Antihypertensives I and II Flashcards
What are the two direct vasodilators?
Hydralazine
Minoxidil
Are the direct vasodilators working on veins or arterioles?
Arterioles
What is the major effect of arteriolar vasodilation?
Decreased afterload
What other effects result from the arteriolar vasodilation?
Nonpostural fall in BP
LV filling pressure high
Reflex increase in cardiac work and HR
Reflex increased plasma renin
The reflex increase in cardiac work & HR and reflex increase in plasma renin caused by direct vasodilators can ultimately result in ______
Increased BP (not the goal of vasodilators)
Must block these two reflexes from occurring using a beta blocker and a diuretic
(Therefore direct vasodilators are 3rd or 4th line antihypertensives)
Which is the more potent direct vasodilator?
Minoxidil
What is a potential side effect of minoxidil?
Hypertrichosis (hair growth, rogaine)
What is a potential side effect of hydralazine?
Lupus-like syndrome (malaise, arthralgia, vasculitis)
How is minoxidil activated?
Gets sulfated in liver
Therefore cannot be given by injection
What are the channels opened by minoxidil?
ATP-sensitive K+ chanels (K-ATP)
What causes K-ATP channels to open and what does the opening do to the membrane potential?
Decreased ATP, increased ADP causes channel opening (decreased metabolic state)
K+ leaves the cell, membrane hyperpolarizes, reduces energy demand of the cell
What happens to the K-ATP channels in cardiac myocyte that is hypoxic/ischemic?
Hypoxia/ischemia –> ATP decreases, ADP increases –> K-ATP channels open –> AP duration decreases, contractility decreases –> energy demand decreases
What happens to smooth muscle cell that is hypoxic?
Hypoxia –> ATP decreases, ADP increases –> K-ATP channels open –> muscle hyperpolarizes –> Ca2+ channels close –> relaxation of vascular smooth muscle
–> increased blood flow
What causes the production of adenosine?
Decrease in ATP, increase in ADP
What is the mechanism of action of adenosine?
Opens K-ATP channels causing vasodilation
What happens to K-ATP channels in pancreatic beta cells when there is an increase in blood glucose?
Increased blood glucose –> Increased ATP, Decreased ADP –> K-ATP channels close –> Ca2+ channels open
–> insulin release increases
What is the mechanism of action of sulfonylureas?
Inhibit K-ATP channels, causing insulin release
Thereby acts as a glucose lowering agent
What is the mechanism of action of diazoxide?
Opens K-ATP channels, causing decreased insulin release
What are the two subunits of the pancreatic Beta cell K-ATP channel?
SUR1
Kir 6.2
What inhibits the SUR1 subunit of K-ATP channel?
Sulfonylureas
What activates the SUR1 subunit of K-ATP channel?
Diazoxide
ADP
What inhibits the Kir 6.2 subunit of K-ATP channel?
ATP
What type of K-ATP channels (VSM, cardiac, pancreatic) is minoxidil selective for?
VSM
What type of K-ATP channels (VSM, cardiac, pancreatic) is adenosine selective for?
Cardiac
VSM
What type of K-ATP channels (VSM, cardiac, pancreatic) is diazoxide selective for?
Pancreatic
VSM
What is unique about the K-ATP channels involved in the cardioprotectant mechanisms of diazoxide and adenosine?
They are mitochondrial K-ATP channels
Describe the concept of ischemic preconditioning
A previous short period of ischemia protects the heart when a longer period of ischemia occurs
What occurs in the early phase (<3 hrs) of ischemia to be protective?
Mitochondrial K-ATP channels open –> closure of mitochondrial permeability transition pore –> sustained mitochondrial function
What occurs in the late phase (24-48 hrs) of ischemia to be protective?
Reperfusion injury salvage kinases (RISK) –> gene transcription –> increased expression of protective proteins like heat shock proteins and superoxide dismutase
What is the role of adenosine in ischemic preconditioning?
Binds Adenosine receptors in the heart, causing opening of both sarcolemmal and mitochondrial K-ATP channels
What is the role of adenosine in the nuclear stress test?
Dilates arterioles in normoxic myocardium, diverting flow from the hypoxic region and enhancing contrast between hypoxic and normoxic areas
What drugs should be avoided during ischemic pre/post conditioning?
Sulfonylureas - inhibit K-ATP channels
Methylxanthines (caffeine, theophylline) - adenosine receptor antagonists, can prevent adenosine from opening mitochondrial K-ATP channels
What is the mechanism of reserpine?
Irreversibly blocks VMAT
Causes depletion of NE in storage vesicles
When used in a large dose, what does reserpine do?
Sedative, tranquilizer
When used in a lower dose, what does reserpine do?
Peripheral sympatholytic, causes vasodilation
What are some of the adverse CNS effects of reserpine?
Increased risk of clinical depression
Exacerbation of parkinsonism
What is the mechanism of clonidine and methyldopa?
Central alpha-2 agonists
Decrease sympathetic outflow to cardiovascular system (inhibit NE release)
Baroreceptor reflexes remain intact
What patient population is methyldopa a first line antihypertensive?
Pregnant patients
What are adverse effects of central alpha-2 agonists?
Drowsiness, somnolence
Dry mouth
Sudden withdrawal causes excess of sympathetic outflow, resulting in exacerbation of hypertension
What is the mechanism of action of metyrosine?
Competitive inhibitor of tyrosine hydroxylase
Inhibits formation of NE at rate limiting step
What is a major clinical use of metyrosine?
Used in management of inoperable pheochromocytomas
What are the two categories of calcium channel blockers?
Dihydropyridines (DHPs)
Non-DHPs
What drugs are the DHPs?
Nifedipine
Amlodipine
What drugs are the non-DHPs?
Verapamil
Diltiazem
Are the calcium channel blockers primarily arteriolar or venous vasodilators?
Arteriolar
What is the action of calcium channel blockers on coronary arteries?
Dilates coronary arteries
Useful in coronary vasospasm
Do DHPs or nonDHPs have cardiodepressant action?
NonDHPs
At what type of L-type Calcium channels do calcium channel blockers act?
1.2 and 1.3
No effect on skeletal muscle or retina
Main effects on cardiac muscle and vascular smooth muscle (vasodilator)
What are the different gating modes of the L-type calcium channel?
2 - long-opening
1 - brief-opening
0 - rare-opening
Which mode of the calcium channel is stabilized by calcium channel blockers?
0 - rare opening
What are the different conformations of the L-type calcium channel?
Closed
Open
Inactivated
What conformation of the calcium channel do nonDHPs bind tighter to?
Open
Bind more tightly when channel is phasic between open and closed conformations (i.e. in cadiac muscle)
Hence, better cardiodepressant effect for nonDHPs
What conformation of the calcium channel do DHPs bind tighter to?
Inactive
Find more inactive state in tonically depolarized cells (always some calcium mediated contraction and tone maintained
What happens to heart rate when cardiac L-type channels are blocked?
Decreases
Because SA node automaticity is decreased
Slows rate of upstroke of action potential
What happens to conduction velocity when cardiac L-type channels are blocked?
Decreased conduction velocity
Because AV node conduction is slowed
Slows rate of upstroke of action potential
What happens to cardiac contractility when cardiac L-type channels are blocked?
Decreased contractility
Reduced inward Ca current during plateau phase
What are adverse effects for DHPs?
Hypotension, flushing, headache
Reflex sympathetic activation
Swollen ankles
What are adverse effects for nonDHPs?
LV dysfunction (decreased contractility) AV block (slowed conduction) Avoid combination with beta-blockers (similar cardiodepressant effect) GI (constipation)
How are calcium channel blockers metabolized?
By CYP450 enzyme CYP3A4 in the liver
Avoid combination with competitive substrates/inhibitors of CYP3A4 (like statins, grapefruit juice)
