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Flashcards in Antihypertensives Deck (22)
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General Goals of Antihypertensives

Antihypertensive drugs act by reducing cardiac output and/or decreasing the peripheral vascular resistance

The main objective of hypertension drug treatment is to attain and maintain goal blood pressure


Regulation of BP

Decrease in BP causes decreased renal blood flow and increased SNS outflow from the CNS to increase BP back to normal

Decreased renal blood flow causes a decreased GFR, increased renin release, increased angiotensin II, and increased aldosterone which all lead to increased Na+ and water retention therefore blood volume and CO output is increased

Increased SNS outflow causes increased systemic vascular resistance, increased venous return, HR, contractility, and CO

Increased vascular resistance via alpha and angiotensin II receptors

Increased venous return due to alpha receptor activation


Arterial BP Equation

Arterial BP = CO * PVR

Peripheral vascular resistance



Thiazide Diuretic Drug

Mechanism of action - inhibits NaCl reabsorption via the Na-Cl channel in early distal tubule of renal nephron

BP decreases due to reduction in blood volume (initially) and reduction in peripheral vascular resistance (after chronic administration; underlying mechanism unclear)
With prolonged treatment plasma volume returns toward normal, but peripheral resistance decreases overall

Low doses are given compared to the high doses in the past to prevent RAAS from being and counteracting the drug


Thiazides Over Time

Thiazides cause Na+ depletion

Initially: decreased blood volume, CO, and BP

Long term: decreased arterial resistance and BP

Counter regulatory mechanisms: increased SNS outflow due to decreased CO and increased RAAS activity work to oppose the diuretic effects


HCT Adverse Effects

Adverse effects - hypokalemia; hyperuricemia; hyperglycemia; weakness, and fatigability; slight hyperlipidemia
Incidence of adverse effects is greatly reduced with the lower doses used today


Calcium Channel Blockers

Nifedipine, verapamil, and diltiazem

Mechanism of action - dilate arteriolar smooth muscle and thus decrease BP (due to decreased peripheral vascular resistance) by inhibiting calcium channel function

Block voltage-dependent L-type calcium channels in heart and vascular smooth muscle (this reduces calcium influx during depolarization)

Some of the meds decrease cardiac contractility and heart rate (thus decreasing cardiac output)


L-type Ca2+ Channels

There are activation or inactivation gates that open up to allow for Ca2+ to come through

Some meds interact with gates and interfere with them opening and closing = verapamil but has effect on heart as well

L-type Ca2+ channels subunits are binding sites for Ca2+ channel blockers and are located in the alpha-1 subunit


Verapamil (Diltiazem)

Decrease SA node automaticity, cardiac contractility, and AV node conduction velocity to a greater degree than nifedipine
Thus, verapamil (and diltiazem) = greater cardiac effects


Nifedipine (and other dihydropyridines)

Are more selective for vascular smooth muscle than verapamil (and diltiazem) and are more potent vasodilators
Thus nifedipine = greater ratio of vascular to cardiac effects (arterioles more sensitive than veins)


Adverse Effects of Ca2+ Blockers

Nifedipine, verapamil, and diltiazem

Adverse effects vary with each specific agent in a manner that correlates with its differential tissue effects

Minor adverse effects include constipation, headache, flushing, and dizziness

Potentially more serious side effects include hypotension, tachycardia, negative inotropy, and AV and SA node depression


Angiotensin Antagonists

Captopril (ACE inhibitor) and losartan (angiotensin II receptor blocker or ARB)


Mechanism of Action: Captopril

Mechanism of action - captopril: inhibition of peptidyl dipeptidase (converting enzyme) to block formation of angiotensin II; increases levels of bradykinin by reducing its degradation; decreased secretion of aldosterone; lowers BP primarily by reducing peripheral vascular resistance

ACE is found on throughout the vasculature not just the lungs
Decreased aldosterone: worried about excess K+ retention when little aldosterone around and get severe hyperkalemia which is dangerous

Angiotensin II is a potent vasoconstrictor
Bradykinin is a potent arteriolar vasodilator (increases NO production); also causes increased production of vasodilator prostaglandins (PGI2 & PGE2)


Mechanism of Action: Losartan

Mechanism of action - losartan: competitive antagonist at AT-1 receptors that bind angiotensin II (thus preventing the effects of angiotensin II)

Other enzymes that can get around the ACE inhibitors
If doesn’t bind to AT1 then can bind to AT2 which lower BP


ACE Inhibitors vs. ARB Targets

ACE inhibitors = inhibit angiotensin I to II and prevents breakdown of bradykinin

ARB: inhibit angiotensin II from its effects of vasoconstriction and aldosterone secretion which leads to increased BP


Adverse Effects of Captopril

Adverse effects - captopril: skin rashes, angioedema; loss of taste (reversible); possible acute renal failure (e.g. in cases of bilateral renal artery stenosis); persistent DRY COUGH; possible hyperkalemia; fetopathic potential

Fetopathic: fetal HTN, lung malformation, and death; cannot give during pregnancy


Detrimental effects of ACE-Inhibitors in Renal Artery Stenosis

During renal artery hypotension, the effects of Ang II on the efferent arteriole predominate so that Ang II increases GFR

Thus, inhibition of Ang II formation may cause acute renal failure in patients with bilateral renal artery stenosis (or in patients with unilateral stenosis who only have a single kidney).

Blood coming in through glomerulus and coming out through efferent arteriole
If blood cannot go through renal artery (stenosis) the control mechanism will enhance angiotensin II to constrict efferent artery to increase GFR; once give ACE inhibitor you knock out angiotensin and the efferent arteriole dilates instead and patient goes into acute renal failure


Adverse Effects of Losartan

Adverse effects - losartan: similar to ACE inhibitors (e.g. hyperkalemia and fetopathic potential) except that cough and angioedema are less of a problem than with ACE inhibitors


Beta Adrenoceptor Blockers

Propranolol (nonselective) and metoprolol (Beta1 selective)

Beta adrenoceptor blocker mechanism of action: competitively blocks responses to catecholamines (e.g. norepinephrine) mediated by beta receptors

Proposed mechanisms of antihypertensive action: reduction in CO, decreased renin release, CNS site of action, decreased peripheral vascular resistance (after chronic administration)
Despite widespread use of beta blockers, the precise mechanism responsible for this important clinical effect remains to be established


Beta Blockers: Acute vs. Chronic Administration

Beta blockers are good anti HTN agents

Acute administration beta 1 blocker = decrease CO
Block beta 2 in skeletal muscle = the baroreceptor response to CO decrease and unopposed alpha receptors you get an increase in alpha receptor dominant effect which increases peripheral vascular resistance because stimulation of alpha receptor gets vasoconstriction

Chronic tx: required a few weeks to cause anti HTN effect; adaptation over time (unknown mechanism)


Proposed Mechanisms for Antihypertensive Affects of Beta Blockers

Most of the proposed mechanisms would occur immediately (acutely), but the BP decrease in response to beta blockers occurs over time (after longer-term drug therapy) in association with a more sustained decrease in the peripheral vascular resistance (PVR)

Acute effects are counter-balanced by compensatory responses and activation of unblocked alpha receptors

Decreased peripheral vascular resistance, HR, contraction, CO, renin release, angiotensin II, aldosterone, Na+, blood volume, etc.
Decreased vascular resistance probably happens due to all the above


Beta Blocker Adverse Effects

Beta adrenoceptor blocker adverse effects (selected)

Bronchoconstriction, bradycardia, impaired cardiac contractility, and depressed A-V node conduction; acute withdrawal syndrome (tachycardia; sudden increase in BP)

Beta 1 selective agents were developed because didn’t want to block the beta 2 receptor and bronchial dilation for asthmatic patients