Lecture 5 Part 1 - Pharmacology - Therapy for HTN: Calcium Channel Antagonists & Arteriolar Vasodilators

types of calcium channels

P-type (Type I)

N-type (Type II)

T-type (Type III)

L-type (Type IV)

Type 1: P-type calcium channels

sensitive to funnel web spider toxin

Type II: N-type calcium channels

sensitive to omega-contotoxin

Type III: T-type calcium channels

sensitive to octanol

Type IV: L-type calcium channels

sensitive to DHP (class I), phenylalkylamine (class II), or benzothiazepine (class III) → named via chemical structure/MoA

examples of class I: DHP medications

amlodipine (norvasc)

nifedipine (procardia, adalat)

felodipine (plendil)

example of class II: phenylalkylamine medication

verapamil (calan)

example of a class III: benzothiazepine

diltiazem (cardizem)

process of cardiac myocyte contraction in vascular tissues

increased cytosolic calcium → enhanced binding of calcium to calmodulin → calcium-calmodulin complex activates myosin light-chain kinase → phosphorylation of myosin light chain → promotes interaction between actin and myosin and leads to sustained contraction of smooth muscle

cardiac myocyte contraction in cardiac cells

calcium binds to troponin C → relief of inhibitory effect of the troponin complex on the contractile apparatus → permits productive interaction of actin and myosin → contraction

voltage-dependent calcium channels (CCBs)

• responsible for excitation-contraction coupling of skeletal, smooth, and cardiac muscle

• regulate aldosterone and cortisol secretion in endocrine cells of the adrenal cortex

• in the heart: involved in the conduction of the pacemaker signals

four effects of CCBs used as medications

1. by acting on vascular smooth muscle, they reduce contraction of the arteries and cause vasodilation

2. by acting on cardiac muscles (myocardium), they reduce the force of contraction of the heart

3. by slowing down the conduction of electrical activity within the heart, they slow down the heartbeat

4. by blocking the calcium signal on adrenal cortex cells, they directly reduce aldosterone production, which correlates to lower blood pressure

dihydropyridine CCB target(s)

vascular

phenylalkylamine CCB target(s)

heart

benzothiazepine CCB target(s)

heart & vascular

types of CCBs

dihydropyridines

phenylalkylamine

benzothiazepine

CCBs treatment

• among preferred drugs for treatment of HTN (both monotherapy & in combination)

• has greater frequency of achieving BP control with calcium channel blockers as monotherapy in pts with isolated systolic HTN, elderly, African Americans (low renin)

CCBs adverse effects

• calcium channels cause baroreceptor reflex-mediated sympathetic discharge

• DHPs can cause tachycardia (minimal with verapamil and diltiazem)

• in verapamil and diltiazem, bradycardia and even sinoatrial node arrest → avoid beta blockers

• peripheral edema (ankle edema)

• gastroesophageal reflux

• constipation

hydralazine (apresoline)

• initially associated with tachycardia and tachyphylaxis due to compensatory CV responses that accompany use of arteriolar vasodilators

• combination therapy:

  • a beta-receptor antagonist AND/OR

  • a diuretic AND/OR

  • a vasodilator

hydralazine (apresoline) mechanism of action

• directly relaxes arteriolar smooth muscle

• mechanisms aren’t clear

• may possibly involve a reduction in intracellular calcium concentrations

hydralazine (apresoline) reflexes

• powerful stimulation of the SNS

• norepinephrine (increase HR & contractility)

• increased plasma renin activity and fluid retention

pharmacological effects/site of action (cardiovascular) in hydralazine (apresoline)

• selective decrease in vascular resistance in arterioles of coronary, cerebral, and renal circulations

• doesn’t relax venous smooth muscle (postural hypotension not common due to preferential dilation of arterioles over veins)

• lowers BP similarly supine vs. upright

bioavailability of hydralazine (apresoline)

• low bioavailability (VERY IMPORTANT KNOW FOR EXAM)

  • hydralazine is N-acetylated in the bowel and the liver

  • 16% in fast vs. 35% in slow acetylators

    • (percentage indicates how much is left)

    • if fast acetylator, need higher dose bc processing drug more quickly

  • rate of acetylation is genetically determined; abt half of the U.S. population acetylates rapidly, and half does so slowly

  • the acetylated compound is inactive; thus, the dose necessary to produce a systemic effect is larger in fast acetylators

hydralazine (apresoline) treatment

• no longer a first-line drug bc of it’s unfavorable adverse-effect profile

• HTN emergencies in pregnant women (preeclampsia)

• combination therapy (hydralazine, beta blocker, and a diuretic better tolerated):

  • congestive heart failure for pts who can’t tolerate ACEI or AT1 receptor blockers

  • combination therapy with nitrates as part of evidence-based therapy

  • may have utility in the treatment of some pts with severe HTN

adverse effects of hydralazine (apresoline) (KNOW)

1. extensions of the pharmacological effects of the drug

2. immunological reactions

hydralazine (apresoline) ADE: extensions of the pharmacological effects of the drug

Extension of the Pharmacological Effects of the Drug:

• headache

• nausea

• flushing

• hypotension

• palpitations

• tachycardia

• dizziness

• angina pectoris

• myocardial ischemia

  • can occur on account of increased oxygen demand induced by the baroreceptor reflex-induced stimulation of the SNS

• heart:

  • reflex tachycardia & coronary artery disease (CAD)

  • myocardial ischemia sufficiently severe and protracted to cause frank MI

• cautions:

  • not advisable in pts with CAD and older pts

  • ^ possibility of precipitating myocardial ischemia due to reflex tachycardia

hydralazine (apresoline) ADE: immunological reactions

Immunological Reactions: Drug-Induced Lupus Syndrome

• ^ related to dose, gender, acetylator phenotype, and race

• cautions:

  • women >> men

  • caucasians >> African-Americans

• positive antinuclear antibody and lupus syndrome

• faster in slow acetylators vs. rapid acetylators (native drug or a nonacetylated metabolite is responsible)

The advantage of hydralazine (apresoline) in HTN treatment includes ______.

a. postural hypertension

b. drug-induced lupus syndrome

c. it's use in Caucasian men

d. its use in pregnancy

The advantage of hydralazine (apresoline) in HTN treatment includes ______.

a. postural hypertension

b. drug-induced lupus syndrome

c. it's use in Caucasian men

d. its use in pregnancy

minoxidil (loniten)

• pro drug (metabolized by hepatic sulfotransferase)

• active: minoxidil N-O sulfate

• eliminated as glucuronide conjugate

minoxidil (loniten) mechanism of action

• activates the ATP-modulated potassium channel permitting potassium efflux

• ^ causes hyperpolarization & relaxation of vascular smooth muscle

pharmacological effects/site of action for minoxidil (loniten)

TL;DR:

• arteriolar vasodilation

• myocardial contractility and in cardiac output

• vasodilation of renal artery

Deep Dive:

• arteriolar vasodilation with no effect on capacitance vessels

• administration of minoxidil is associated with a reflex increase in myocardial contractility and in cardiac output

• increased venous return and adrenergically mediated increase in myocardial contractility

• renal circulation (complex effect):

  • vasodilate renal artery but systemic hypotension can decrease renal blood flow

  • renal function usually improves in pts who take minoxidil for HTN

  • potent stimulator of renin release

minoxidil (loniten) treatment

• best reserved for the treatment of severe HTN that responds poorly to other antiHTN medications ← especially in male pts with renal insufficiency

• used successfully in the treatment of HTN in both adults and children

major ADEs of minoxidil (loniten)

1. retention of salt and water (edema)

2. CV effects

3. hypertrichosis (excessive hair growth) (extended treatment)

4. other/some rare but serious ADEs

major ADE of minoxidil (loniten): edema

Retention of Salt and Water (Edema) from increase proximal tubular reabsorption

• thiazides may not be sufficiently efficacious

• ^ may be necessary to use a loop diuretic ← especially if pt has any degree of renal dysfunction

major ADE of minoxidil (loniten): CV effects

Cardiovascular Effects

• (reflex)

• due to baroreceptor-mediated activation of SNS

• increased HR

• increased myocardial contractility

• increased myocardial oxygen consumption

• myocardial ischemia ← can be induced in pts with CAD

• concurrent administration of beta-adrenergic blocker

major ADE of minoxidil (loniten): hypertrichosis (excessive hair growth)

Hypertrichosis (excessive hair growth)

• extended treatment

• topical minoxidil (rogaine)

• now used to treat hair loss

rare but serious ADEs of minoxidil (loniten)

1. rashes

2. Stevens-Johnson syndrome

3. serosanguineous bullae

4. glucose intolerance

5. formation of antinuclear antibodies

6. thrombocytopenia

The side effects of minoxidil (loniten) include the following, except _____.

a. fluid and salt retention

b. cyanide toxicity

c. Stevens-Johnson syndrome

d. myocardial ischemia

The side effects of minoxidil (loniten) include the following, except _____.

a. fluid and salt retention

b. cyanide toxicity

c. Stevens-Johnson syndrome

d. myocardial ischemia