Treatment of Hypertension (Drugs)

Classes of antihypertensive drugs:

• Diuretics• Centrally-acting Sympathetic Inhibitors• Peripherally-acting Sympathetic Inhibitors• Vasodilators• Calcium channel Inhibitors• ACE Inhibitors

Diuretics:

Reduction in blood volume via facilitation of sodium excretion is the basicbeneficial response to diuretic administration, usually leading to a significant drop in BP.

For mild - moderate cases, restriction of dietary sodium may do the trick.If not, diuretic therapy alone is often sufficient. In more severe hypertension,other drugs are used (eg. ACE inhibitors) together with diuretics, with the latterhelping to minimize sodium retention that might be triggered by a drop in renalblood pressure (while the ACEIs will block the increased release of renin triggerby the same drop in renal BP)

- Thiazides (eg. hydrochlorothiazide)

• considered most appropriate for mild - moderate hypertensionwith otherwise normal heart and kidney function

• numerous attendant side effects: hypokalemia (corrected using Ksupplements); hyperlipidemia; risk of hyperglycemia (inhibition ofinsulin release)

- Loop Diuretics (eg. furosemide)

• relied on for severe hypertension; congestive heart failure

• K+-sparing Diuretics (eg. spironolactone)useful in congestive heart failure for patients on digitalis

Centrally-acting Sympathetic Inhibitors:

In moderate to severe hypertension, reduction of sympathetic outflow would usually be beneficial, but attendant side effects can be significant, greatly limiting the use of this class of drugs. Drugs in this class fall into two basic subclasses:

vasomotor center-acting and ganglionic blockers

- Methyldopa

• metabolized to methyldopamine and methylnorepinephrine entersadrenergic synaptic vesicles, replacing norepinephrine and acting as a false transmitter (also happens in peripheral adrenergic nerveendings, but, there, the ‘false’ transmitter appears to act as ‘normal’ agonist)

• stimulate alpha-adrenoceptors (mainly alpha2: action blocked byalpha2 antagonists) in the solitary tract nucleus

• adverse effects: marked sedation; also nightmares, depression,vertigo

- Clonidine

• alpha2 agonist will cause transient increase in BP, later converting to a drop in BP owing to action on alpha2 receptors and ‘imidazoline’ receptors located in the rostral ventrolateral medulla to enhance inhibition of sympathetic outflow. (Newer derivatives selective for the ‘imidazoline’ receptor appear to have far few side effects)

• other uses: analgesic; reduce withdrawal symptoms with addictivedrugs; decrease intraocular pressure

• adverse effects: strong sedation; dry mouth; depression

• rapid withdrawal after chronic use can lead to life-threateninghypertensive crisis

Peripherally-acting Sympathetic Inhibitors:

Actually, many of the drugs in this class have actions on both central andperipheral adrenergic systems, but their effects are largely if not completely accounted for by their peripheral action. Most are used for mild-moderate hypertension; some are also used in severe hypertension in addition to powerful vasodilators. These drugs fall into three convenient subclasses: vesicle depletion, alpha-adrenergic receptor antagonists and beta-adrenergic receptor antagonists

- Reserpine

• for mild- moderate hypertension, acts by blocking uptake ofbiogenic amines (DA, NE, E, and 5-HT) into synaptic vesicles largely in peripheral synapses, leading to depletion of theseneurotransmitters loss of NE from sympathetic nerve endings onvessels leads to net vasodilatation (with little postural hypotensionat normal doses)

• central action accounts for most side effects: sedation, depression, parkinsonism

- Selective alpha1 blockers (eg. prasozin; terazosin)

• block alpha1 receptors in arterioles and venules, and causesignificant vasodilatation, with empirically less tachycardia asfound with non-selective blockers or direct-acting vasodilators;some risk of significant postural hypotension

- Beta blockers (eg. metoprolol; propanolol; atenolol; pindolol;)

• major action in decreasing cardiac output and inhibiting reninrelease

metoprolol (Lopressor®), a selective beta1 blocker, with few side effects

atenolol, a relatively selectively beta1 blocker (#1 beta blocker antihypertensive), having few side effects but longer-lasting than metoprolol

propanolol useful in severe hypertension, preventing reflex tachycardia as well and acting in the kidney to inhibit renin secretion; little postural hypotension

Vasodilators:

As a group, useful drugs in this class act by dilating arterioles, reducingafterload. Vasodilatation by itself will, however, cause significantly increased sympathetic outflow to the heart (via baroreceptors and renin release), leading to tachycardia and increased contraction, which may oppose their hypotensive action. Consequently, these drugs are used in combination with beta blockers and diuretics to minimize any compensatory physiological responses.

Different ways of categorizing these drugs exist: route of administration;clinical use; site of action. Orally active drugs (hydralazine and minoxidil) may be useful for long-term treatment, whereas parenteral drugs (nitroprusside,nitroglycerin and diazoxide) are used for hypertensive emergencies. With regard to site of action, there are two subclasses: dilators of arterioles and dilators of both arterioles and venules.

- Hydralazine

• precise mechanism is not known, but claimed to antagonize SR IP3receptors

• primarily dilates arteriolar resistance vessels, causing significantdrop in BP

• strong sympathetic reflex: minimized by co-administration of betablocker

• risk of lupus-like syndrome in 10-20% of patients receiving highdosages

Calcium Channel Inhibitors:

All of these drugs act by blocking voltage-gated calcium channels in (largely) arterioles and in cardiac muscle, resulting in vessel relaxation and decreased heart rate and contractility, the latter minimizing compensatory responses to decreased BP. They include:

• Verapamil (diphenylalkylamine) significant depression of cardiac function

• Diltiazem (benzothiazepines)

• The Dihydropyridines (eg.nicardipine)more effective vasodilators than suppressors of cardiac function

Main use of calcium channel blockers is in monotherapy (where appropriate) for mild-moderate hypertension, as alternatives to diuretics or beta-blockers, particularly in the elderly. Also, quite useful in patients with concomitant angina.

ACE Inhibitors/ Angiotensin receptor antagonists:

Angiotensin-converting enzyme (ACE) inhibitors (eg. captopril) are veryeffective in reducing hypertension caused by renal artery stenosis, renal disease and malignant hypertension (arteriole inflammation), where excessive levels ofrenin are released, causing high levels of angiotensin II, a potent vasoconstrictor and releaser of aldosterone. ACE inhibitors lower circulating angiotensin II and increases bradykinin, a potent vasodilator.

Cardiac output is unaffected in patients with normal heart function, but is significantly increased in individuals with congestive heart failure. Hence, the other major use for ACE inhibitors is for CHF.

Side effects include hyperkalemia, angioedema and dry cough (due to increased bradykinin)

Antagonists of angiotensin receptors (eg. losartan) are potentially moreselective (no effect on bradykinin levels, hence no cough; no angioedema;independent of ACE).