B4.043 Pharmacology of Drugs to Treat HTN Flashcards
risk of end organ damage is…
proportional to BP elevation
why does systolic BP increase with age
progressive stiffening of arterial circulation
discuss the differences between black and white patients with respect to HTN risk
HTN common in black people and occurs at a younger age
higher proportion of black people sensitive to salt in the diet
black patients 3-5x more likely to have renal complications and end stage kidney disease
which treatments work best for black patients
CCBs
diuretics
combination therapies work similarly in white and black patients
mechanism of action of diuretics
deplete body of sodium and reduce blood volume
mechanism of actions of agents that interact with angiotensin
reduce peripheral vascular resistance
mechanism of action of direct vasodilators
relax vascular smooth muscle and dilate resistance vessels
mechanism of action of sympatholytic agents
reduce peripheral vascular resistance, inhibit cardiac function, and increase venous pooling
starting point for antihypertensive treatment
lifestyle modifications
- exercise
- weight reduction
- reduction of dietary fats, salt, alcohol
- avoid or reduce smoking
why do lifestyle modifications help?
reduce risks
reduce number and doses of antihypertensive meds required for treatment
why can drug treatment be a hard sell
high BP not normally felt
need to take drugs despite feeling healthy
most common cause of treatment failure
noncompliance
in HTN meds there are wide variations in:
responsiveness to individual drugs
toxicity or frequency and nature of adverse effects
first line agents used in HTN
thiazide diuretics
ACE inhibitors
angiotensin receptor blockers (ARBs)
calcium channel blockers (CCBs)
mechanism of action of thiazides
inhibit NaCl reabsorption in distal convoluted tubule
2 main clinical uses for thiazide diuretics
- at low dose lower BP
2. at high dose second to loop diuretics in CHF
examples of thiazide/ thiazide like diuretics
names ending in -thiazide
chlorthalidone, indapamide, metolazone
preferred thiazide
cholorothalidone
long half life and proven reduction of CVD
what groups respond particularly well to thiazides
black and eldery
this drug class is composed of sulfonamides
thiazide/thiazide like diuretics
2 non heart related uses of thiazides
nephrolithiasis: reduce urinary Ca concentration
nephrogenic diabetes insipidus: reduce polyuria and polydipsia, paradoxical effect due to plasma volume reduction
primary adverse effects of thiazides
hypokalemia metabolic alkalosis
hyponatremia
hyperglycemia
hyperlipidemia
hyperuricemia
hypercalcemia
other thiazide toxicities
weakness, fatigability, paresthesias, erectile dysfunction
why does erectile dysfunction occur with thiazides
probably related to volume depletion
can add a PDE5 inhibitor like sildenafil to combat this
3 types of drugs that interact with the renin-angiotensin system
- direct renin inhibitor
- angiotensin converting enzyme inhibitors
- angiotensin receptor blockers
examples of ACE inhibitors
end in -pril
benazepril, captopril, enalapril, fosinopril, Lisinopril, moexipril, perindopril, quinapril, Ramipril, or trandolapril
captopril
active drug
all others are prodrugs
mechanism of action of ACE inhibitors
inhibits conversion of angiotensin I to angiotensin II
BP lowering mostly due to decrease in peripheral vascular resistance
why is there vasodilation with ACE inhibitors?
reduced angiotensin induced vasoconstriction
increased bradykinin levels
effects of increased bradykinin levels due to ACE inhibitors
- contribute to the antihypertensive effect
2. causes adverse effects of coughing and angioneurotic edema
how can you get rid of a cough with with ACE inhibs
switch to an ARB
gets rid of bradykinin effects
therapeutic characteristics of ACE inhibitors
lower BP without compromising blood supply to heart, brain, or kidneys
few, mild adverse effects
do not cause reflex sympathetic activation because of concurrent baroreceptor resetting/vagal activation
effectiveness of ACE inhibitors in different population
effective orally for monotherapy
lower BP in 50% of patients
most effective in young/middle ages Caucasians
less effective in elderly and African americans
what populations of patients are ACE inhibitors first choice treatments for
diabetics
chronic renal disease
LVH
adverse effects of ACE inhibitors
dry, hacking, nonproductive cough in 5-20% of patients
hyperkalemia
angioedema and anaphylaxis
acute renal failure in patients with bilateral renal artery stenosis
taste disturbances
pruritic maculopapular rash
when should you not use ACE inhibitors
in combo with ARBs or direct renin inhibitor in pregnancy (2nd and 3rd trimester)
examples of ARBs
end in -sartan
2 important differences between ARBs and ACEI
- ARBs more specific than ACEI: do not affect bradykinin metabolism (less angioedema and cough)
- more complete inhibition of angiotensin action bc other enzymes can also generate angiotensin II
examples of calcium channel blockers
verapamil, diltiazem (act on SA and AV nodes)
dihydropyridines (act in periphery): amlodipine and all others that end in -dipine
mechanism of action of CCBs
blocking slow calcium channels will reduce intracellular Ca2+ > relax arteriolar smooth muscles > vasodilation and lower BP
strongest CCB vasodilator
dihydropyridines like nifedipine
CCB w strongest cardiac effects
verapamil
diltiazem
action somewhere between nifedipine and verapamil
most likely CCB to produce reflex tachycardia
dihydropyridines
cause pronounced vasodilation without inhibition of AV conduction
CCBs that DO NOT cause reflex tachycardia
verapamil and diltiazem
depress SA and AV node conduction
potential harmful cardiac effect of verapamil and diltiazem
bradycardia due to myocardial depression in the presence of SA node dysfunction
contraindicated in patients with SA or AV node abnormalities or CHF
most common side effects of dhydropyridines
vascular side effects
headache, flushing, dizziness, and peripheral edema
most common side effect fo verapamil
constipation
mechanism of action of sympatholytic drugs
lower BP by acting on adrenergic receptors to reduce sympathetic vasomotor tone either as:
-peripheral antagonists that block receptors at nerve endings
OR
-central agonists that stimulate medullary receptors
why are sympatholytic drugs not recommended for monotherapy
produce postural hypotension and sodium retention
add a diuretic
cardioselective (B1 specific) B blockers
atenolol
betaxolol
bisoprolol
metoprolol
cardioselective and vasodilatory B blockers
nebivolol
NO production
noncardioselective B blockers
nadolol
propranolol
be careful w asthmatics (B2 blocker too)
B blockers with intrinsic sypathomimetic activity
acebutolol
penbutolol
pindolol (B2 agonist)
carteolol (NO production)
B blockers with combined a activity
carvedilol (a1 antagonist, blocks Ca2+ entry)
labetalol (a1 antagonist)
mechanism of action of B blockers
lower BP by blocking B adrenergic receptors in:
- heart to reduce CO (slow HR)
- kidneys to reduce renin recreation
- CNS to reduce sympathetic vasomotor tone
efficacy in different populations
genetic and age efficacy opposite to diuretics
more effective in Caucasians and young hypertensives
why are B blockers combined with other drugs?
counteract reflex tachycardia caused by vasodilation and increased renin secretion caused by thiazide and loop diuretics
adverse effects of B blockers
may worsen symptoms in patients with: -reduced myocardial reserve -asthma -peripheral vascular insufficiency -diabetes may decrease exercise tolerance in patients with HF (usually increases exercise tolerance in most people, however)
how do B blockers predispose to atherosclerosis
increase plasma triglycerides
decrease HDL cholesterol
how do B blockers pose a risk of new onset diabetes
delay recovery of normoglycemia because they inhibit hyperglycemia responses mediated by epinephrine
this is why they are no longer 1st line treatment
risk of abrupt cessation of B blockers
tachycardia, HTN, angina, MI
renin inhibitor drug
aliskiren
discuss the mechanism of action of aliskiren
orally active
dose dependent reduction of plasma renin
dose dependent reduction of BP
safety and tolerability similar to ACEI
when should you avoid aliskiren
pregnancy
when taking ACEI or ARBs
drugs that blocks renin secretion
clonidine
B blockers
mechanism of action of clonidine
reduce renal sympathetic nerve activity
may also exert direct renal activity
a1 antagonists
doxazosin, prazosin, terazosin
mechanism of action of a1 antagonists
reduce NE induced vasoconstriction to dilate both arteries and veins
BP falls bc of decreased peripheral resistance
when are a1 antagonists considered second line agents
in pts with benign prostatic hyperplasia
common adverse effects of a1 antagonists
orthostatic hypotension, esp in older adults
drowsiness, dizziness, palpitations, headache, easy fatigability
central acting sympatholytic drugs (a2 agonists)
clonidine
methyldopa
guanfacine
why are a2 agonists last line drugs
significant CNS adverse effects, especially in older adults
mechanism of action of a2 agonists
at in CNS as agonist on presynaptic a2 receptors in brainstem and reduce peripheral vascular resistance
how can a2 agonists be given
orally- clonidine
transdermal patch- 2 hrs (methydopa) or 8-12 hrs (clonidine)
which drug is limited to pregnancy?
methyldopa
oral direct vasodilator
hydralazine minoxidil (K+ channel opener)
IV direct vasodilators
sodium nitroprusside (NO) diazoxide (hyperpolarization by activating K+ channels) fenoldopam (dopamine agonist) enalaprilat (ACEI) nicardipine (CCB) hydralazine (preeclampsia/eclampsia)
mechanism of direct vasodilators
act directly on vascular smooth muscle to cause relaxation and reduce vascular resistance
which drugs dilate arteries selectively without affecting venous smooth muscle
hydralazine
minoxidil
diazoxide
fenoldopam
which drug dilates both arteries and veins
sodium nitroprusside
adverse effects of vasodilators
hypotension accompanied by:
- reflex tachy
- increased myocardial contractions
- increased renin secretion
- fluid retention
- headaches
- flushing
- palpitations
- dizziness
distinct adverse effect of hydralazine
lupus like syndrome
distinct adverse effect of minoxidil
hypertrichosis
topical ointment used to treat baldness
what is resistant hypertension
hypertensive even with 2 drugs
example of compensatory mechanisms evoked by one drug being treated with addition of other drugs
hydralazine decreases vascular resistance
compensatory reflex tachy (add B blocker)
compensatory salt and water retention (treat with diuretic)
recommendations for treatment in pregnancy
B blocker (labetalol) CCB (nifedipine) methyldopa and hydralazine may be used
