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DiltiazemDiltiazem ONE OF The CALCIUM ONE OF The CALCIUM

CHANNEL BLOCKER DRUGSCHANNEL BLOCKER DRUGS

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Generic NameGeneric Name:: diltiazem (dil TYE a zem).diltiazem (dil TYE a zem).

Brand NamesBrand Names:: Cardizem, Cardizem CD, Cardizem Cardizem, Cardizem CD, Cardizem

LA, Cardizem SR, Cartia XT, Dilacor LA, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Tiazac.XR, Diltia XT, Tiazac.

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Description :Description :

Diltiazem hydrochloride, is a Calcium channel Diltiazem hydrochloride, is a Calcium channel antagonist and widely used in the treatment antagonist and widely used in the treatment of certain types of cardiovascularof certain types of cardiovascular..

Chemically :Chemically : Chemically, diltiazem hydrochloride is Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5H)-one,3-(acetyloxy)-1,5-Benzothiazepin-4(5H)-one,3-(acetyloxy)-5[2 (dimethylamino)ethyl]-2,-3-dihydro-2( 4-5[2 (dimethylamino)ethyl]-2,-3-dihydro-2( 4-methoxyphenyl)-, mono-hydrochloride, (+ )-methoxyphenyl)-, mono-hydrochloride, (+ )-cis.cis.

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The chemical structure :The chemical structure :

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Physical properties :Physical properties :

Diltiazem hydrochloride It is soluble Diltiazem hydrochloride It is soluble in water, methanol and chloroform in water, methanol and chloroform and has a molecular weight of and has a molecular weight of 450.98 .450.98 .

the drug was stable at storage the drug was stable at storage temperatures, 5-55°C, for 12 temperatures, 5-55°C, for 12 weeks.weeks.

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Clinical Pharmacology :Clinical Pharmacology :

Diltiazem (DTZ) is a calcium antagonist widely Diltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina and-related used in the treatment of angina and-related heart diseases.heart diseases.

The therapeutic effects of diltiazem The therapeutic effects of diltiazem hydrochloride its ability to inhibit the cellular hydrochloride its ability to inhibit the cellular influx of calcium ions during membrane influx of calcium ions during membrane depolarization of cardiac and vascular smooth depolarization of cardiac and vascular smooth muscle.muscle.

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PharmacodynaPharmacodynamic :mic :

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1- Mechanisms of Action:1- Mechanisms of Action:

Diltiazem blocks the transport of calcium Diltiazem blocks the transport of calcium into the smooth muscle cell.into the smooth muscle cell.

Since calcium is important in muscle Since calcium is important in muscle contraction.contraction.

blocking calcium transport relaxes artery blocking calcium transport relaxes artery muscle and dilates coronary arteries and muscle and dilates coronary arteries and other arteries of the body other arteries of the body

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Hypertension:Hypertension: Diltiazem produces its antihypertensive effect Diltiazem produces its antihypertensive effect

by relaxation of vascular smooth muscle. by relaxation of vascular smooth muscle.

Angina :Angina :

This is With calcium antagonists has several This is With calcium antagonists has several advantages. Unlike other antianginal agents it advantages. Unlike other antianginal agents it does not alter heart rate, blood pressure, or does not alter heart rate, blood pressure, or conduction.conduction.

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2- Pharmacological Effect :2- Pharmacological Effect : Like other calcium channel antagonists, Like other calcium channel antagonists,

diltiazem decreases SA and AV conduction diltiazem decreases SA and AV conduction and has a negative inotropic effect.and has a negative inotropic effect.

Diltiazem hydrochloride decreases Diltiazem hydrochloride decreases vascular resistance (VR), increases cardiac vascular resistance (VR), increases cardiac output (COP) (by increasing stroke output (COP) (by increasing stroke volume), and produces a slight decrease in volume), and produces a slight decrease in heart rate. heart rate.

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PharmacokinetiPharmacokinetic : c :

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1.1. Absorption :Absorption :

Diltiazem is well absorbed from the Diltiazem is well absorbed from the gastrointestina1tract .gastrointestina1tract .

Route of drug administeration: Intranasal,Route of drug administeration: Intranasal, Intraperitoneal,Oral, Intraperitoneal,Oral,

Intracerebroventricular,Intravenous.Intracerebroventricular,Intravenous.

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2. Distribution :2. Distribution :

The plasma half-life of diltiazem is The plasma half-life of diltiazem is approximately 3.0-4.5 h.approximately 3.0-4.5 h.

Therapeutic blood levels of diltiazem Therapeutic blood levels of diltiazem appear to be in the range of 40-200 ng/mL.appear to be in the range of 40-200 ng/mL.

The diltiazem hcl is 70% to80% bound to The diltiazem hcl is 70% to80% bound to plasma protein.plasma protein.

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3. Metabolism :3. Metabolism :

Diltiazem hydrochloride is metabolized by the Diltiazem hydrochloride is metabolized by the liver it is hepatic first-pass effect .liver it is hepatic first-pass effect .

The two primary metabolites of diltiazem are The two primary metabolites of diltiazem are desacetyldiltiazem and desmethyldiltiazem.desacetyldiltiazem and desmethyldiltiazem.

Drugs which induce or inhibit hepatic Drugs which induce or inhibit hepatic microsomal enzymes may alter diltiazem microsomal enzymes may alter diltiazem disposition.disposition.

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4. Excreation :4. Excreation : The diltiazem excreated by kidney and in bile.The diltiazem excreated by kidney and in bile.

Diltiazem metabolites have been identified in Diltiazem metabolites have been identified in the urine of humans. Only 2% to 4% of the urine of humans. Only 2% to 4% of unchanged diltiazem appears in the urine. unchanged diltiazem appears in the urine.

These metabolites are more slowly excreted.These metabolites are more slowly excreted.

The elimination half-life after single or The elimination half-life after single or multiple dosing is 4 to 9.5 hours (mean 6.5 multiple dosing is 4 to 9.5 hours (mean 6.5 hours).hours).

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CONTRAINDICATIONCONTRAINDICATION

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1.1. Cardiac Conduction :Cardiac Conduction : Diltiazem hydrochloride prolongs AV Diltiazem hydrochloride prolongs AV

node refractory periods.node refractory periods.

2. Congestive Heart Failure :2. Congestive Heart Failure : Diltiazem has a negative inotropic Diltiazem has a negative inotropic

effect.effect.

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3. Hypotension :3. Hypotension : Decreases in blood pressure.Decreases in blood pressure.

4. Acute Hepatic Injury :4. Acute Hepatic Injury : Mild elevations of transaminases with Mild elevations of transaminases with

and without elevation in alkaline and without elevation in alkaline phosphatase and bilirubin. phosphatase and bilirubin.

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5. Nursing Mothers :5. Nursing Mothers : Diltiazem is excreted in human milk.Diltiazem is excreted in human milk.

6. Pregnancy6. Pregnancy :: Have embryo and fetal lethality, a Have embryo and fetal lethality, a

propensity to cause abnormalities of the propensity to cause abnormalities of the skeleton, heart, retina, and tongue of skeleton, heart, retina, and tongue of embryo. embryo.

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Drug InteractionsDrug Interactions

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1.1. Beta Blockers :Beta Blockers : Diltiazem hydrochloride with propranolol Diltiazem hydrochloride with propranolol

resulted in increased propranolol 50%.resulted in increased propranolol 50%.

2. Cimetidine2. Cimetidine ::   Increase in diltiazem plasma levels Increase in diltiazem plasma levels

(58%) after a 1-week course of (58%) after a 1-week course of treatment.treatment.

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3. Digitalis :3. Digitalis : Diltiazem hydrochloride with digoxin Diltiazem hydrochloride with digoxin

increased plasma digoxin concentrations increased plasma digoxin concentrations approximately 20%. approximately 20%.

4. Cyclosporine :4. Cyclosporine : A reduction of cyclosporine dos ranging from A reduction of cyclosporine dos ranging from

15% to 48% . 15% to 48% . The effect of cyclosporine on diltiazem plasma The effect of cyclosporine on diltiazem plasma

concentrations has not been evaluated. concentrations has not been evaluated.

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5. Carbamazepine :5. Carbamazepine : Diltiazem with carbamazepine result in Diltiazem with carbamazepine result in

elevated serum levels of carbamazepine elevated serum levels of carbamazepine (40% to 72% increase).(40% to 72% increase).

6. Benzodiazepines6. Benzodiazepines :: Diltiazem increased of benzodiazepinesDiltiazem increased of benzodiazepines(midazolam and triazolam). (midazolam and triazolam).

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7. Lovastatin :7. Lovastatin : Diltiazem (120 mg)with lovastatin Diltiazem (120 mg)with lovastatin

resulted in a 3-4 times increase in resulted in a 3-4 times increase in lovastatin.lovastatin.

8. Rifampin8. Rifampin :: Rifampin with diltiazem lowered the Rifampin with diltiazem lowered the

diltiazem plasma concentrations to diltiazem plasma concentrations to undetectable levels. undetectable levels.

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9. Anesthetics :9. Anesthetics : with anesthetics may be potentiated with anesthetics may be potentiated

by calcium channel blockers. by calcium channel blockers.

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ADVERSE ADVERSE REACTIONSREACTIONS

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1.1. Cardiovascular :Cardiovascular : Angina, arrhythmia, AV block (second- or Angina, arrhythmia, AV block (second- or

third-degree), congestive heart failure, third-degree), congestive heart failure, hypotension, palpitations, tachycardia.hypotension, palpitations, tachycardia.

2. Nervous System2. Nervous System :: Abnormal dreams, gait abnormality, Abnormal dreams, gait abnormality,

hallucinations, insomnia, nervousness, hallucinations, insomnia, nervousness, personality change, tremor. personality change, tremor.

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3.3. Gastrointestinal :Gastrointestinal : Anorexia, constipation, diarrhea, dry Anorexia, constipation, diarrhea, dry

mouth, nausea,vomiting, weight mouth, nausea,vomiting, weight increase.increase.

4. Dermatological4. Dermatological :: Petechiae, photosensitivity, pruritus.Petechiae, photosensitivity, pruritus.

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The toxic dose in man is not known.The toxic dose in man is not known. The resultant are bradycardia, The resultant are bradycardia, hypotension, heart block, and hypotension, heart block, and

cardiac failure.cardiac failure.

OVERDOSAGE OVERDOSAGE

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1.1. Bradycardia :Bradycardia : Administer atropine (0.60 to 1.0 mg).Administer atropine (0.60 to 1.0 mg).

2. High-Degree AV Block2. High-Degree AV Block :: Administer atropine (0.60 to 1.0 mg).Administer atropine (0.60 to 1.0 mg). should be treated with cardiac pacing.should be treated with cardiac pacing.3. Cardiac Failure :3. Cardiac Failure : Administer inotropic agents Administer inotropic agents

(isoproterenol, dopamine, or dobutamine) (isoproterenol, dopamine, or dobutamine) and diuretics.and diuretics.

4. Hypotension :4. Hypotension : Vasopressors (e.g., dopamine or Vasopressors (e.g., dopamine or

levarterenol bitartrate).levarterenol bitartrate).

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DOSAGE AND DOSAGE AND ADMINISTRATIONADMINISTRATION

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1.1. Hypertension :Hypertension : Usual starting doses are 120 to 240 Usual starting doses are 120 to 240

mg once daily. usually observed by 14 mg once daily. usually observed by 14 days of chronic therapy.days of chronic therapy.

2. Angina2. Angina :: Starting with a dose of 120 mg to 180 Starting with a dose of 120 mg to 180

mg once daily. over 7 to 14 days.mg once daily. over 7 to 14 days.

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Route of drug Route of drug administerationadministeration: : Intranasal,Intraperitoneal,Oral, Intranasal,Intraperitoneal,Oral, Intracerebroventricular,Intravenous.Intracerebroventricular,Intravenous.

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Doasage :Doasage : Usual capsules contain diltiazem Usual capsules contain diltiazem

hydrochloride beads at doses of hydrochloride beads at doses of 120,180,240,300,360and 420 mg.120,180,240,300,360and 420 mg.

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Side EffectsSide Effects

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Less serious side effects :Less serious side effects : Flushing(redness). Flushing(redness). headache. headache. Constipation,diarrhea,or nausea. Constipation,diarrhea,or nausea.

Fatigue or triedness . Fatigue or triedness . Decrease blood pressure and worsening. Decrease blood pressure and worsening. rash.rash. Difficulty urinating.Difficulty urinating. Slow heart rateSlow heart rate Tingaling sensation in the arm. Tingaling sensation in the arm.

but more common slow heart rate and but more common slow heart rate and constipation.constipation.

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More serious side effects :More serious side effects : Allergic reaction.Allergic reaction. Abnormal behavior or psychosis.Abnormal behavior or psychosis. Jaundice.Jaundice. Sever dizziness.Sever dizziness. Slurred speech.Slurred speech. Confusion..Confusion.. PruritisPruritis Leg swelling.Leg swelling. Heart failure.Heart failure.

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ConclusionConclusion::

Amldipine: Amldipine: it is widely used ca channel blocker in it is widely used ca channel blocker in

controlling morning blood pressure because controlling morning blood pressure because of its long half life 30-50h .of its long half life 30-50h .

Nifedipine:Nifedipine: Is used in treatment of hypertension,angina Is used in treatment of hypertension,angina

and to control preterm labour.It is not used if and to control preterm labour.It is not used if there is ischemic heart disease,hepatic there is ischemic heart disease,hepatic dysfunction or chronic malabsorption dysfunction or chronic malabsorption syndrome. syndrome.

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Feldopine(piendil):Feldopine(piendil): Is indicated mainly for treatment Is indicated mainly for treatment

hypertension and arrhythmia and the hypertension and arrhythmia and the most common side effect reported most common side effect reported with feldopine administerated as with feldopine administerated as monotherepy were peripheral edema monotherepy were peripheral edema and headache.and headache.

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Verpamil: Verpamil: It is used to tretment stable It is used to tretment stable

angina,un stable angina .Most angina,un stable angina .Most common adverse reaction : common adverse reaction : constipation ,dizziness and nausea.constipation ,dizziness and nausea.

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Diltiazem :Diltiazem : its used to treatment the high blood its used to treatment the high blood

pressure ,control chest pain and to pressure ,control chest pain and to slow unusually fast heartbeats.slow unusually fast heartbeats.

contraindication:is contraindication:is pregnancy ,nursing mother,allergic pregnancy ,nursing mother,allergic reaction ,kidney,liver,BV,or heart reaction ,kidney,liver,BV,or heart disease.disease.

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Thank youThank you

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Provised by:Provised by:

Dr. HananDr. Hanan

Produced by:Produced by:

Ahlam FahdAhlam Fahd