Striated muscle: Voluntary Skeletal muscle, Cardiac Muscle
Smooth muscle: Involuntary-blood vessels, gut, uterus
Peripheral Blood vessels: Vessels that are outside the heart and brain in the systemic circulation (e.g. carotid artery–>Supplies blood to brain, renal artery, femoral, illiac arteries)
-Voltage sensitive Calcium channels (L-type) mediate entry of extracellular Calcium ions into smooth muscle, cardiac myocytes and SA, AV nodal cells in response to electrical depolarisation.
-In both smooth muscle and cardiac myocytes, calcium ions is a trigger for contraction.
-Calcium channel antagonists, inhibit Calcium channel function.
- In smooth muscles, this leads to relaxation, especially in arterial beds
- These drugs may also produce negative inotropic (decrease force of contraction) and chronotropic (decrease frequency/HR) effects in heart
Types of calcium channel blockers (CCBs) approved for clinical uses:
-Phenylalkylamines, dihydropyridines, benzothiazepines, diphenylpiperazines and one diarylaminopropylamine
Diltiazem (Benzothiazepines)–>Both cardiac and periphery
Mibefradil –>Non Selective
*Commonly used CCBs: Verpamil, Diltiazem, [Amlodipine, Nifedipine, Felodipine, Nimodipine-All DHPR]
Note: Although all of them bind to the a1 subunit of the L-Type calcium chanels and reduce calcium influx, there are fundamental differences amongst verapamil, diltiazem and DHPR
-Differences include pharmacological characteristics, drug interactions and toxicities
(b) Mechanisms of action of CCBs:
1. All CCBs relax arterial smooth muscle, with little effect on most venous beds so they do not affect cardiac preload significantly
***The marked peripheral vasodilation can be seen with DHPR (accompanied by robust baroreceptor-reflex mediated increase in sympathetic tone).
2. In cardiac muscle, CCBs can produce a negative inotropic effect (Decrease in force) and negative chronotropic effect.
-Sympathetic tone: Rate of firing of sympathetic neurons
3. In the SA and AV nodes, depolarisation depends predominantly on Calcium ions movement through the slow L-type channel.
*Compared to DHPR, verapamil not only reduces the magnitude of calcium current through L-type channels but also decreases the rate of channel recovery.
Verapamil and diltiazem depresses the rate of SA pacemaker firing and slows AV conduction–> Thus it can be used to treat supraventricular tachyarrhythymias.
(c) Unique properties of each class
- Dihydropyridines (DHPR)
-Nifedipine (prototype DHPR) [Selectively dilates arterial resistance vessels]
-The decrease in arterial blood pressure elicits baro-receptor mediated sympathetic reflex which results in tachycardia and positive inotropy
–However, this increase in heart contractility is not suficient to compensate for the vasodilation.
- Other DHPRs (amlodipine, felodipine, Nicardipine, Nimodipine)
-Similar cardiovascular effects with nifedipine
Amlodipine–>Less reflex tachycardia, possibly due to its long t1/2 (35-50 hrs) which produces minimal peaks and troughs in plasma concentrations.
*These DHPRs do not cause myocardial depression and lack negative chronotropic effects, thus they are less effective in monotherapy (only drug used) of stable angina.
For Stable angina, Verapamil, diltiazem or a B-adrenergic antagonist is preferred.
Nimodipine–>Lipid soluble and can be used to relax cerebral vasculature (Enters BBB)
-Effective in inhibiting cerebral vasospasm and can be used to treat patients with neurological defects associated with cerebral vasospasm after subarachnoid hemorrhage.
- Verapamil and Diltiazem
–Although verapamil does cause vasodilation, reflex tachycardia is blunted or abolished by the negative chronotropic effects on the heart.
–Verapamil reduces peripheral vascular resistance (↓TPR) and blood pressure (↓BP) with minimal changes in heart rate
-In patients with congestive heart failure (occurs when the heart is unable to provide sufficient pump action to maintain blood flow to meet the needs of the body), IV verapamil can cause a marked decrease in contractility and left ventricular function–>Worsens condition.
-Relief of exercise induced angina (Stable angina) seen with verapamil is due primarily to a reduction in oxygen demand.
–Diltiazem decreases both heart rate (modest negative chronotropic effects) and mean arterial blood pressure.
Summary (Point to note): While both drugs produce similar effects on the SA and AV node, the negative inotropic effect of diltiazem is smaller. Thus decrease in heart rate is observed.
(d) Metabolism and Pharmacokinetics of CCBs
1. First-pass metabolism and absorption. Although absorption of these drugs are high, bioavailability is significantly reduced by first pass hepatic metabolism.
2. Onset of action. Effects are evident within 30-60 mins of an oral dose, with the exception of slowly absorbed and longer acting agents (amlodipine and felodipine) or slow release formulations (nifedipine)
3. Protein binding. All CCBs are extensively to plasma proteins. Half lifes vary widely.
4. Hepatic metabolism. Repeated oral administration will increase bioavailability and t1/2 due to saturation of hepatic metabolism (CYP 450-used up)
(a) Diltiazem metabolism. Major Metabolite of diltiazem is desacetyldiltiazem which has only half the potency of diltiazem as a vasodilator.
(b) Verapamil metabolism. N-demethylation of verapamil results in the production of norverapamil (t1/2-10 hours) which is biologically active but much less potent than the parent compound.
(c) Metabolites of DHPR are inactive or weakly active.
*5. Patients with cirrhosis (liver damage where healthy cells are replaced by scar tissue). Bioavailabilities and half lives of CCBs may be greatly increased due to lack of CYP450 enzymes. Dosage should be decreased accordingly.
*6. Elderly patients. Half lifes of these agents may be longer in them.
7. Racemic mixtures. With the exception of diltiazem and nifedipine, all CCBs are administered as racemic mixtures (equal amounts of enantiomers).
(e) Adverse Reactions of CCBs
-The most common side effects caused by CCBs, esp. the DHPR, are due to excessive vasodilation:
1. Dizziness, Headache, Flushing
2. Nausea/Gastroseophageal reflux-induced nausea (Physiologically, nausea is typically associated with decreased gastric motility and increased tone in the small intestine) + (often reverse peristalsis in the proximal small intestine)
-CCBs inhibit contraction of lower oseophageal sphincter, reflux occurs
4. Constipation (Smooth Muscles relax-Peristalsis does not occur) [Common side effect of verapamil]
5. Gingival hyperplasia
6. Peripheral oedema
7. Pulmonary oedema
10. Worsened myocardial ischemia (due to nifedipine) especially with immediate release formulations.
- May result from excessive hypotension and decreased coronary perfusion.
- Coronary steal. Selective coronary vasodilation in non-ischemic regions when the ischemic regions are already maximally dilated, maximum perfusion already.
- Increase in sympathetic tone and reflex tachycardia
(f) Drug interactions/Contraindications/Important Considerations
***Very Important: IV verapamil with a Beta blocker is contradindicated because of AV block and/or severe depression of ventricular function.
-Patients with ventricular dysfunction, SA or AV nodal conduction disturbances (Refer to mechanisms of action, Part C) or systolic blood pressures <90mmHg should not be treated with verapamil or diltiazem
-Concerns about the long-term safety of short-acting nifedipine because of abrupt vasodilation with reflex sympathetic activation.
-If sustained-release forms of nifedipine were used, there is no long-term adverse outcomes associated nor significant reflex tachycardia.
-With longer half life CCBs with favourable pharmokinetics (e.g. amlodipine or felodipine), there is less abrupt vasodilation, baroreceptor reflex less likely to be invoked.
Refer to pg 9: Treatment of Angina Lecture Notes
Refer to pg 12: Treatment of Hypertension with CCBs
(g) Mechanopharmacological therapy: Drug-eluting Endovascular stents
- Intracoronary stents: Scaffold that is placed into narrow, diseased vessels however no drug is released.
Major Drawback: Long term efficacy is limited by the subacte luminal restenosis within the stent (in-stent restenosis)
Possible causes: Smooth muscle proliferation within the lumen
Led to the development of drug-eluting endovascular stents
- Drug eluting Endovascular stent: A peripheral/coronary scaffold placed into narrow, diseased peripheral/coronary arteries that slowly releases the drug to block cell proliferation and prevent fibrosis as well as clots.
Function: Ameliorate angina and reduce adverse events in patients with acute coronary syndromes.
*With concurrent local anti-proliferative therapies, drug-eluting stents can be really beneficial in clincal practice.
- Two drugs used in intravascular stents: Paclitaxel and Sirolimus (rapamycin)
Paclitaxel Drug Profile:
–Cytotoxic drug used in the treatment of cancer
Mechanism: Inhibits cellular proliferation by binding to and forming rigid polymerized microtubules, thereby preventing cell division.
Sirolimus/Rapamycin Drug Profile:
–Immunosuppresent/Antibiotic drug used in the treatment of autoimmune diseases, prevents tissue rejection in organ transplants
Mechanism: Binds to cytosolic immunophillin (FKBP 12). The FKBP-12 sirolimus complex inhibits the protein kinase mTOR, thus inhibitng cell cycle progression.
-Link to Pharmacology B: Lecture Immunosuppressants
*Immunophilin: endogenous cytosolic peptidyl-prolyl isomerases that interconvert between the cis and trans positions
Note: Inhibition of cellular proliferation by sirolimus and paclitaxel not only affects vascular smooth muscle cell proliferation but also weaken the formation of an intaact endothelial layer within the stented artery
Important considerations of stents:
1. Stents might induce damage to the vascular endothelial layer. This leads to thrombosis.
-To prevent thrombosis, patients are treated with anti-platelet agents, including Clopidogrel (up to 6 months) and aspirin (for life)
-Sometimes used in conjunctoin with IV administered GPIIB/IIIa inhibitors (class of antiplatelet medications)–>Includes Abciximab, Eptifibatide, Tirofiban
Note: Inhibition of cellular proliferation by sirolimus and paclitaxel not only affects vascular smooth muscle cell proliferation but also weaken the formation of an intaact endothelial layer within the stented artery.
Thus, anti-platelet therapy is continued for several months after intracoronary stenting with drug-eluting stents.
-Rate of restenosis with drug-eluting stents is reduced greatly compared to bare metal stents (However, there is an increased risk of thrombosis especially if anti-platelet therapy is stopped prematurely.)