothelium and smooth muscle. Stimulation of these receptors is associated with vasoconstriction thus their blockade results in vasodilation. Although bosentan blocks both the ETA and ETB receptor subtypes it has more affinity for the ETA subtype.
Pharmacokinetics
Metabolized via CYP 2C9 and 3A4 to three primary metabolites; one which contributes 10-20% to bosentan’s pharmacological activity.
Bosentan is also a strong inducer of both CYP2C9 and 3A4.
Adverse Effects
The main side effects associated with bosentan are:
- *Cardiovascular:** edema
- *CNS:** headache
- *Endocrine and metabolic:** spermatogenesis inhibition Respiratory: respiratory tract infection
Contraindications
Pregnancy
Bosentan is a FDA pregnancy category X drug. It is highly teratogenic and it should never be used during pregnancy; patients should be advised to use at least two reliable forms of contraception whilst taking the drug.
Epoprostenol
Used for Pulmonary Hypertension
Mechanism of Action
Epoprostenol is a synthetic form of PGI2 (prostacyclin). It is a strong vasodilator of all vascular beds. In addition, it is a potent endogenous inhibitor of platelet aggregation, and is capable of decreasing thrombogenesis and platelet clumping in the lungs.
Pharmacokinetics
Epoprostenol is given via continuous IV infusion. It is rapidly hydrolysed to two active metabolites. It has a half-life of less than 6 min.
Adverse Effects
The main side effects associated with epoprostenol are:
CV: tachycardia, flushing, hypotension
CNS: headache, anxiety
GI: nausea, vomiting
Neuromuscular & skeletal: arthralgia, jaw pain
Contraindications
Hypersensitivity, chronic use in patients with heart failure due to severe left ventricular systolic dysfunction; and in patients who develop edema during dose initiation.
Drugs Used to Treat Hypertension Emergencies
Parenteral vasodilators
Sodium Nitroprusside, Nitroglycerin, Hydralazine
B-blockers
Labetalol, Esmolol
Dopamine receptor agonists
Fenoldopam
Calcium-channel blockers
Nicardipine
Alpha-blockers
Phentolamine
Potassium-channel opener
Diazoxide
Drug Selection (Hypertensive Emergencies)
Sodium Nitroprusside is the drug of choice for the treatment of hypertensive emergencies. Both nicardipine and fenoldopam are reasonable alternatives.
Sodium Nitroprusside
Clinical Applications
Management of Hypertensive Emergencies Sodium nitroprusside is the drug of choice.
Heart Failure
Controlled Hypotension Sodium nitroprusside is used for controlled hypotension to reduce bleeding during surgery
Mechanism of Action
Sodium nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance. The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme. The result is increased intracellular cGMP, which relaxes vascular smooth muscle. The decrease in peripheral resistance will lead to an increase in cardiac output by decreasing afterload.
Pharmacokinetics
Onset of action: BP reduction < 2min
Duration of action: 1-10 min
Sodium nitroprusside is rapidly broken down to cyanide, which is converted to thiocyanate and excreted slowly in the urine. High doses or kidney or liver failure can result in cyanide and thiocyanate toxicity.
Aqueous solution is sensitive to light and must be made up directly before each administration and covered with opaque foil.
Adverse Effects
Hypotension: Most serious toxicity
Reflex tachycardia: Exerts strong reflex tachycardic effect due to prompt vasodilation.
Other effects: Goose bumps, abdominal cramping, nausea, vomiting, headache, muscle twitching, sweating.
Cyanide toxicity: Rare, and can be treated with sodium thiosulfate infusion, which converts cyanide ions to inactive thiocyanate.
Nitroglycerin
Clinical Applications
Management of Hypertensive Emergencies (nitroglycerin is the drug of choice for hypertensive emergencies in patients with cardiac ischemia or angina, or after cardiac bypass surgery)
Acute Decompensated Heart Failure
Controlled Hypotension
Mechanism of Action
Nitroglycerin forms free radical nitric oxide. In smooth muscle, nitric oxide activates guanylyl cyclase which increases intracellular cGMP leading to dephosphorylation of myosin light chains and smooth muscle relaxation. Nitroglycerin is produces a vasodilator effect on the peripheral veins and arteries with more prominent effects on the veins. Nitroglycerin primarily reduces cardiac oxygen demand by decreasing preload, modestly reducing afterload, dilating coronary arteries and improving collateral flow to ischemic regions.
Pharmacokinetics
Onset of action: BP reduction = 2-5 min
Duration of action: 5-10 min (after infusion)
Adverse Effects
Hypotension: Most serious toxicity
Other effects: Headache, methemoglobinemia, allergic reactions, flushing
Esmolol
Clinical Applications
Management of Hypertensive Emergencies is used particularly for aortic dissection or postoperative hypertension
Mechanism of Action
Competitively blocks B1 receptors
Pharmacokinetics
Rapid acting B-blocker – IV admin
Onset of action: BP reduction = 1-2 min
Duration of action: 10-20 min
Adverse Effects
Hypotension
Other effects: Nausea, thrombophlebitis, painful extravasation
Fenoldopam
Clinical Applications
Management of Hypertensive Emergencies particularly useful for patients with renal failure
Mechanism of Action
Selective agonist at postsynaptic dopamine-1 receptors resulting in arterial vasodilation. Produces hypotensive effect by decreasing peripheral vascular resistance with increased renal blood flow, diuresis and naturesis.
Pharmacokinetics
IV admin
Onset of action: BP reduction = <5 min
Duration of action: 30 min
Adverse Effects
Hypotension
Reflex tachycardia
Other effects: May increase intraocular pressure, dizziness, headache, GI disturbances
Contraindications
Glaucoma
Nicardipine
Clinical Applications
Management of Hypertension
Management of Hypertensive Emergencies
Mechanism of Action
Calcium-channel blocker
Pharmacokinetics
IV admin for the treatment of hypertensive emergencies
Onset of action: BP reduction = 2-10 min
Duration of action: 40-60 min (after infusion)
Adverse Effects
Hypotension
Reflex tachycardia
Other effects: Dizziness, headache
Phentolamine
Clinical Applications
Management of Hypertensive Emergencies. In particular phentolamine is used for the treatment of patients with catecholamine-related emergencies (eg, pheochromocytoma, cocaine and amphetamine toxicity, clonidine withdrawal, and MAO inhibitors drug interactions).
Mechanism of Action
Non-selective Alpha-adrenergic receptor blocker.
Pharmacokinetics
Onset of action: BP reduction = 1-2 min
Duration of action: 10-15 min
Adverse Effects
Hypotension
Reflex tachycardia
Other effects: Chest pain, nasal congestion, arrhythmia
Diazoxide
Clinical Applications
Management of Hypertensive Emergencies (occasionally)
Treatment of hyperglycemia secondary to insulinoma
Mechanism of Action
Prevents vascular smooth muscle contraction by opening potassium channels and stabilizing the membrane potential at the resting level.
Pharmacokinetics
Onset of action: BP reduction = 5 min
Duration of action: 4-12 h
Adverse Effects
Hypotension: can be excessive
Reflex tachycardia
Na+ and H20 retention
Other effects: Inhibition of insulin release
