Antihypertensive Agents I & II: Dr. Panavelil

What are the dihydropyridine type Ca2+ channel blockers?

*Nifedipine*, amlopidine, felopidine, isradipine, nicarpidine. More prominent effects of vasodilation and coronary flow relative to diltiazem and verapamil. Less interactions with digoxin and warfarin. *Vascular selectivity and approved indications* vary widely among the group.

Aliskiren (Tekturna)

*Non-peptide renin inhibitor*. Inhibits formation of angiotensin II by inhibiting renin within the RAAS system. Prevents formation of angiotensin I and II. Do not affect bradykinin in lungs (no cough and angioedema). Adverse: HA, dizziness, GI events, hyperkalemia when used with ACE inhibitor. *Cat D*.

How do α-blockers work to lower blood pressure?

*Sympathoplegic* They antagonize the vasoconstrictor effects of catecholamines and reduce bp by decreasing both venous tone and systemic arterial resistance.

At what anatomic sites do antihypertensive agents work?

1 or more of the following: 1) Arterioles to decrease resistance 2) Venules to increase capacitance 3) Heart 4) Kidneys to decrease blood volume

What are the two classes of drugs that act on the RAAS system>?

1) ACE inhibitors 2) Competitive inhibitor of angiotensin II at its receptors

Which antihypertensive agents can contribute to lassitude (lack of energy)?

1) Alpha-blockers (Prazosin) 2) Peripheral NE depleting agents (guanethidine) 3) Vasodilators

What are the ACE inhibitors covered in lecture?

1) Captopril (Capoten) 2) Enalapril (Vasotec) 3) Lisinopril (Prinivil-Zestril) 4) Benazepril (Lotensin) 5) Fosinopril (Monopril) 6) Moexipril (Univasc) 7) Quinapril (Accupril) 8) Ramipril (Altace) 9) Perdinopril (Aceon, Coversyl)

What are the α2-receptor agonists covered in lecture?

1) Clonidine (Catapres) 2) alpha-methyl DOPA (Aldomet) 3) Guanfacine (Tenex) - CNS active agent 4) Guanabenz (Wytensin) - CNS active agent

What is the selective aldosterone receptor antagonist (SARA) covered in lecture?

1) Eplerenone (Inspra)

What are the vasodilators covered in lecture?

1) Hydralazine 2) Diazoxide (Hyperstat) 3) Nitroprusside (Nipride) 4) Fenoldopam (Corlopam)

Which antihypertensive agents commonly produce sedation?

1) Inhibitors of NE synthesis (alpha-methyl DOPA/Aldomet) 2) Transmitter depleting agents (reserpine) 3) Sympathetic tone inhibitors (clonidine) 4) β-blockers (propranolol)

What are the ARBS covered in lecture?

1) Losartan (Cozaar) 2) Valsartan (Diovan)

What are the α1-receptor blockers covered in lecture?

1) Prazosin (Minipress) 2) Phenoxybenzamine 3) Phentolamine

What are the β-receptor blockers covered in lecture?

1) Propranolol (Inderal) 2) Metoprolol (Lopressor) 3) Atenolol (Tenormin) 4) Nebivolol (Bystolic) 5) Bisoprolol (Zebeta) 6) Pindolol (Visken) 7) Esmolol

What are the nerve terminal blockers covered in lecture?

1) Reserpine (Serpasil) 2) Guanethidine (Ismelin)

What are the diuretics covered in lecture?

1) Thiazide 2) Loop 3) K+ Sparing

What are the ganglionic blockers covered in lecture?

1) Trimethaphan (Arfonad) 2) Mecamylamine (Inversine)

What are the Ca-channel blockers covered in lecture?

1) Verapamil (Isoptin, Calan) 2) Diltiazem (Cardizem) 3) Nifedipine (Procardia)

What are the pharmacokinetics of Ca2+ channel blockers?

3-8 hour 1/2 life after p.o. dose Tid dosing. Sustained release preps available. Adverse: Infrequent constipation, dizziness, HA, fatigue.

How does taking captopril with food affect it's bioavailability?

70%- fasting 30-40% with food

How is HTN defined?

A sustained diastolic bp > than 90 mmHg, accompanied by an elevated systolic bp > 140 mmHg. HTN results from an increased peripheral vascular smooth muscle tone, which leads to increased arteriolar resistance and reduced capacitance of the venous system.

Enalapril

ACE inhibitor Prodding that has to be activated by de-esterification to enalaprilat. Enalaprilat is available in i.v. form for hypertensive emergencies. Lisinopril is the lysine derivative of enalaprilat.

What is malignant hypertension?

Accelerated HTN causing damage to vessels in end organs (heart, kidneys, retina, brain). This is a medical emergency.

What is the MOA of Ca2+ channel blockers?

Act by binding to voltage-dependent Ca2+ channels, preventing the channels from opening upon depolarization. The end result is inhibition of Ca2+ influx across the plasma membrane. Entry of Ca2+ through v.g. channels triggers further release of Ca2+ from sarcoplasmic stores. Blocking this inward movement of Ca2+ relaxes muscles, dilating arterioles. CCBs bind preferentially to the inactivated state of the channel , which occurs when cells are firing repetitively (such as in the AV node), or when cells are depolarized (as in areas damaged by ischemia). Therefore these drugs act on channels in tissues that are depolarized or damaged. *Smooth muscle relaxation.*

Hydralazine (Apresoline)

Acts directly on arteriolar sm to induce relaxation. Decreased peripheral resistance causes reflex tachy and CO (almost always administered with a beta-blocker and diuretic). Adverse: HA, N/V, arrhythmia, angina. *Lupus-like syndrome* with high-dosage (reversible).

What is the renin inhibitor covered in lecture?

Aliskiren (Tekturna)

How are ACE inhibitors eliminated?

All ACE inhibitors, *except Fosinopril and Moexipril* are eliminated via the kidney.

Prazosin (Minipress) Doxazosin (Cardura) Terazosin (Hytrin)

All produce a competitive block of α1 adrenoreceptors. They relax arterial and venous smooth muscle. Cause minimal effects on CO, renal blood flow and GFR, therefore long term tachycardia and increase renin release do not occur. Postural hypotension may occur. Prazosin- mild to mod HTN. Specific for α1 blocking (little effect on α2), therefore no CNS or peripheral actions Doxazosin and Terazosin are similar, but have longer 1/2 lives. Adverse: reflex tachycardia and first dose syncope. concomitant use of beta-blocker may be needed to blunt reflex tachy.

Which Ca2+ channel blockers have the least interactions with digoxin and warfarin?

Amlopidine and nicarpidine.

What is angiotensin III?

Angiotensin II is converted to angiotensin III in the adrenal glands. Angiotensin II and angiotensin III both cause the release of aldosterone.

What are the long-acting ACE inhibitors?

Benazepril, Fosinopril, Moexipril, Quinapril and Ramipril. All are prodrugs that are hydrolyzed to their active form in the liver.

Diltiazem

Benzothiazepine CCB. Effects: Reduces HR, bp, may increase CO, improves myocardial perfusion, reduced LV after load, may reduce coronary vasospasm and ischemia following angioplasty. Uses: *variant angina/Prinzmetal's angina* (relieves coronary artery vasospasm). P.o.--> 1st pass with 40-60% bioavailability 10-35% of absorbed dose is metabolized to deacetyldiltiazem (somewhat cardiac active) Adverse: same as verapamil.

Why are beta blockers contraindicated in pts with asthma?

Beta-blockers such as propranolol have a β2-mediated bronchoconstrictiion effect.

Labetalol and Carvedilol

Both are alpha and beta blockers that are used in hypertensive emergencies.

How is the kidney responsible for long-term blood pressure control?

By controlling the volume of blood. Drugs that lower bp may promote salt and water retention, by diminishing renal perfusion and by increasing the secretion of renin and aldosterone (central acting sympatholytics and vasodilators). Therefore, diuretics, renin-angiotensin suppressors and/or salt restriction are essential for patients with advanced hypertension. Without these precautions, antihypertensive agents can cause edema.

How does angiotensin II contribute to HTN?

By maintaining high vascular resistance in hypertensive states associated with high plasma renin activity, such as in renal arterial stenosis, intrinsic renal disease, and malignant hypertension, as well as essential HTN after treatment with Na+ restriction, diuretics or vasodilators.

What are the adverse effects of β-blockers?

CNS- lethargy, fatigue, insomnia (atenolol has lower CNS effects bc it is water-soluble) General- hypotension, HDL decrease, elevated triglycerides, rebound hypertension and arrhythmias on withdrawal. CONTRA in ashtmatics!

Guanabenz (Wytensin)

Centrally-active α-adrenergic *agonist* similar to guanfacine.

Nifedipine

Dihydropiridine, second generation Ca2+ channel blocker. Has higher affinity for vascular Ca2+ channels than cardiac. Minimal cardiac effects (bc it binds to a different Ca2+ channel site than verapamil and diltiazem). Uses: Prinzmetal's angina (variant), HTN, Raynaud's Short 1/2 life; requires multiple dosing. Rapidly well-absorbed, extensive 1st pass (50-70% bioav). Adverse: peripheral edema, flushing, HA, weakness, syncope, hypotension, palpitations MI has been associated with nifedipine therapy.

How do vasodilators reduce bp?

Dilate blood vessels by acting directly on sooth muscle cells through non-autonomic mechanisms. *Three molecular pathways of vasodilation are 1) NO, 2) opening of K+ channels, leading to hyper polarization, and 3) blockade of Ca+ channels.* Compensatory mechanisms: salt retention and tachycardia.

Which Ca2+ channel blocker is a benzothiazepine?

Diltiazem. Affects cardiac and smooth muscle cells. It has less pronounced cardiac effect than verapamil.

Verapamil

Diphenyl alkyl amine, Ca2+ channel blockers. p.o.--> extensive 1st pass, 20-35% bioavailability. i.v.--> active from 1-60 minutes Active metabolite- norverapamil. Both cross CNS and placenta. Uses: angina, HTN, supraventricular arrhythmias (more effective than digoxin for controlling a. fib), reduction of LV hypertrophy (afterload-reducing) Contra: CHF, AV conduction abnormalities MOA: Least selective CCB. Inhibits influx of Ca2+ across cell membrane. Slows cardiac conduction decreasing HR (neg inotropic) and O2 demand. Interactions: Increases digoxin levels (90% protein bound)

What side effects are common with all antihypertensive agents?

Dizziness, HA, drowsiness, palpitations, drug induced hypotension.

What are the therapeutic uses of Ca2+ channel blockers?

Do not require addition of a diuretic because they have an intrinsic diuretic (Na+) effect. Used for *patients with asthma, DM, angina and vascular disease*. *Produce fewer compensatory responses, therefore they are preferred over direct vasodilators like hydrazine or minoxidil.*

What is a sympatholytic/sympathoplegic?

Drug that reduces the effect of sympathetic nervous system.

What are ISA drugs?

Drugs with *intrinsic sympathomimetic activity*, which is β2 agonist activity. *Pindolol* (Visken) and *Acebutolol* (Sectral) are oral, beta-receptor antagonists that have ISA. Pindolol is the β-blocker with the highest degree of ISA, and nonselective antagonist qualities. The partial agonist potential of pindolol is greater for β2 than β1, a characteristic that render pindolol a "vasodilatory β-blocker".

What are the adverse effects of ACE inhibitors?

Dry cough, rashes, fever, altered taste, hyperkalemia. K+ levels must be monitored. First dose may induce syncope and angioedema. *Fetotoxic (Cat D)*

What is rebound hypertension?

Elevated blood pressure resulting from loss of antihypertensive drug effect.

Trimethaphan (Arfonad)

Ganglionic blocker for ht. crisis and acute aortic dissection. Induces controlled hypotension for neurosurgery. Sympathoplegia and parasympathoplegia side effects.

What are the adrenergic nerve terminal blockers?

Guanadrel, Guanethidine, Reserpine. Lower bp by preventing normal physiologic release of NE from post-ganglionic sympathetic neurons. NOT USED IN US.

What is essential hypertension?

HTN of an unknown cause. Also called primary hypertension.

Esmolol (Brevibloc)

Highly β1 selective i.v. drug for intraoperative and postoperative HTN management. 9 min 1/2 life. Beta-blockade eliminated within 20 minutes after drug discontinuation.

What is the most common cardiovascular disease?

Hypertension. Sustained arterial pressure damaged the blood vessels in the kidneys, heart and brain and leads to increased incidence of renal failure, coronary disease, cardiac failure and stroke.

What is orthostatic hypotension?

Hypotension on assuming an upright position. Also called postural hypotension.

Fenoldopam (Corlopam)

I.v. dopamine DA1 agonist used for actor tx of severe HTN. Dilates renal and mesenteric vascular beds via stimulation of postsynaptic DA1 receptors. Adverse: increase in IOP. In pts with HTN and renal dysfunction, fenoldopam improves renal blood flow and creatinine clearance (whereas nitroprusside, with a similar profile, does not).

Clonidine (Catapres)

Imidazoline, which is an *agonist* that acts on imidazoline/α2 adrenoreceptors in the CNS, lowering neural NE release. Mild to mod HTN that has not responded to diuretics alone. Does not reduce GFR or renal blood flow, and can be used in pts with HTN and renal disease. Major compensatory response in Na+ retention. Sudden discontinuation may cause severe rebound HTN (can give phentolamine). p.o., well-absorbed, excreted by kidney, given in combo with a diuretic. Adverse: sedation, drying of nasal mucosa, rebound HTN, bradycardia aggravation in pts with sinus node dysfunction

What are the pharmacogenetics of ACE inhibitors according to Dr. P?

In black pts, ACE inhibitors should be used in combo with a diuretic.

Where is ACE most active?

In the endothelium of pulmonary vasculature, because of the long length of pulmonary capillaries.

What are the other names for angiotensin converting enzyme (ACE)?

Kininase II or peptidyl dipeptidase

Which Ca2+ channel blockers allows for once daily dosing due to its prolonged duration of action (24 hrs)?

Lercanidipine, a *lipophilic* dihydropyridine. Vascular selectivity.

How do loop diuretics and thiazides differ in reference to Ca2+?

Loop- increase the Ca2+ content of urine Thiazide- decrease the Ca2+ content of urine

What is the MOA of ACE inhibitors?

Lower bp by reducing peripheral vascular resistance without reflex increase in CO, rate or contractility. By reducing angiotensin II levels, ACE inhibitors also decrease secretion of aldosterone, resulting in decreased Na+ and water retention. ACE also has a fxn in inactivation of bradykinin, a potent vasodilator that works via release of NO. Therefore ACE inhibitors, prevent the inactivation of bradykinin, allowing for a vasodilatory effect. ACE inhibitor also work by stimulating the Kallikrein-Kinin system.

Spironolactone

MOA: Aldosterone antagonist that is a K+ sparing diuretic Uses: In combo w/ thiazides. Counteracts Na+ and water retention observed with other antihypertensives. In combo w/ β-blockers and ACE inhibitors. Contra: Pts with inadequate kidney fxn Admin: p.o. Adverse: Electrolyte imbalance

Thiazides

MOA: Initially increase Na+ and water excretion, which causes a decrease in extracellular volume, resulting in decreased CO and renal blood flow. With long term tx, plasma volume approaches normal, but peripheral resistance decreases. Adverse: Increase in blood glucose and cholesterol, reductions in serum K+

Eplerenone (Inspra)

MOA: Selective aldosterone receptor antagonist (SARA). Similar in action to spironolactone at the aldosterone receptor. Has a lower incidence of endocrine related side fx due to reduced affinity for other steroid receptors. Uses: Urinary excretion of Na+ to treat HTN Metabolism: CYP34A Adverse: Hyperkalemia, esp. in renal insufficiency and DM.

What is the most common drug used to treat chronic HTN in pregnant women?

Methyldopa (Aldomet). Can cause fluid retention and tolerance can develop. Detrimental effects on serum lipids. Serum prolactin levels can increase.

Minoxidil (Loniten)

More potent than hydrazine, with longer duration of action. Causes vasodilation or arterioles, but not capacitance of venules. Orally to tx severe to malignant HTN, that is refractory to other drugs. Adverse: Reflex tachy (must give with b-blocker), severe Na+ and water retention (must give with diuretic), volume overload, edema and CHF. *Hypertrichosis (hirsutism)*.

Where are alpha receptors found?

Most blood vessels and in high concentrations in the arterioles of the skin, kidney, nervous system and mucosal surfaces. α1 on post-synaptic membranes; vasoconstrictor effect of NE α2 on pre- and post-synaptic membranes Function via phospholipase C, IP3 and DAG pathway to promote vasoconstriction.

Losartan (Cozaar) and Valsartan (Diovan)

Nanopeptide ARBs that block angiotensin receptors-AT1 subtype in blood vessels and other tissues very selectively. Effects are: 1) Vasodilation 2) Block aldosterone secretion Advantage: Work at the receptor level, making angiotensin II produced by mechanisms other than ACE inactivation in its function (no dry cough side effect, angioedema) *Fetotoxic*

Which Ca2+ channel blocker is more selective for cardiac vessels than peripheral vessels?

Nicarpidine, a dihydropiridine (hint: niCARpidine) Oral and i.v. available. Trade name Cardene.

What CCBs are indicated to treat variant angina, i.e. Prinzmetal's angina?

Nifedipine (dihyropropyridine)--> vascular selective Diltiazem (benzothiazepine)--> cardiac selective

Which Ca2+ channel blocker is used to subarachnoid hemorrhage?

Nimopidine, a dihydropiridine. Because of its selectivity for cerebral arterioles.

Is angiotensin I vasoactive?

No. It is converted to octapeptide angiotensin II by angiotensin-converting enzyme (ACE) in the lungs.

What are the pharmacokinetics of β-blockers?

Orally active. Many undergo 1st pass metabolism. It takes several weeks for their full effects to develop.

Diazoxide (Hyperstat I.V.)

Parenteral, nondiuretic thiazide. Direct acting arteriolar vasodilator. For pts with coronary insufficiency, administered IV with a b-blocker. Used for hypertensive emergencies such as encephalopathy and eclampsia. Adverse: excessive hypotension

What is the baroreceptor reflex?

Primary autonomic mechanism for blood pressure homeostasis. Includes sensory input from carotid sinus to the vasomotor center and output via the parasympathetic and sympathetic motor nerves.

What is stepped care?

Progressive addition of drugs to a regimen, starting with a diuretic and adding in stepwise fashion, a sympatholytic, a vasodilator and then ACE inhibitor.

What is the MOA of beta-adrenergic blocking agents (sympathoplegics)?

Reduce bp by primarily decreasing cardiac output. After a few days their action may include decreasing vascular resistance. May decrease sympathetic outflow from the CNS and inhibit the release of renin from the kidneys, decreasing the formation of angiotensin II and secretion of aldosterone.

How do diuretics lower blood pressure?

Reduction of blood volume and by a direct vascular effect that is not well defined. Diuretics and β-blockers are the 1st line drug therapy for HTN. Low dose diuretic therapy is effective in preventing stroke, MI, CHF and total mortality. *The maximal antihypertensive effect of thiazides is achieved with doses less than those required for maximal diuretic effect.*

Loop diuretics

Relatively ineffective as antihypertensives, but act promptly in pts who have poor renal function. MOA: Cause decreased renal vascular resistance and increased renal blood flow by increasing the Ca2+ content of the urine.

What is the function of renin?

Renin catalyzes the generation of the decapeptide angiotensin I from angiotensinogen (an α2 globulin), which is synthesized in the liver.

What are the adverse effects of verapamil?

Sinus bradycardia, reflex sinus tachycardia, transient asystole, AV block of any degree. May require atropine therapy. Contraindicated in CHF and AV conduction disorders. Hypotension with syncope, dizziness, flushing, lethargy, tinnitus, HA, peripheral edema, constipation (worst of the CCBs), N/V.

What is a false transmitter?

Substances stored in the vesicles and released into the synaptic cleft, but lacking the effect of a true transmitter.

What are central-acting sympatholytics?

Sympathoplegic action is at the level of the brainstem, where they interfere with the tonic output of the CNS vasomotor control centers. Reduction of sympatho-adrenal activity produces arterial and venous vasodilation.

Methyl DOPA (Aldomet)

Synthetic phenyl alanine derivative. *Prodrug for alpha methyl NE.* α2-agonist, reducing sympathoadrenal activity. Reduced peripheral resistance and bp. Can use in pts with renal insufficiency. Adverse: drowsiness, sedation, hemolytic anemia.

What is reflex tachycardia?

Tachycardia resulting from lowering of blood pressure, mediated by the baroreceptor reflex. A homeostatic measure.

What are the therapeutic uses of β-blockers?

They are not the 1st line agents for HTN unless pts have angina, HF or prior cardiac incidents. Useful in treating conditions that co-exist with HTN such as tachyarrythmia, MI, angina and migraine headache. Used as ophthalmic perps for ocular HTN. More effective in the young than the elderly. Note: Panavelil states the β-blockers are more effective in white pts than black pts, but there is significant research to discredit this.

What are the therapeutic uses of ACE inhibitors?

Used for HTN, CHF, renal syndrome such as diabetic nephropathy and scleroderma. They do not change CO or HR. Unlike direct vasodilators, they do not have reflex sympathetic activation, therefore they can be safely used in ischemic heart disease. Most effective in conditions associated with high plasma renin activity. Use in DM- diminish proteinuria and stabilize renal fxn in pts, even in the absence of lowered bp. Improve renal dynamics by decreasing arteriolar resistance and reducing intraglomerular capillary pressure.

Sodium Nitroprusside

Used in controlled IV infusions for treatment of hypertensive emergencies. Arteriolar and venous dilation. Metabolized rapidly (needs continuous infusion). Adverse: hypotension by overdose. Metabolism--> cyanide (tx with sodium thiosulfate-->thiocyanate) *Oral nitroprusside is poisonous!*

What is end organ damage?

Vascular damage in the heart, kidney, retina or brain. HTN is usually the cause.

What is the effect of angiotensin II?

Vasoconstrictive and neurohormonal effects, such as enhancing the sympathetic nervous system. It causes renal salt and water retention by direct internal actions and by stimulating the adrenal gland to release aldosterone.

What are the antihypertensive agents of choice for pts with compromised renal function?

Vasodilators, bc they keep renal perfusion most nearly adequate after lowering bp.

Why is verapamil not used in pts with CHF?

Verapamil has negative inotropic effects.

What is the least selective of the Ca2+ channel blockers?

Verapamil, a diphenyl alkyl amine. It has significant effects of cardiac and vascular smooth muscle cells. Used to tx tachyarrhythmias, angina and migraine.

When are ACE inhibitors recommended?

When diuretics or α-blockers are contraindicated or ineffective.

What causes the release of renin from the kidneys?

When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the prorenin already present in the blood into renin and secrete it directly into the circulation.

Guanfacine (Tenex)

p.o. α2-adrenergic *agonist*. Produces decrease in sympathetic outflow, resulting in reduction in peripheral vascular resistance, HR, and bp. More selective for α2 than clonidine, longer-acting and less rebound HTN. Reduces LV hypertrophy. Neutral effects of glucose tolerance. *Sexual dysfunction is main problem*.

Which beta blockers have β1+ β2 + α1 receptor activity?

β1+ β2 + α1 Labetolol (Normodyne, Trandate)- α1 effect > β effect Carvedilol (Coreg)- β effect > α1 effect

Which beta blockers have equal affinity for β1 and β2?

β1= β2 Propanolol (Inderal) Nadolol (Corgard) Penbutolol (Levatol) Pindolol (Visken) Timolol (Blocadren)

Which beta blockers have a much greater affinity for β1 than β2?

β1>>> β2 Metoprolol (Toprol) Acebutolol (Sectral) Atenolol (Tenormin) Betaxolol (Kerlone) Esmolol (Brevibloc) Nebivolol (Bystolic)