Ca channel blockers Flashcards
What is the common pharmacologic property of CCBs
- COMMON PHARMACOLOGIC PROPERTY: selective inhibition of L-type Ca2+ channels
o Inhibition of inward flow associated with channel opening
Types of Ca channels and role
o L-type: long lasting
Function: inward Ca2+ flow → initiate contraction vie Ca2+ induced release from SR
Blocked by CCB
Activity ↑ by catecholamines
o T-type: transient
Open at more negative potentials
Role in initial depol of SA/AV node
Upregulated in myocardial failure
B blockers vs CCBs
- Cellular mechanisms: B vs Ca2+ blockade
o Common effect: negative inotrope
o Only Ca2+ channel blockers will affect vascular tone
o Only B-blockers will inhibit RAAS (↓ renin release)
Major indications
o Stable effort angina → induce coronary vasodilation + ↓ afterload
o Hypertension
o SVTs: dihydropyridine only → effect on AV node
o Vascular protection: ↑NO formation + improved endothelial fct
MOA CCB
- Inhibition of vascular constriction
o Ca2+ interact with calmomodulin → Ca2+-calmo complexes → stimulate MLCK → MLC-Pi → myosin actin interaction → contraction
o AMPc inhibit MLCK
Types of CCBs
Dihydropyridines
Non Dihydropyridines
Dihydropyridines: binding site
- Bind same sites on α1-subunit of L-type Ca2+ channels: N sites
Dihydropyridines: effect
- Effect on vascular SM > myocardium > nodes
o Vascular selectivity
Dihydropyridines: drugs
Nifedipine (1st generation)
Amlodipine (2nd generation)
Felodipine
Other 2nd generation dihydropyridines
Benidipine, Cilnidipine, Isradipine, Lacidipine, Lercanidipine, Nicardipine, Nisoldipine
3rd generation dihydropyridines
Nifedipine: Electrophysiologic action
- Arteriolar dilation
- Negative inotropic effect is compensated by
o Reflex tachycardia
o Arteriolar unloading
Nifedipine: pharmacoK
- Short acting → rapid vasodilation and ↓BP → rapid reflex tachycardia
- Hepatic metabolism: CYP450 → inactive metabolites
- Excretion: urine
- Onset 24h
Nifedipine: side effects
- Head ache (all arteriolar vasodilators)
- Ankle edema from precapillary dilation
- Hypotension/organ underperfusion
- Mild diuretic effect
Nifedipine: CI
- HOCM and SAS → exacerbation of PG
- Myocardial failure/LV dysfct (negative inotrope)
- Hypotension
- CHF
Nifedipine: drug interaction
o Inhibition of CYP3A4: cimetidine and grapefruit juice → ↑ blood levels
o Phenobarbital, phenytoin, rifampin → hepatic enzyme inducers → ↓ blood levels
Amlodipine: pharmacoK
- Slow onset of action, long duration → charged nature of the molecule
o Peak 6-12h
o ½ life 35-48h - Extensive hepatic metabolism → inactive metabolites
Amlodipine: side effects
- Peripheral edema in 10%
Amlodipine: CI
- Same as other DHP
- ↓ dose with liver fialure
- Drug interaction: no effects with digoxin or cimetidine
o High doses of simvastatin
Advantages of amlodipine
long ½ life
good tolerability
almost no drug interaction
effective
Felodipine: electrophysiologic action
- Like other long acting DHP
Felodipine: CI
- Drug interaction:
o Cimetidine ↑ blood levels
o Anticonvulsivants: ↓ levels
3rd generation dihydropyridines action
- Inhibit T-type Ca2+ channels on vascular SM
o Present on post glomerular arterioles
↓postglomerular resistance
↓ intraglomerular pressure
Non-dihydropyridines: site of action
- Different site of action on α1-subunit
Non-dihydropyridines: effect
- Act on nodal tissue: ↓ SA node rate and AV node conduction
o Block slow inward Ca2+ current ICa-L - Effect on nodes > myocardium = vascular SM
o ↓ myocardial contraction
o Some peripheral vasodilation
o → ↓ myocardial O2 demand
Verapamil: Electrophysiologic action
- ↓/Inhibit action potential formation in AV node
o Ca2+ mediated depolarization
o Can induce AVB
o Inhibit 1 limb of re-entry circuit (AV node) - ↑ effective refractory period + AVB
o ↓ ventricular rate in SVTs (Aflutter/fib)
o Ineffective for ventricular arrhythmias - Arteriolar dilation + negative inotrope
o CO do not ↑ as much as expected with vasodilation
o Most likely from negative inotrope effects
Verapamil: action depends on
- Action is frequency dependent.
o Better access to binding sites if Ca2+ pore is open
o ↑HR → channel open more frequently
Verapamil: pharmacoK
- Effect 2h, peak 3h
o ½ life 3-7h → ↑ If
Chronic use
Renal/hepatic insufficiency - Hepatic metabolism: high 1st pass
o P450 system including CYP3A4
o Can increase blood values of statins (ketoconazole) - Bioavailability 10-20%
o Active metabolite: norverapamil
Rapid ↑ [plasma] after PO dose
o High protein bound 87-93% - Secretion: 75% kidneys, 25% GI
- Dosage: slow release preparations
Verapamil: side effects
- Classic side effects of vasodilation: headache, facial flushing, dizziness
o ↓ by long acting preparations - Constipation reported in Hu
- Rare other side effects
o Pain in gums
o Facial pain
o Epigastric pain
o Hepatotoxicity
o Transient mental confusion
Verapamil tox: treatment
o Ca2+ gluconate or chloride
o Positive inotrope: dobutamine
o Vasoconstrictor: epinephrine, NE
o Atropine → shorten AV conduction
o Isoproterenol
Verapamil: CI
- SSS, AV node dysfct
- Ventricular tachycardia
- WPW syndrome + Afib → risk of anterograde conduction through accessory pathway
- Myocardial dysfct/CHF
o Not if 2nd to SVT
Verapamil: drug interaction
o B blockers: may potentiate bradycardia or heart block
Combine with hydrophilic B-blocker (vs metabolized in liver) → atenolol
o Digoxin: toxicity potentiation
Verapamil inhibit P-glycoprotein (digoxin transporter) → [digoxin] blood levels
↓ renal clearance
Monitor for AVB
o Statins
Verapamil inhibit CYP3A4 → ↑ blood levels of atorva/simva/lovastatin
Also ↑ cyclosporine, carbamazepine, theophylline, ketoconazole, sildenafil
o Phenobarbital, phenytoin, rifampin → hepatic enzyme inducers → ↓ blood levels
Diltiazem: electrophysiologic action
- Bind to different site than verapamil but similar EP effects
- Main effect: depression of AV node
o Prolongation of functional + effective refractory periods
Diltiazem: pharmacoK
- Bioavailability: 90% absorbed, 45% available (1st pass hepatic metabolism)
o Bound to protein 80-86% - Onset 15-30min, peak 1-2h
o ½ life 4-7h
o Dosage q6-8h required for sustained effect - Hepatic metabolism: acetylated → deacetyldiltiazem (40% of activity)
o Accumulate with chronic tx - Excretion: 35% kidneys, 65% GI
Diltiazem: side effects
- Headache, dizziness, ankle edema in 6-10%
- Bradycardia, 1st degree AVB
- Hypotension
Diltiazem: toxicity
treated like verapamil
Diltiazem: CI
o Preexisting marked depression of SA/AV node
o WPW
o Hypotension
o Myocardial failure
Diltiazem: drug interaction
o No effect on blood digoxin levels
o B blockers: ↑ propranolol bioavailability by displacing from binding sites
o Inhibit CYP3A4 cytochrome
Diltiazem: advantages/disadvantages
o Low side effect profile
o Modest negative inotropic effect
o SA node inhibition
Non-dihydropyridines: drugs
Verapamil
Diltiazem
Diltiazem: toxicity c/s
- Sinus bradycardia/bradyarrhythmias
o Heart block, QT prolongation, junctional rhythms - Hypotension: vasodilation + ↓ inotropy
- Other signs
o GI upset
o Hypothermia
o CNS depression (hypotension)
o Noncardiogenic pulmonary edema
o Hyperglycemia: inhibition of insulin release
o HypoK+, hypoNa+
o Metabolic acidosis (tissue hypoperfusion)
Diltiazem: toxicity tx
No specific antidote → several mechanisms contributing to c/s
- ↓ absorption of drugs
o Gastric decontamination if ingested <2h (contra indicated is symptomatic)
o Hemodialysis not effective since high protein bound
o IV lipid emulsion - ↑ myocardial fct
o Ca2+ administration
o Insulin-glucose
o Glucagon
o Vasopressors
o Atropine
o Temporary PM placement - Supportive care
