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12. Pharmacology > Ca channel blockers > Flashcards

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
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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

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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)
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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

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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
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6
Q

Types of CCBs

A

Dihydropyridines
Non Dihydropyridines

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7
Q

Dihydropyridines: binding site

A
  • Bind same sites on α1-subunit of L-type Ca2+ channels: N sites
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8
Q

Dihydropyridines: effect

A
  • Effect on vascular SM > myocardium > nodes
    o Vascular selectivity
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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

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10
Q

Nifedipine: Electrophysiologic action

A
  • Arteriolar dilation
  • Negative inotropic effect is compensated by
    o Reflex tachycardia
    o Arteriolar unloading
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11
Q

Nifedipine: pharmacoK

A
  • Short acting → rapid vasodilation and ↓BP → rapid reflex tachycardia
  • Hepatic metabolism: CYP450 → inactive metabolites
  • Excretion: urine
  • Onset 24h
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12
Q

Nifedipine: side effects

A
  • Head ache (all arteriolar vasodilators)
  • Ankle edema from precapillary dilation
  • Hypotension/organ underperfusion
  • Mild diuretic effect
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13
Q

Nifedipine: CI

A
  • HOCM and SAS → exacerbation of PG
  • Myocardial failure/LV dysfct (negative inotrope)
  • Hypotension
  • CHF
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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

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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
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16
Q

Amlodipine: side effects

A
  • Peripheral edema in 10%
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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
Q

Verapamil: action depends on

A
  • Action is frequency dependent.
    o Better access to binding sites if Ca2+ pore is open
    o ↑HR → channel open more frequently
26
Q

Verapamil: pharmacoK

A
  • 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
Q

Verapamil: side effects

A
  • 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
Q

Verapamil tox: treatment

A

o Ca2+ gluconate or chloride
o Positive inotrope: dobutamine
o Vasoconstrictor: epinephrine, NE
o Atropine → shorten AV conduction
o Isoproterenol

29
Q

Verapamil: CI

A
  • 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
Q

Verapamil: drug interaction

A

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
Q

Diltiazem: electrophysiologic action

A
  • Bind to different site than verapamil but similar EP effects
  • Main effect: depression of AV node
    o Prolongation of functional + effective refractory periods
32
Q

Diltiazem: pharmacoK

A
  • 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
Q

Diltiazem: side effects

A
  • Headache, dizziness, ankle edema in 6-10%
  • Bradycardia, 1st degree AVB
  • Hypotension
34
Q

Diltiazem: toxicity

A

treated like verapamil

35
Q

Diltiazem: CI

A

o Preexisting marked depression of SA/AV node
o WPW
o Hypotension
o Myocardial failure

36
Q

Diltiazem: drug interaction

A

o No effect on blood digoxin levels
o B blockers: ↑ propranolol bioavailability by displacing from binding sites
o Inhibit CYP3A4 cytochrome

37
Q

Diltiazem: advantages/disadvantages

A

o Low side effect profile
o Modest negative inotropic effect
o SA node inhibition

38
Q

Non-dihydropyridines: drugs

A

Verapamil
Diltiazem

39
Q

Diltiazem: toxicity c/s

A
  • 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
Q

Diltiazem: toxicity tx

A

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

12. Pharmacology (10 decks)

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