Calcium Channel Blockers Flashcards
How are calcium channel blockers administered
Enterally
Exception: Clevidipine (IV only and t1/2 of 1 minute)
How is the GI absorption of calcium channel blockers
Good
Exception: Clevidipine (IV only and t1/2 of 1 minute)
Describe Vd and protein binding for CCB
Vd - Large
Protein binding: high
Exception: Clevidipine
How are CCB metabolized
Extensive hepatic metabolism
- all are substrates for CYP3A4
Exception: Clevidipine (plasma esterases)
Additionally: Verapamil and diltiazem inhibit CYP3A4
Which calcium channel blockers are dependent on renal excretion
None
Describe the mechanism of action of calcium channel blockers
Bind alpha 1c subunit of the L-type Ca channel
- -> Prevent/delay opening V-gated C channels
- -> Reduce IC Ca influx during depolarization
- -> Reduced SR Ca induced Ca release
- -> Reduced Ca availability
- Reduced VSM resting tone
- Reduced myocardial contractility
- Increase length of Phase 0 pacemaker potential
(slowing automatic depolarisation)
Clinical effects
Dihydropyridines (SELECTIVE VSM)
1. Relaxation VSM –> reduced PVR and afterload
Nondihydropyridines (NON-SELECTIVE)
- Decreased cardiac contractility
- Decreased heart rate
- Decreased myocardial O2 demand
- Relaxation VSM with afterload reduction
Which of the CCB can be given
- IV and Oral
- Oral only
- IV only
IV and Oral
- Verapamil
- Diltiazem
Oral only
- Nifedipine
- Amlodipine
IV only
1. Clevidipine
Are the CCBs water or lipid soluble. Why is this relevant
Extremely lipid soluble
Some are basically not soluble at all in water
High lipid solubility is relevant in the context of the treatment of severe overdose. High lipid solubility means that dialysis is unlikely to get rid of enough molecules to make such a difference over a reasonable time frame
Consider intralipid –> positive outcomes despite a 20% adverse event rate
High lipid solubility also prolongs duration of action owing to the slow removal of these drugs from their site of action (lipid deposits are formed at the site of action
How are all CCBs metabolized
Hepatic CYP3A4
Except Clevidipine - plasma esterases
Which CCBs inhibit CYP3A4
Verapamil + diltiazem
Describe a mnemonic for remembering CYP450 enzyme inhibitors and inducers
INHIBITORS (SICKFACES.COM Group)
Sodium Valproate Isoniazid Cimetidine Ketoconazole Fluconazole Alcohol (acute/binge), Amiodarone Chloramphenicol, Ciprofloxacin Erythromycin Sulfonamides . Cranberry Juice Omeprazole Metronidazole
Group: Grapefruit Juice
INDUCERS (BS CRAMP GPS induces rage)
Barbiturates
St John’s Wort
Carbamazepine
Rifampicin
Alcohol (Chronic)
Phenytoin
Griseofulvin
Phenobarbitol
Sulfonylureas
Why do dihdropyridines and non-dihydropyridines have different physiological effects
L-type Calcium channels are complex transmembrane proteins made up of four repeating sections (motifs) each made up of 6 subunits.
Different classes of calcium channel blockers interact with their targets in slightly different ways which explains their selectivity and different clinical effect
Dihydropyridines
- -> are slow to interact with receptors in depolarized tissues (myocardium)
- -> Interact with vascular isoforms of calcium channels
Non-dihydropyridines
- RMP and isoform of calcium channel are irrelevant to these drugs. They enter the Calcium channel and block it.
Which has the greatest Vasodilatory effect of the calcium channel blockers
Nifedipine
Which CCB has the greatest negative inotropic and negative chronotropic effect between diltiazem and verapamil
Verapamil (‘Verapa-kill’)
Summarise the physiology related to the L-type Calcium channels in:
- Cardiac myocyte
- Pacemaker cells
- Vascular Smooth Muscle
L-type Calcium channels
- Cardiac myocyte (Inotropy)
- -> Phase 2, plateau phase of cardiac AP - Pacemaker cells (chronotropy)
- -> Phase 0 (slow depolarisation) - VSM (SVR)
- -> Regulate IC Calcium concentration
