Block 3: vasodilators
Terms
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- Name three vasodilators
-
hydralazine
minoxidil
sodium nitroprusside - name an alpha1 blocker
- prazosin
- name two adrenergic inhibitors
-
guanethidine
reserpine - name two alpha2 agonists
-
methyldopa
clonidine - name a beta-adrenergic antagonist
- propranolol
- name two calcium channel blockers
-
amlodipine
verapamil - What is the most common form of hypertension
- essential
- a 5-6 mmHg decrease in diastolic pressure reduces the probability of strokes by...
- 35-40%
- BP =
- CO x TPR
- CO =
- HR x SV
- what does hydralazine do
-
RELAXES ARTERIAL SMOOTH MUSCLE
direct relaxation of arterial vascular smooth muscle with little effect on venous and capacitance vessels - what is a serious adverse effect of hydralazine
- baroreceptor reflex mediated stimulation of the sympathetic nervous system evoked by the vasodilation and decreased BP -> inc heart rate, contractility, plasma renin and fluid retention
- what can the increased contractility and oxygen demand of the heart in response to the baroreceptor reflex of hydralazine cause
- cardiac ischemia --> CONTRAINDICATED in patients with CAD and patients over 40
- What is given to minimize the adverse effects of hydralazine
- sympatholytic agents
- when is hydralazine most often used
- oral antihypertensive during pregnancy
- what does minoxidil do?
- nothing, first it has to be metabolized to minoxidil sulfate
- what does minoxidil sulfate do
- activates the ATP-modulated potassium channel in ARTERIOLE smooth muscle --> hyperpolarization and relaxation with little effect on venous and capacitance vessels
- what is an adverse effect of minoxidil
- reflex barorecept increase in heart rate, contractility, plasma renin and fluid retention which counteracts the antihypertensive effect of minoxidil
- as with hydralazine, what can the increased contractility and oxygen demand in the heart after minoxidil administration lead to
- cardiac ischemia --> CONTRAINDICATED in patients with CAD and ventricular hypertrophy
- what is coadministered with minoxidil to minimize adverse effects
- sympatholytic agents (beta antagonists)
- What occurs with topical minoxidil treatment
-
hair growth --> Rogaine
**can still have measurable cardiovascular effects in some people - what does sodium nitroprusside do?
- nothing, it has to be activated to nitric oxide
- what does nitric oxide do
- activates guanylate cyclase-> cGMP -> activates GMP dependent myosin light chain phosphatase -> dephosphorylates myosin light chain -> decreased contractile state of smooth muscle -> vasodilation in ARTERIOLES and VENULES
- why must sodium nitroprusside be given by continuous IV infusion
- it is unstable and decomposes when exposed to light
- what does prazosin do
- alpha blocker - reduces arterial resistance and venous capacitance by inhibiting the vasoconstriction induced by endogenous catecholamines
- what is the major adverse effect of alpha blockers like prazosin
-
first dose phenomenon = orthostatic hypotension in ~50% of patients
- most likely to occur if patients are taking beta antagonists or diuretics - are alpha blockers like prazosin typically effective as a sole treatment for hypertension
- no- they typically evoke Na and water retention
- what does guanethidine do
- inhibits adrenergic function- inhibits PERIPHERAL postganglionic adrenergic neurons -> concentrated within the neurosecretory vesicles where it replaces and depletes the active transmitter norepinephrine
- what are the adverse effects of guanethidine due to
- sympathetic dysfunction- postural hypotension, sexual dysfunction, diarrhea
- what does reserpine do
- inhibits adrenergic function- binds to storage vesicles in central and peripheral adrenergic neurons, interferes with a transmitter uptake system and renders vesicles dysfunctional -> nerve endings lose their ability to concentrate and store norepi and dopamine
- what are adverse effects of reserpine
- sedation, and inability to concentrate and severe depression
- what does methyldopa do
- central sympatholytic agent (alpha 2 agonist)- acts centrally to reduce sympathetic activity by depleting neuronal stores of norepi
- what is the metabolism of methyldopa
- converted by adrenergic neurons -> alpha-methyl-dopamine -> alpha-methyl-norepinephrine -> substituted for norepi in secretory vesicle
- when is methyldopa often used
- as an oral antihypertensive during pregnancy
- what does clonidine do
- alpha 2 agonist that reduces the activity of neurons in the brainstem responsible for generating and maintaining sympathetic activity
- what happens in clonidine overdose
- can activate alpha 2 receptors on vascular smooth muscle cells causing vasoconstriction
- name some adverse effects of methyldopa and clonidine
- dizziness, reduced libido, sedation and depression
- what can sudden withdrawal of alpha 2 agonists cause
- withdrawal syndrome with blood pressure rising to levels above those that were present prior to treatment
- how do calcium channel blockers work
- block Ca influx through voltage gated calcium channels in arterial smooth muscle -> prevents Ca from binding calmodulin ->prevents myosin light chain kinase from phosphorylating myosin light chain -> prevents interactions between myosin and actin -> DECREASING vascular resistance and BP
- do calcium channel blockers work on venous smooth muscle
- no, only arterioles
- name two dihydropyridine calcium channel blockers
-
nifedipine
amlodipine - name a non-dihydropyridine calcium channel blocker
- verapamil
- how do dihydropyridine calcium channel blockers differ from non-dihydropyridine calcium channel blockers
- nifedipine and amlodipine cause baroreceptor reflex increase in sympathetic activity and tachycardia; verapamil reduces BP without evoking tachycardia due to an additional direct negative chronotropic effect
- What is a consequence of the direct arteriole vasodilation of calcium channel blockers
- they may increase venous return -> CONTRAINDICATED in patients with impaired cardiac function such as ventricular hypertrophy, ischemic heart disease, or CAD
- What has nifedipine actually been shown to do
- increase the risk of ischemic heart disease
- in what patient population can long acting calcium channel blockers be well tolerated
- patients with angina and arrhythmia; can be effective monotherapy in low-renin populations (elderly and African-American populations)
- name adverse effects of calcium channel blockers
-
cardiac depression
cardiac arrest
bradycardia
AV block
congestive heart failure -
Nifedipine:
Coronary vasodilation...
peripheral vasodilation...
HR...
Contractility...
Rate of recovery of Ca channels...
AV conduction... -
Coronary vasodilation...++++
peripheral vasodilation...++++
HR...REFLEX INCREASE
Contractility...REFLEX INC
Rate of recovery of Ca channels...NO CHANGE
AV conduction...NO CHANGE -
verapamil:
Coronary vasodilation...
peripheral vasodilation...
HR...
Contractility...
Rate of recovery of Ca channels...
AV conduction... -
Coronary vasodilation...++
peripheral vasodilation...++
HR...DECREASE
Contractility...DECREASE
Rate of recovery of Ca channels...DECREASE
AV conduction...SLOWS - what does propranolol do
- a beta adrenergic antagonist- reduces myocardial contractility and cardiac output by blocking any endogenous sympathetic beta1 stimulation of the cardiac SA node and ventricular muscle
- what do beta antagonists like propranolol do to renin and angiotensin II
- reduce renin and decrease angiotensin II
- what is propranolol useful for
- treatment of angina and arrhythmias; may decrease mortality after acute myocardial infarction by about 10%
- what population may have a lesser antihypertensive response to beta andrenergic antagonists like propranolol
- elderly and African Americans
- name adverse effects of propranolol
-
erectile dysfunction
depression
insomnia - in what population is propranolol contraindicated in
- patients with asthma since blocking beta2 receptors can lead to bronchoconstriction