Vasodilators and sympathoplegics Flashcards
Calcium channel blockers
Dihydropyridines and non-dihydropyridines
Dihydropyridines (DHPs)
Amlodipine Clevidipine Felodipine Isradipine Nicardipine Nifedipine Nisoldipine
Non-dihydropyridines
Diltiazem
Verapamil
K channel openers
Diazoxide
Minoxidil
Dopamine agonist
Fenoldopam
Nitric oxide modulators
Hydralazine Nitroprusside Organic nitrates: Isosorbide dinitrate Nitroglycerin
B-blockers
Acebutolol Atenolol Betaxolol Bisoprolol Carteolol Carvedilol Emolol Labtalol Metoprolol Nadolol Nebivolol Penbutolol Pindolol Propranolol Timolol
a1-adrenergic antagonists
Doxazosin
Prazosin
Terazosin
Centrally acting a2 agonists
Clonidine
Guanabenz
Guanfacine
Methyldopa
Vasodilators general MOA
- Relax smooth muscle of arterioles, decreasing peripheral vascular resistance and thus arterial blood pressure
- Nitros relax veins too
- Intact sympathetic reflexes prevent orthostatic hypotension and sexual dysfunction
- Work best when used in combo with other antihypertensives to prevent compensatory responses
Dihydropyridines MOA
- Prototypes: nifedipine, amlodipine
- Blocks L-type Ca channels in the vasculature > cardiac channels
Non-dihydropyridines MOA
- Prototypes: verapamil, Diltiazem
- Nonselective block of vascular and cardiac L-type Ca channels
Ca-channel blockers pharmacodynamics
- Block L-type Ca channels (voltage gated) responsible for Ca influx into smooth muscle, cardiac myocytes, and SA and AV nodal cells
- CCBs bind more effectively to open channels and inactivated channels and reduce frequency of opening in response to depolarization
- All CCBs cause vasodilation, decreasing peripheral resistance; arterioles more sensitive than veins - decreased after load and decreased O2 demand by heart
- Reduced contractility throughout the heart and decreases in SA node pacemaker rate and AV node velocity (non-DHPs more cardiac effects than DHPs)
Ca-channel blockers pharmacokinetics
- All orally active but have high first-pass metabolism, high plasma protein binding, extensively metabolized
- nifedipine, clevidipine, verapamil, and diltiazem have IV forms
- Amlodipine has a long half-life (35-50 hr, most others 2-12 hrs)
Ca-channel blocker contraindications
-Generally well-tolerated
- DHPs: excessive hypotension, dizziness, headache, peripheral edema, flushing, tachycardia, rash and gingival hyperplasia.
- -nifedipine: increased risk for MI, stroke, death; short acting should not be used for chronic HTN
- Non-DHPs: Dizziness, headache, peripheral edema, constipation (verapamil), AV block, bradycardia, heart failure, lupus-like rash (diltiazem), pulmonary edema, coughing and wheezing. Contraindicated in individuals taking a B-blocker - verapamil > diltiazem; slow heart rate, can slow AV conduction causing heart block
- Nifedipine does not decrease AV conduction, use in AV conduction abnormalities
- Non-DHP negative ionotropic effect may worsen heart failure; amlodipine or felodipine can be used in angina or HTN
CCBs drug-drug interactions
- Verapamil may increase digoxin blood levels
- DHPs: additive w/ other vasodilators
- Non-DHPs: additive w/ other cardiac depressants and hypotensive drugs
CCB clinical uses
-Long-trem outpatient therapy of HTN, hypertensive emergencies, angina
K channel openers (Diazoxide) MOA
-Opens K channels in smooth muscle
K channel openers (Diazoxide) pharmacodynamics
- Increased K permeability hyper polarizes the smooth muscle membrane, reducing the probability of contraction
- arteriolar dilator resulting in reduced systemic vascular resistance and MAP
K channel openers (Diazoxide) pharmacokinetics
- Relatively long-acting
- High protein binding w/ unknown metabolism
- administered as 3-4 injections 5-15 minutes apart, sometimes IV
K channel openers (Diazoxide) adverse effects and contraindications
- Excessive hypotension resulting in stroke and MI
- Hypotensive effects are greater in those with renal failure (reduced protein binding) and those pre-treated with B-blockers to prevent tachycardia (administer smaller doses)
- Hyperglycemia - renal insufficiency
- Should be avoided in patients with ischemic heart disease and cardiac failure
- diazoxide causes Na and water retention but not normally a problem due to short duration of use
K channel openers (Diazoxide) clinical uses
-Hypertensive emergencies
K channel openers (Minoxidil) MOA
-Active metabolite opens K channels in smooth muscle
K channel openers (Minoxidil) Pharmacodynamics
- Increased K permeability hyper polarizes the smooth muscle membrane, reducing the probability of contraction
- Dilation of arterioles but not veins, more efficacious than hydralazine
K channel openers (Minoxidil) contraindications
- Headache, sweating, hypertrichosis (abnormal hair growth)
- Reflex sympathetic stimulation and Na and fluid retention resulting in tachycardia, palpitations, angina, and edema
- Must be used in combo with B-blocker and loop diuretic to avoid these effects
K channel openers (Minoxidil) clinical uses
- Long-term outpatient therapy of severe HTN
- Topical formulas (Rogaine) for hair growth
K channel openers (Fenoldopam) MOA
Agonist at D1 receptors
K channel openers (Fenoldopam) Pharmacodynamics
Peripheral arteriolar dilator, natriuretic
K channel openers (Fenoldopam) Pharmacokinetics
-Continuous IV infusion due to rapid metabolism and short half life
K channel openers (Fenoldopam) adverse effects and contraindications
- Tachycardia, headache, flushing
- Should be avoided in patients with glaucoma due to increases in intraocular pressure
K channel openers (Fenoldopam) clinical uses
Hypertensive emergencies, peri- and postoperative hypertension
NO modulators (hydralazine) MOA
-Stimulates the release of NO from endothelium resulting in increased cGMP levels
NO modulators (hydralazine) Pharmacodynamics
- Dilation of arterioles but not veins
- Reflex tachycardia
NO modulators (hydralazine) Pharmacokinetics
- Well-absorbed with high first pass metabolism
- Metabolism occurs in part via acetylation, bioavailability varies among individuals
NO modulators (hydralazine) adverse effects and contraindications
- Headache, nausea, anorexia, palpitations, sweating and flushing
- In patients with ischemic heart disease, reflex tachycardia, and sympathetic stimulation, it may provoke angina or ischemic arrhythmias
- peripheral neuropathy or drug fever - rare
NO modulators (hydralazine) clinical uses
- long-term outpatient HTN
- combination with nitrates effective in heart failure
- first line therapy for HTN in pregnancy with methyldopa
- parenteral formulation in HTN emergencies
NO modulators (Na nitroprusside) MOA
-Release NO resulting in increase cGMP levels
NO modulators (Na nitroprusside) pharmacodynamics
- Powerful dilation of arterial and venous vessels, reduces peripheral vascular resistance and venous return
- in absence of heart failure, BP decreases and cardiac output doesn’t change
- When CO is already low due to heart failure, CO often increases due to after load reduction
NO modulators (Na nitroprusside) pharmacokinetics
- Rapid metabolism with rapid onset and short duration
- IV infusion with continuous monitoring of BP
NO modulators (Na nitroprusside) adverse effects
-Excessive hypotension
-Cyanide and thiocyanate are released during metabolism
Cyanide poisoning can occur if infusions administered for several days - metabolic acidosis, arrhythmias, excessive hypotension, death
NO modulators (Na nitroprusside) clinical uses
-hypertensive emergencies, acute decompensated heart failure
Organic nitrates (nitroglycerin) MOA
- Release of NO via enzymatic metabolism
- Relaxes most types of smooth muscle (veins > arteries), no direct effect on cardiac or skeletal muscle
- Increases venous capacity, decrease ventricular preload, pulmonary vascular pressures and heart size reduced
- Decreases platelet aggregation
NO modulators (Na nitroprusside) pharmacokinetics
- High first pass, sublingual route typically used
- Therapeutic levels reached within minutes, last 15-30
- Oral, transdermal, and buccal allow for longer release
- tolerance may occur with continuous exposure; 8 hours between doses to prevent tolerance
NO modulators (Na nitroprusside) adverse effects and contraindications
- Orthostatic HTN, syncope, throbbing headache
- Tolerance (diminished release of NO due to reduced bioactivation; reduced availability of sulfhydryl donors; increased generation of ROS; diminished ability of calcitonin gene-related peptide (CGRP); compensatory responses - tachycardia, increased cardiac contractility, retention of salt and water)
- Contraindicated with increased intracranial pressure
- transdermal patches must be removed before use of defibrillators
NO modulators (Na nitroprusside) drug-drug interactions
-synergistic hypotension with PDE5 inhibitors (sildenafil, tadalafil, vardenafil)
NO modulators (Na nitroprusside) clinical uses
hypertensive emergencies, angina, heart failure
B-blockers facts
- Useful in preventing the reflex tachycardia that results from tx with direct vasodilators in severe HTN
- Reduce mortality after MI and some reduce mortality in pts with heart failure
B-blockers MOA
-non-selective B-blocker but others are more specific
Non-selective, Non-ISA B-blockers
Propranolol, carvedilol
Non-selective, ISA B-blockers
Labetalol
B1 selective, Non-ISA B-blocker
Metoprolol, Atenolol
B-blocker pharmacodynamics
- Non-selective agents that decrease BP by decreasing cardiac output
- May decrease peripheral vascular resistance depending on cardioselectivity and partial agonist activities
- Some exhibit vasodilating activity
- Do not usually cause hypotension in healthy, normotensive individuals
- Blockade of B1 receptors inhibits renin release
- Several B-blockers exhibit local anesthetic action due to blockade of Na channels and resultant membrane stabilization
B-blocker pharmacokinetics
- Except esmolol, all are available as oral preps
- cavedilol, metoprolol, and propranolol available as extended release tablets
- Atenolol, esmolol, labetalol, metoprolol, and propranolol available parenterally
- Wide range of half-lives
- Low to moderate lipid solubility (except propranolol and penbutolol)
- Propranolol and penbutolol cross the BBB
B-blocker adverse effects and contraindications
- Asthma/COPD: blockade of B2 receptors may lead to increase in airway resistance. None of the B1 specific are specific enough to avoid B2 blockade - avoid in asthmatics
- Diabetes: glycogenolysis is partially inhibited after B2 blockade; mask signs of hypoglycemia and delays recovery from insulin-induced hypoglycemia - caution in insulin-dependent DM - benefit outweighs risk after MI
- Most common side effects are bradycardia and fatigue, sexual dysfunction and depression
- Chronic use causes poor lipid profiles (increased VLDL and reduced HDL)
- Sudden withdrawal causes rebound HTN, angina, and possibly MI - up regulation of receptor synthesis
B-blocker drug-drug interactions
Can cause heart block, especially if combined with CCB verapamil or diltiazem which slow conduction
B-blocker clinical uses
- HTN: metoprolol and atenolol are most widely used
- Heart failure: administration may worse acute CHF, even if stable compensated HF, cardiac decompensation if CO is dependent on sympathetic drive; gradual increase in dose may prolong life in CHF: carvedilol, bisoprolol, and metoprolol reduce mortality
- Ischemic heart disease: may reduce frequency of angina episodes, improve exercise tolerance. Timolol, metoprolol, and propranolol prolong survival after MI
- Cardiac arrhythmias: effective in treatment of supra ventricular and ventricular arrhythmias
- Glaucoma: topical drops of timolol, betaxolol, carteolol and others reduce pressure
- B1 selectivity advantageous in pts w/ comorbid asthma, diabetes, or peripheral vascular disease
- Agents w/ partial B2-agonist activity may be advantageous in pts w/ bradyarrhythmias or peripheral vascular resistance
a1-blockers (prazosin) MOA
reversible antagonists at a1 receptors
a1-blockers (prazosin) pharmacodynamics
- Prevent vasoconstriction of both arteries and veins, BP reduced by lowering peripheral vascular resistance
- Relaxes smooth muscle of the prostate
- Retention of salt and water occur when used w/o a diuretic
- Associated w/ no change or improvement (increased HDL) in lipid profiles
a1-blockers (prazosin) adverse effects and contraindications
- Generally well-tolerated
- Orthostatic hypotension, dizziness (1st dose), palpitations, headache, lassitude
- less increase in reflex tachycardia than non-selective alpha adrenergic blockers (alpha2 receptor inhibition of NE release from nerve endings is unaffected)
a1-blockers (prazosin) drug-drug interactions
-most effective when used in combination with other agents (B-blocker and diuretic)
a1-blockers (prazosin) clinical uses
-primarily used in men with concurrent HTN and BPH
a2-agonists (clonidine, methyldopa) MOA
- reduce sympathetic outflow from vasomotor centers in the brainstem allow the centers to retain or increase sensitivity in baroreceptor control
- Agonists at central a2 receptors
a2-agonists (clonidine, methyldopa) Clinical uses
- methyldopa is used for HTN in pregnancy
- clonidine is still commonly used but not the others
Clonidine
-Pharmacodynamics: lowers BP by reducing cardiac output (decreased HR and relaxation of capacitance vessels) and reducing peripheral vascular resistance
- Adverse effects: sedation, dry mouth, depression, sexual dysfunction
- Transdermal prep has less sedation than oral but may cause skin reaction
- Abrupt withdrawal can lead to life-threatening HTN crisis
Methyldopa
- Pharmacodynamics: lowers BP by reducing peripheral vascular resistance, variable reduction in heart rate and cardiac output
- Pharmacokinetics: methyldopa is analog of L-dopa, converted to a-methylnorepinephrine by an enzymatic pathway that directly parallels synthesis of NE from L-dopa
- Adverse effects: sedation, dry mouth, lack of concentration, sexual dysfunction
