Drug class 7: Calcium Channel Blockers (CCBs)

Calcium Channel Blockers

7.1 Subtypes

1. Dihydropyridine/DHPs (Amlodipine, Felodipine, Nimodipine, Nifedipine)

2. Benzothiazepine (Diltiazem)

3. Phenylalkylamine (Verapamil)

7.2 Mechanism

1. Block inward current of calcium into cells in vascular smoth muscle, myocardium and cardiac conducting system via L-type Ca2+ chns.

2. Dihydropyridines– Act mainly on vascular smooth muscle to reduce peripheral vascular resistance (Decrease TPR), minimal effect on normal myocardial cells at therapeutic doses.

3. Nimodipine and Flunarizine (Not used in australia-Treatment of migraine headaches or vertigo)– Prevent cerebral ischemic damage from reactive vasospasm after subarachnoid hemorrhage by dilating cerebral vessels and increasing blood flow.

4. Verapamil-Mainly cardiac effects, reducing contractility, heart rate and almost negligible effect on vascular smooth muscle.

5. Diltiazem (Partial)– Acts on both cardiac and vascular smooth muscle but it has less effect on cardiac cells than verapamil.

*CCBs differ in their chemical nature, sites of action and therapeutic effects (Not all CCBs are born equal)

7.3 Clinical Indications

1. Hypertension

2. Angina

*Clinically decreased afterload and reflex increases in heart rate compensate for CCB-induced negative inotropic effects except in patients with impaired left ventricular function (e.g. CHF).

7.4 Precautions

1. Myasthenia-like neuromuscular disease (muscle weakness) -CCBs may increase risk of muscle weakness and respiratory depression (mostly with verapamil)

2. Cardiovascular

-Contraindicated in cardiogenic shock. In heart failure or significantly impaired left ventricular function, there is a risk of furthur depression of cardiac function (greatest risk with verapamil-Cardio-specific, followed by diltiazem, least risky would be DHPs)

*Even though Diltiazem is less risky in LVF failure, exercise caution regardless.

-Angina symptoms may worsen when starting a DHP (due to reflex cardiac stimulation/Baroreceptor reflex-Tachycardia, Increased contractility occurs). May occur if CCBs stopped abruptly.

-Aortic stenosis. DHRs may cause coronary hypoperfusion and systemic hypotension.

3. Hepatic Impaired (Dose reduction may be required)

4. Elderly. *Start treatment at a lower dose

5. Pregnancy

-Maternal hypotension, primarily caused by short-acting products, may cause fetal hypoxia (CAT C-AUS)

However, nifedipine is used for pre-term (premature) labour

6. Breastfeeding

-Limited data is available for Nifedipine, Diltiazem and Verapamil but Nifedipine seems safe to use. *Avoid breastfeeding in on any CCBs.

7.5 Side effects/Adverse effects

-Adverse effect profile varies between specific CCBs according to relative effects on vascular, myocardial and conducting tissue. Check each CCB.

-DHPs especially cause headache, flushing peripheral edema and palpitations.

1. Rash

2. Constipation (Verapamil)

3. Cough, Wheezing

4. Nausea, Headache, Flushing (Hypotension related)

5. Pulmonary edema

6. Peripheral edema

7. Arrhythmias-Bradycardia (Diltiazem, Verpamil)

8. Fatigue

9. Gingival Hyperplasia

10. Abdominal pain (Not in Joe’s notes)

*All the above are common side effects.

Infrequent side effects:

DHPs-Pulmonary edema, hypotension, tachycardia, chest pain, dyspepsia (Indigestion, impaired digestion), Constipation (General-Not Verapamil), Paraesthesia (Abnormal Sensation of tingling), Muscle Cramps, Polyuria (Excessive urine produced), Rash

Diltiazem: AV-block

Verapamil: Elevation of hepatic enzymes, AV-block, developing or worsening of heart failure

Rare:

Parkinson’s disease

DHPs:Cerebral and myocardial ischemia (Following excessive fall in BP)

Diltiazem:Hypersensitivity reactions including Stevens-Johnson syndrome (SJS) and exfoliative dermatitis, hepatitis, gingival hyperplasia

Verapamil: Gynaecomastia, hepatitis, gingival hyperplasia

7.6 Comparative information

For hypertension:

-Effect of CCBs on arterial pressure is similar to that of other antihypertensives e.g. diuretics, B-blockers and Ace-inhibitors

*Diltiazem and verapamil had no advantage over diuretics or beta-blockers in terms of overall prevention of cardiovascular events (however specifically, there is less occurance of stroke and more MI with diltiazem)(More heart failure with  verapamil)–>Increased incidence of adverse effects.

*Long-acting Nifedipine and Felodipine are as effective as diuretics or beta-blockers in the elderly (difference in preventive efficacy cannot be ruled out)

For Heart Failure:

*Verapamil and Diltiazem are contraindicated with patients with CHF and can be combined with B-blockers only under close surveillance and only in patients without ventricular dysfunction.

*Amlodipine and Felodipine have been shown to not increase deaths/morbidity in CHF.

For Prevention of angina:

-Their symptomatic efficacy is similar to that of B-blockers. However, only controlled release verapamil has been shown to decrease the incidence of cardiovascular events in stable angina and reduce risk of re-infarction and death after MI.

For other indications:

*Verapamil is useful for the prevention and treatment of Sino-ventricular tachycardias (SVTs) and for ventricular rate control in Atrial Filbrilation and atrial flutter.

*Nimodipine is used to prevent and treat ischemic neurological deficits after subarachnoid hemorrhage (CROSS BBB)

*Nifedipine used for pre-mature labour.

7.7 Duration of action

-Duration of action of DHPs differ depending on pharmacokinetics and formulation used.

-Nifedipine and Felodipine absorbed rapidly and have relatively short half-lives. Controlled release products are available to prolong their duration of action and facilitate once daily dosage.

*Amlodipine and Lercanidipine have a longer half life and can be administered once daily. *Note: They have slower onset of action, which may take longer to reach maximal response.

7.8 Practice Points

*DHP-induced peripheral edema does not require treatment with diuretics, which may put patient at risk of volume depletion.

7.9 Types of CCBs

1. Amlodipine

Indications: (a) Hypertension (includes combinations with olmesartan, telmisartan, valsartan, valsartan + Hydrochlorothiazide combination)  (b) Angina

  • Combination with atorvastatin (Cholesterol lowering class)
  • Combination with perindopril (ACE-inhibitor) (For Hypertension if already maintained on perindopril and amlodipine) or (For stable coronary heart disease if already maintained on perindopril and amlodipine)

2. Felodipine

Indications: Hypertension (includes combination with ramipril) [Rf]

***Counselling: Swallow tablet whole, do not crush or chew. Avoid grapeful juice as it may increase the risk of side effects with felodipine.

3. Lercanidipine

Indications: Hypertension (Includes combination with enalapril) [El]

Precautions: Treatment with cyclosporin (Immunosuppressant) (manufacturer contraindicates combination)

  • Renal impaired-Contraindicated if Creatinine Clearance <12ml/min
  • Hepatic impaired-Contraindicated in severe hepatic impairment

4. Nifedipine

Indications: (a) Hypertension (b) Angina (c) Pre-term labour/Premature Labour (Accepted indication)

*Counselling-Swallow controlled release tablet whole, do not crush or chew.

*Practice points:

  • When treating angina, controlled release tablets may be more appropriate than conventional tablets as they do not increase heart rate to the same extent.
  • Stop nifedipine if marked hypotension or dyspnea (shortness of breath) occurs.

5. Nimodipine

Indications: Prevention and treatment of ischemic neurological deficits following subarachnoid hemorrhage

*Precautions:

  • Ethanol content (infusing at 2mg/hour for 24 hours will deliver about 50g of ethanol)
  • Cerebral edema or severly raised intra-cranial pressure (Caution: Use with close monitoring)
  • Hypotension-Risk of aggravation
  • Other drug interactions: Manufacturer contraindicates use of oral nimodipine with rifampicin, phenobarbitone, phenytoin or carbamazepine (Treatment with drugs that affect CYP3A4 may affect nimodipine’s clearance and activity)
  • Treatment with disulfiram (treatment of alcohol disorders) or metronidazole (antibiotic) may cause reactions with ethanol as nimodipine infusion contains ethanol (about 25%)
  • Hepatic impaired: Requires lower dosage in hepatic impairment, monitor BP and pulse rates

*Adverse effects:

Rare: Bradycardia, Paralytic ileus (Paralysis of the intestine)

*Administration advice

-Give infusion via a central catheter using an infusion pump.

*DO NOT use PVC giving sets because of loss of nimodipine and contamination by plasticisers; use polyethylene sets instead.

*Counselling: (For Tablets) Avoid grapefruit juice as it may increase the risk of side effects with nimodipine.

*Practice Points: High morbidity and mortality after aneurysmal subarachnoid hemorrhage is associated with neurological damage from bleeding (initial and recurrent) and cerebral ischemia due to reactive vasospasm. Early medical treatment aims to prevent vasospasm and re-bleeding and to stablise the patient for surgery.

6. Diltiazem

Indications: (a) Angina (b) Hypertension (controlled release) (c) Atrial Filbrilation (Ventricular Rate control-Accepted Indication)

Precautions:

1. Cardiovascular-Contraindicated in severe bradycardia and sick sinus syndrome (SSS), second or third-degree AV block (without pacemaker) or hypotension (systolic BP <90mmHg)

-Diltiazem may cause hypotension, bradycardia and shows cardiac conduction.

-Treatment with drugs that can cause bradycardia will worsen heart rate and cause hypotension. *Monitor cardiac function.

*Diltiazem is metabolised by CYP3A4. It also inhibits CYP3A4, thus Diltiazem may increase the concentration of other drugs metabolised by this enzyme–> Leading to toxicity

7. Verapamil

Indications: (a) SVT with atrioventricular nodal re-entry (b) Atrial Filbrilation or atrial flutter (Ventricular rate control) (c) Hypertension, including combination with trandolapril [Tv] (d) Angina

Precautions:

1. Cardiovascular

-Contraindicated in severe bradycardia, sick sinus syndrome, 2nd or 3rd degree AV block (without pacemaker), hypotension (systolic BP<90mmHg), AF or atrial flutter complicating Wolff-Parkinson-White syndrome or wide complex ventricular tachycardia (IV use).

-Verapamil may worsen first degree AV block (greater risk than with diltiazem)

2. Other drugs

(a Treatment with anti-arrhythmics. Increase risk of heart failure, bradycardia may furthur decrease heart rate and cause hypotension. Use of beta-blockers is not recommended, unless under specialist supervision. *Monitor cardiac function.

(b) Contraindicated with Dabigatran (anti-coagulant). Combination not allowed.  Dabigatran can however be used with conventional and controlled released verapamil.

*Administration advice: 

-Give IV injections slowly under continuous ECG monitoring over 2-3 minutes. Rapid IV administration may result in hypotension, bradycardia, heart block and asystole (flatline, no cardiac electrical activity)

*Counselling

-Swallow controlled release products whole. DO NOT CRUSH OR CHEW if necessary, capsules may be opened and the contents can be sprinkled onto apple sauce and taken immediately.

-Verapamil may increase the effects of alcohol so that patients may be more easily affected and the effects last longer. Limit alcohol intake until you know whether you are affected like this. 

*It is metabolised by CYP3A4. Administration with drugs that inhibit this enzyme may increase its concentration and risk of adverse effects. Combination with inducers may decrease its concentration and possibly its efficacy.

*Verapamil also inhibits P-glycoprotein. If given with one of the enzyme’s substrates, the substrate’s concentration and risk of adverse effects may increase.

7.10 Drug Interactions

  • Amlodipine, Felodipine, Lercanidipine, Nifedipine , Nimodipine, Diltiazem and Verapamil  Acronym: (AFL, Not Now Damn Vexing)
  • CCBs also cause hypotension. Thus, administration with other drugs that can decrease BP can result in additional hypotension!!!
  • Amlodipine specific

-Cyclosporin

-Ritonavir (Ritonavir with indinavir increases amlodipine concentration and possibly risk of adverse effects. Monitor for adverse effeects and reduce amlodipine dose if neccessary.

  • Diltiazem specific

*Diltiazem is metabolised by CYP3A4. It also inhibits CYP3A4, thus Diltiazem may increase the concentration of other drugs metabolised by this enzyme–> Leading to toxicity

1. Alfentanil

2. Atorvastatin

3. Atazanivr (Increases concentration of diltiazem and its metabolite, increasing the drug’s therapeutic and adverse effects. Both drugs also increase the PR interval)

4. Buspirone (Anti-anxiolytic)

5. Calcineurin inhibitors (e.g. Tacrolimus, Sirolimus, Cyclosporin)

6. Carbamazepine (Anti-epileptic)

7. Cilostazol (Improves walking speed in patients with intermittent claudition/Muscle pain)

8. Cimetidine (Anti-histamine)-Inhibit diltiazem’s metabolism, increasing its concentration, therapeutic and adverse effects. Monitor clinically and decrease diltiazem dose if necessary.

9. Cisapride

10. Colchichine (Anti-Gout)

11 Cyclosporin

12. Digoxin

13. Efavirenz (May decrease the concentration of diltiazem and its metbaolites, possibly decreasing its efficacy, monitor clinical effects and increase dose of Diltiazem if necessary)

14. Eplerenone

15. Impiramine

16. Ivabradine

17. Methylprednisolone

18. Midazolam

19. Phenytoin

20. Rifampicin (Increase metabolism of diltiazem, possibly decreasing its therapeutic effects; monitor clinical effects and incresae dose if necessary)

21. Ritonavir (Combination with Indinavir may incresae diltiazem concentration and possibly risk of adverse effects. Monitor adverse effects and reduce diltiazem dose if neccesary.)

22. Simvastatin

23. Tigacrelor (ADP inhibitor)

24. Triazolam

  • Felodipine specific

1. Erythromycin (inhibits felodipine metabolism, increasing its concentration, with possible increase in adverse effects)

2. Itraconazole (Decreases metabolism of felodipine increasing its concentration and risk of adverse effects. The risk of heart failure may also increase as they both have a negative inotropic effect.)

*Avoid combination or monitor for adverse effects. Reduce felodipine dose if necessary.

3. Tacrolimus

  • Lercanidipine specific

1. Cyclosporin

2. Ketoconazole (Markedly increases concentration and activity of lercanidipine). *Avoid combination or monitor BP and reduce dose if required.

3. Metoprolol-Decreases lercanidipine concentration and may reduce its activity. *Monitor BP and adjust dose if necessary.

  • Nifedipine specific

1. Cimetidine (Cimetidine incresaes nifedipine concentration and risk of adverse effects). Use an alternative H2 antagonists or monitor for adverse effects and reduce nifedipine dose if necessary.

2. Fluconazole (Inhibits nifedipine metabolism, increasing its concentration and risk of adverse effects). *Monitor BP and for adverse effects of nifedipine (e.g. ankle swelling and decrease dose if necessary)

3. Indinavir (Combination with ritonavir may increase nifedipine concentration. It increases the risk of adverse effects. *Monitor BP and for adverse effects of nifedipine-Ankle swelling)

4. Itraconazole

4. Magnesium sulfate

5. Rifampicin (May increase metabolism of nifedipine and reduce its efficacy. Monitor BP and increase nifedipine dose if necessary-May need to be substantial)

6. Tacrolimus

  • Nimodipine

-Causes bradycardia. Administration with other drugs that slow down the heart rate may result in additional bradycardia.

-Use of oral nimodipine with rifampicin, phenobarbitone, phenytoin or carbamazepine (Contraindicated)

  • Verapamil

-Combining verapamil with dysarrhythmics increases risk of heart failure, bradycardia and proarrhythmic effect. 

*Avoid such combinations with anti-arrhythmics unless there is no alternative (Refer to pg 195 of extra CCB notes for specific interactions)

*Verapamil slows cardiac conduction and causes bradycardia. Administration with other drugs that also decrease heart rate may cause additive bradycardia and hypotension. *Monitor Cardiac function.

*Avoid combination of verapamil with beta-blockers, including eye drops (unless under specialist supervision)

*It is metabolised by CYP3A4. Administration with drugs that inhibit this enzyme may increase its concentration and risk of adverse effects. Combination with inducers may decrease its concentration and possibly its efficacy.

*Verapamil also inhibits P-glycoprotein. If given with one of the enzyme’s substrates, the substrate’s concentration and risk of adverse effects may increase. 

1. Buspirone

2. Carbamazepine

3. Colchicine

4.  Cyclosporin

5. Dabigatran

6. Digoxin

7. Eletriptan

8. Eplerenone

9. Erythromycin

10. Everolimus

11. Sirolimus and derivatives

12. Ivabradine

13. Midazolam

14. Phenobarbitone (increases metabolism of verapamil. Decreases its concentration and therapeutic effect. *Monitor clinical effect and increase dose of verapamil if necessary)

16. Rifampicin (Increases metabolism of verapamil, decreasing its concentration and therapeutic effect–>IV verapamil seems unaffected). *Avoid combination if possible, otherwise monitor clinical effect and increase verapamil dose if necessary.

17. Simvastatin

 

7.11 Important Clinical Points

For hypertension:

*CCBs are effective in any age group (including children), White or Black populations with low renin levels (as monotherapy or combined with other antihypertensive agents including diuretics, B-blockers or ACE-inhibitors).

-As monotherapy, the CCBs that have been used to treat hypertension to be equally effective, controlling BP in approx 60%-80% of patients with mild to moderate hypertension.

Safe to use in patients with COPD, peripheral atherosclerotic disease or Raynaud’s phenomenon. 

-Additional benefits in hypertensive patients with concomitant angina pectoris, supraventricular tachycardia (verapamil) or peripheral vascular disease (nifedipine).

*CCBs Not Recommended as first line anti-hypertensive therapy.

*In patients with diabetic nephropathy, diltiazem is the CCB (but not the drug) of choice. It reduces proteinuria. Nifedipine should not be used in patients as it increases proteinuria.

 

For Angina:

In chronic stable agina and unstable angina, CCBs are the second or third line agents after Beta-blockers and oral nitrates. CCBs appear to be as effective as B-blocker

(This means that oral nitrates is first line therapy in stable, unstable angina followed by beta-blockers and CCBs)

*In prinzmetal angina, CCBs are the drug of choice (particularly diltiazem and verapamil).

 

 

 

 

 

 

 

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