Ca channel blockers Flashcards

1
Q

What is the common pharmacologic property of CCBs

A
  • COMMON PHARMACOLOGIC PROPERTY: selective inhibition of L-type Ca2+ channels
    o Inhibition of inward flow associated with channel opening
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Types of Ca channels and role

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

B blockers vs CCBs

A
  • 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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Major indications

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

MOA CCB

A
  • Inhibition of vascular constriction
    o Ca2+ interact with calmomodulin → Ca2+-calmo complexes → stimulate MLCK → MLC-Pi → myosin actin interaction → contraction
    o AMPc inhibit MLCK
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Types of CCBs

A

Dihydropyridines
Non Dihydropyridines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Dihydropyridines: binding site

A
  • Bind same sites on α1-subunit of L-type Ca2+ channels: N sites
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Dihydropyridines: effect

A
  • Effect on vascular SM > myocardium > nodes
    o Vascular selectivity
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Dihydropyridines: drugs

A

Nifedipine (1st generation)
Amlodipine (2nd generation)
Felodipine

Other 2nd generation dihydropyridines
Benidipine, Cilnidipine, Isradipine, Lacidipine, Lercanidipine, Nicardipine, Nisoldipine

3rd generation dihydropyridines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Nifedipine: Electrophysiologic action

A
  • Arteriolar dilation
  • Negative inotropic effect is compensated by
    o Reflex tachycardia
    o Arteriolar unloading
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Nifedipine: pharmacoK

A
  • Short acting → rapid vasodilation and ↓BP → rapid reflex tachycardia
  • Hepatic metabolism: CYP450 → inactive metabolites
  • Excretion: urine
  • Onset 24h
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Nifedipine: side effects

A
  • Head ache (all arteriolar vasodilators)
  • Ankle edema from precapillary dilation
  • Hypotension/organ underperfusion
  • Mild diuretic effect
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Nifedipine: CI

A
  • HOCM and SAS → exacerbation of PG
  • Myocardial failure/LV dysfct (negative inotrope)
  • Hypotension
  • CHF
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Nifedipine: drug interaction

A

o Inhibition of CYP3A4: cimetidine and grapefruit juice → ↑ blood levels
o Phenobarbital, phenytoin, rifampin → hepatic enzyme inducers → ↓ blood levels

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Amlodipine: pharmacoK

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Amlodipine: side effects

A
  • Peripheral edema in 10%
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Amlodipine: CI

A
  • Same as other DHP
  • ↓ dose with liver fialure
  • Drug interaction: no effects with digoxin or cimetidine
    o High doses of simvastatin
18
Q

Advantages of amlodipine

A

long ½ life
good tolerability
almost no drug interaction
effective

19
Q

Felodipine: electrophysiologic action

A
  • Like other long acting DHP
20
Q

Felodipine: CI

A
  • Drug interaction:
    o Cimetidine ↑ blood levels
    o Anticonvulsivants: ↓ levels
21
Q

3rd generation dihydropyridines action

A
  • Inhibit T-type Ca2+ channels on vascular SM
    o Present on post glomerular arterioles
     ↓postglomerular resistance
     ↓ intraglomerular pressure
22
Q

Non-dihydropyridines: site of action

A
  • Different site of action on α1-subunit
23
Q

Non-dihydropyridines: effect

A
  • 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
24
Q

Verapamil: Electrophysiologic action

A
  • ↓/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
25
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
26
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
27
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
28
Verapamil tox: treatment
o Ca2+ gluconate or chloride o Positive inotrope: dobutamine o Vasoconstrictor: epinephrine, NE o Atropine → shorten AV conduction o Isoproterenol
29
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
30
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
31
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
32
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
33
Diltiazem: side effects
* Headache, dizziness, ankle edema in 6-10% * Bradycardia, 1st degree AVB * Hypotension
34
Diltiazem: toxicity
treated like verapamil
35
Diltiazem: CI
o Preexisting marked depression of SA/AV node o WPW o Hypotension o Myocardial failure
36
Diltiazem: drug interaction
o No effect on blood digoxin levels o B blockers: ↑ propranolol bioavailability by displacing from binding sites o Inhibit CYP3A4 cytochrome
37
Diltiazem: advantages/disadvantages
o Low side effect profile o Modest negative inotropic effect o SA node inhibition
38
Non-dihydropyridines: drugs
Verapamil Diltiazem
39
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)
40
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