Calcium Channel Blockers Flashcards
What determines the direction of flow for ions?
concentration gradient and electrical gradient
What kind of potential do excitable cells have?
negative inward potential across the membrane due to the selective permeability of the resting membrane to K+
Describe the concentration gradient of K+ across an excitable cell membrane
K+ is high inside (155 mM) and low outside the cell (4 mM)
Describe the concentration gradient of Na+ across an excitable cell membrane
Na+ is low inside (12 mM) and high outside the cell (145 mM)
The membrane potential gradient across a cell membrane is maintained by what?
maintained by active transport of Na+ out of the cell and K+ into the cells, and by channels that selectively permit K+ to run out of the cell at voltages near the resting membrane potential
Nerst Equation
Emem = (RT/F) ln ([K+out]/[K+in])
at 37 degrees C, Emem = -98 mV
Calcium distribution across the cell membrane
Ca2+ is very low inside (100 nM) and high outside the cell (1.5 mM)
Location/Function of L-type Cav1.2 voltage gated channel
cardiac, smooth muscle / Ca2+ entry triggers contraction
Location/Function of L-type Cav1.3 voltage gated calcium channels
neurons, endocrine cells / trigger for hormone secretion
What is the result of blocking calcium channels in vascular smooth muscle?
Vasodilation, decrease in blood pressure, and relief of angina pectoris
What is the result of blocking calcium channels in cardiac muscle and SA/AV node?
antiarrhythmic
Describe Ca2+-inducedd Ca2+ release (CICR)
Ca2+ influx via Cav1.2 induces release of Ca2+ from intracellular stores via RYR2 (ryanodine receptor 2) in the SR
What is required for the contraction of cardiac and smooth muscle?
Extracellular Ca2+
Describe cardiac muscle contraction
Ca2+ ions released from the SR binds to troponin C; Ca2+ binding by troponin C causes displacement of tropomyosin; displacement of tropomyosin allows myosin to bind actin; contraction
In skeletal muscle contraction, mechanical couple occurs between what?
mechanical coupling between Cav1.1 and RYR1
Clinical applications of calcium channel blockers
angina pectoris, arrhythmia, and hypertension
Three distinct classes of calcium channel blockers
Dihydropyridines, Phenylalkylamines, and Benzothiazepines
Structure activity of dihydropyridines
dihydropyridine ring, aryl group, chiral center, ester linked side chains
What does the (+) enantiomer of dihydropyridines do?
blocks current; interferes with opening
What does the (-) enantiomer of dihydropyridines do?
potentiates current; interferes with gate closing
Mechanism of Dihydropyrdines involves
involves interference with gating
Members of the dihydropyridine class
Nifedipine (Procardia)
Isradipine (DynaCirc)
Felodipine (Plendil)
Amlodipine (Norvasc)
Nisoldipine (Sular)
Nimodipine (Nimotop)
Nicardipine (Cardene)
Clevidipine
What is Clevidipine metabolized by?
esterases
What is significant about Amlodipine (Norvasc)
slow-onset of action; less likely to produce reflex tachycardia
Describe Clevidipine (Cleviprex)
short acting DHP; formulated with lipids derived from soy and egg (watch for allergies)
How is Clevidipine used?
given I.V. to treat hypertension when PO administration of drugs is not possible/desirable
Tissue selectivity of Dihydropyridines
more potent in relaxing smooth muscle - esp. coronary artery
do not compromise cardiac function
not antiarrhythmic
Tissue selectivity of DHPs is due to
amino acid differences in channel splice variants
differences in membrane potential properties
characteristics of dihydropyridine block
voltage dependent - the affinity of drug for the channel is different at different voltages
No frequency dependence
Marked tonic block
clinical consideration for the vascular selectivity of DHPs
marked decrease in peripheral resistance (dilation of arterioles, little affect on venules); decreased afterload; little effect on HR or force of contraction
Only DHP where reflex tachycardia is NOT secondary to vasodilation
amlodipine
Used in sub-arachnoid hemorrhage to prevent neuropathy
Nimodipine (exhibits selectivity for cerebral arteries)
DHP with the lowest vascular specificity
Nifedipine
General clinical considerations for DHPs
DHPs reduce oxygen demand in the heart - efficacy in angina; do not depress cardiac function (except nifedipine); and may inhibit atherosclerosis
Pharmacokinetic Factors for DHPs
All DHPs are highly bound to serum proteins; All DHPs undergo extensive first pass metabolism in the liver; Amlodipine has slow onset and long duration of action
DHP with a slow onset and a long duration of action
Amlodipine
Phenylalkylamine calcium channel blocker
Verapamil (Calan, Isoptin)
Clinical considerations for Verapamil
Causes vasodilation, but less potent than DHPs; slows conduction through the SA and AV nodes; reflex tachycardia is blunted
Verapamil’s inhibitor effect on the heart is due to
Frequency dependent block
Characteristics of phenylalkylamine block
Marked frequency dependence; very little tonic block
Benzothiazepine calcium channel blocker
Diltiazem (Cardizem)
Clinical considerations for Benzothiazepine
causes vasodilation; less potent than DHPs; slows conduction through SA/AV nodes; initial reflex tachycardia
Compare Diltiazem to Verapamil (affects on heart)
Diltiazem directly inhibits the heart less than verapamil, but more than DHPs
Diltiazem exhibits what kind of block of Ca2+ channels
exhibits frequency dependent block of Ca2+ channels
Characteristics of benzothiazepine block
Some tonic block; some frequency dependence
Side effects of DHPs
facial flushing; ankle edema, tachycardia, headaches
Side effects of Diltiazem
ankle edema, dizziness
Side effects of Verapamil
constipation; ankle edema; facial flushing, dizziness
Negative effects of Nifedipine
prompt release nifedipine formulations may increase the risk of subsequent heart attacks
