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Prepared &Presented By

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abdulrahman magdy

on 14 July 2015

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Transcript of Prepared &Presented By

Drug Interactions
Therapeutic Index (margin of safety ) :
The ratio between the minimal toxic dose and the minimal effective dose of a drug ,
used as a measure of the relative safety of the drug for a particular treatment.
Drugs with Narrow therapeutic Index :

Aminophylline
Warfarin
Carbamazepine

Most of the drugs are metabolised by cytochrome P450 group enzymes,
Enzyme inducers
,These drugs increase the metabolism of other drugs by inducing CYP enzymes
and reduce their plasma levels and efficacy e.g.
Carbamazepine , barbiturates , rifampicine …

Enzyme Inhibitors,
These drugs reduce the metabolism of other drugs and increase their plasma levels e.g. Macrolide antibiotics ( Clarithromycin,Erythromycin) ,Itraconazole, Fluconazole ,
Antidepressants (Fluoxetine, Paroxetin) ,



Prepared &Presented By :
Pharmacist /
Magdy Rashed

Drug Interactions
Drug Interactions Definition :

A drug interaction occurs when a drug interferes in a negative or positive way with another drug.

It Can increase or lower the drug levels or their efficacy or increase their toxicity.
Risk Factors
High Risk Patients :
Elderly, young, multiple disease , Multiple drug therapy
Renal, Hepatic impairment

High Risk Drugs :
Narrow therapeutic index drugs
Recognised enzyme inhibitors or inducers


Drug Interactions Definition :

A drug interaction occurs when a drug interferes in a negative or positive way with another drug. It Can increase or lower the drug levels or their efficacy or increase their toxicity.
Risk Factors
High Risk Patients : Elderly, young, multiple disease
Multiple drug therapy
Renal, Hepatic impairment

High Risk Drugs :
Narrow therapeutic index drugs
Recognised enzyme inhibitors or inducers


Drug Interactions
Therapeutic Index
( Margin Of Safety )
Drug Interactions
Therapeutic Index (margin of safety ) :
The ratio between the minimal toxic dose and the minimal effective dose of a drug ,
used as a measure of the relative safety of the drug for a particular treatment.
Drugs with Narrow therapeutic Index :

Aminophylline
Warfarin
Carbamazepine

Most of the drugs are metabolised by cytochrome P450 group enzymes,

Enzyme inducers
:
These drugs increase the metabolism of other drugs by inducing CYP enzymes
and reduce their plasma levels and efficacy e.g.
Carbamazepine , barbiturates , rifampicine …

Enzyme Inhibitors,
These drugs reduce the metabolism of other drugs and increase their plasma levels e.g. Macrolide antibiotics ( Clarithromycin,Erythromycin) ,Itraconazole, Fluconazole ,
Antidepressants (Fluoxetine, Paroxetin)
,


Drug Interactions
Drug Interactions Types :

1. Drug–Drug interaction
2. Drug-Food/Nutrition interaction :
(eg. Milk, Grapefruit juice, etc)

3. Drug-Herb interaction :
(eg. Garlic, Spanich)
4. Drug-Disease interaction :
(Hepatic failure, Renal failure, Congest.HF ,Hypothyroidism,
Hyperthyroidism )
Mechanisms :
1. Pharmacokinetic interactions :
Alterations in Absorption .
Alterations in Distribution & Plasma protein binding .
Alterations in Hepatic Metabolism .
Alterations in Excretion .
2. Pharmacodynamic interactions .
PHARMACOKINETIC DRUG INTERACTIONS
a. Complexation/Chelation .
b. Altered GI transit .
c. Altered Gastric PH .
d. Alteration in gastrointestinal microflora .
a. Induction of metabolism .
b. Inhibition of metabolism .
a. Increased renal blood flow .
b. Inhibition of active tubular secretion .
c. Alterations in tubular reabsorption .
ALTERATIONS IN ABSORPTION
Rate & Amount
A. Complexation/ Chelation :
Antacids (Mg2+, Al3+ ions)
Make complex with Tetracycline,Ciprofloxacin
Reduced absorption of Tetracycline, ciprofloxaxcin
B. Altered GI Transit
antimuscarinic drugs
Buscopan Tablets
delay gastric emptying
reduce the rate, but not the extent, of paracetamol absorption

Metoclopramide
Increase
The Gastric Emptying
increases the rate of absorption of Nabroxone
( Some drugs for migraine used in USA contain Metoclopramide with paracetamol )
C. Altered gastric PH
H2 blockers (Ranitidine)
Reduce acid secretion
Increase PH
Reduce dissolution of Itraconazole
Reduce of Itraconazole Absorbtion
ALTERATIONS IN Distribution & PLASMA PROTEIN BINDING
Bounded molecules are inactive

Only unbound molecules are pharmacologicaly
active

ALTERATIONS IN DISTRIBUTION & PLASMA PROTEIN BINDING
Distribution
Clearance
Vd

The volume of plasma that gets filtered of drug/ unit time .

The measure of the space available in the body to contain the drug.
Vd =
Total Amount Of Drug In The Body
Conc. Of Drug In Plasma
=
Low Vd eg.
Warfarin & cotrimoxazole
High Vd
Clearance
Low Extraction Ratio
eg. Warfarin & cotrimoxazole
High Extraction Ratio
Therapeutic Drug Monitoring :
Eg, In case of Warfarin, monitor Prothrombin Time
ALTERATIONS IN DISTRIBUTION
& PLASMAPROTEIN BINDING
cotrimoxazole
(High Protein Binding)

Displaces the Warfarin from plasma protein binding

Elevates free Warfarin level
Increase the risk of Bleeding

ALTERATIONS IN HEPATIC METABOLISM
Active Drug
Metabolism
Inactive Drug

( Pro-Drug )
Eg. Codiene
( pro- drug )
Metabolism
Active Morphine
ASA
Metabolism
Active Salicylic Acid
Lipid Soluble Non-Polar
Metabolism
Water Soluble Polar
Excretion Kidney
Bile
Biological Membrane
Tubular
Reabsorbtion
( By Passive Reabsorbtion )
ALTERATIONS IN HEPATIC METABOLISM
Metabolising Enzymes ( CYP 450 )
( Most Important : CYP3A4 ,CYP2D6 , CYP2C9 , CYP2C19 , CYP1A2 )
Inducers : Induse the synthesis of M. Enzymes , so increase metabolism & decrease drug ( substrate ) efficacy causing therapeutic failiure
withdrawal may cause toxicity so, dose adjustment of concomitant
drugs is important

eg, Carbamazepine , Rifampicine , Phenobarbital ,
Induserses have delayed onset & prolonged recovery according to its half life
Carbamazepine is a self inducer so , must be initiated at low dose
then increased at wkly intervals ( half life decreases by time )
Inhibitors : more common , inhibit M. Enzymes action , so decrease metabolism & increase the conc. of D. & may cause toxicity ,
Inhibitory effect occur within 2-3 days
( pro-drugs conc. becomes sub-therapeutic )

e.g , Macrolide antibiotics ( Clarithromycin, Erythromycin ) , Fluconazole, Itraconazole , Antidepressants (Fluoxetine, Paroxetin) , Amiodarone , Grape fruits


Note : 1- not all CYP450 are important .
2- some drugs are metabolised by more than one enzyme .
3- each CYP450 have special gene differ from one to another .
ALTERATIONS IN HEPATIC METABOLISM
Examples of Common Drug Interactions Involving the CYP450 Enzyme System
Carbamazepine
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
Ethinyl estradiol
More Ethinyl estradiol
Metabolite ( Inactive )
Unplanned pregnancy
CYP Inducers
Itraconazole
CYP Inhibitors
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
Atorvastatin
Less Atorvastatin Metabolite
Myopathy


Rhabdomyolysis
ENTERO-HEPATIC RECIRCULATION
( Biliary Recycling )
ALTERATIONS IN RENAL CLEARANCE

2-Tubular Reabsorption :
*Depend on pH of urine
*Lipid soluble-Unionized drugs are reabsorbed back .
ALTERATIONS IN RENAL CLEARANCE
1-Glomerular Filtration :
*Only Unbound drugs
*Depends on renal Bl. Flow
eg, Hydralazine (Vasodilator) Raise the clearance of Digoxin
2-Tubular Reabsorption :
*Lipid soluble-Unionized drugs are reabsorbed back
*Depend on pH of urine
eg, Antacids Reduced tubular reabsorption of Salicylates (Aspirin)
3-Tubular Secretion :
*Competitive
*Carrier-Mediated transport processes
eg, Probenecid Inhibits tubular secretion of Penicillins
ALTERATIONS IN RENAL CLEARANCE

Increase in Renal blood flow
Hydralazine (Vasodilator)
Dilates the renal blood vessels
Increase the renal blood flow
Raise the clearance of Digoxin
2-Tubular Reabsorption :
Antacids
Reduce acid secretion
Increase the PH of urine
Reduced tubular reabsorption of Salicylates (Aspirin)
Increased Renal clearance of Aspirin
Inhibition of Active tubular secretion :
Probenecid
Inhibits tubular secretion of Penicillins
Icreased half life of Penicillins Single dose therapy
ALTERATIONS IN HEPATIC METABOLISM
Clopidogrel
CYP2C19 Inhibitors
Omeprazole ,
Esomeprazole ,
Fluxetine ,...
CYP2C19
Active Drug
1-Glomerular Filtration : *Only Unbound drugs

*Depends on renal Bl. flow
1-Glomerular Filtration : *Only Unbound drugs
*Depends on renal Bl. flow
3-Tubular Secretion :
*Competitive
*Carrier-Mediated transport processes

2-Tubular Reabsorption :
*Depend on pH of urine
*Lipid soluble-Unionized drugs are reabsorbed back .
1-Glomerular Filtration : *Only Unbound drugs
*Depends on renal Bl. flow
Pantoprazole , & to lesser extent Rabeprazle & Lansoprazole are more safe , Also H2 antagonist (Not cimetidine) can be used instead
Escitalopram Or Paroxetine can be used instead with monitoring due to possible PD interaction
NB. SSRIs + Plavix increase the risk of bleeding
Inhibits
Pharmacokinetic Drug Interactions
Atorvastatin
Itraconazole
Clarithromycin
Warfarin
Amiodarone
Rifampin
Escitalopram
Fluoxetine
Paroxetine
Clopidogrel
http://reference.medscape.com/drug-interactionchecker
Atorvastatin
Itraconazole
Serious
- Use Alternative
Possible serious or life-threatening interaction, Myopathy or Rhapdomyolysis .
Monitor closely. Use alternatives if available. Limit atorvastatin dose to 20 mg/day
Significant

- Monitor Closely
atorvastatin will increase the level or effect of itraconazole by P-glycoprotein (MDR1) efflux transporter.
Significant interaction possible, monitor closely.
Onychomycosis
Atorvastatin
Serious
- Use Alternative
Clarithromycin
High likelihood serious or life-threatening interaction. Avoid unless benefits outweigh risks and no alternatives available. Do not exceed atorvastatin dose of 20 mg/day when coadministered with clarithromycin
Serious
- Use Alternative
clarithromycin will increase the level or effect of atorvastatin by P-glycoprotein (MDR1) efflux transporter. High likelihood serious or life-threatening interaction. Contraindicated unless benefits outweigh risks and no alternatives available. Do not exceed atorvastatin dose of 20 mg/day when coadministered with clarithromycin
Serious
- Use Alternative
Clarithromycin
CYP3A4 Inhibitor
Both increase QTc interval. High likelihood serious or life-threatening interaction. Contraindicated unless benefits outweigh risks and no alternatives available.
Significant
- Monitor Closely
clarithromycin will increase the level or effect of itraconazole by :
P-glycoprotein (MDR1) efflux transporter. Significant interaction possible, monitor closely.
affecting hepatic/intestinal enzyme CYP3A4 metabolism. Potential for interaction, monitor.
Itraconazole
CYP3A4 Inhibitor
Serious
Use Alternative
Amiodarone
amiodarone increases levels of warfarin by inhibiting hepatic enzyme CYP2C9 within one to several weeks and may persist for months after the amiodarone is discontinued. Possible serious or life-threatening interaction. Monitor INR closely. An empiric 30% to 50% reduction in anticoagulant dosage has been recommended.
Warfarin
Serious
- Use Alternative
Both increase QTc interval. High likelihood serious or life-threatening interaction. Contraindicated unless benefits outweigh risks and no alternatives available.
Significant
- Monitor Closely
clarithromycin will increase the level or effect of itraconazole by :
P-glycoprotein (MDR1) efflux transporter. Significant interaction possible, monitor closely.
affecting hepatic/intestinal enzyme CYP3A4 metabolism. Potential for interaction, monitor.
Warfarin
Amiodarone
CYP2C9 Inhibitor
CYP450
Use alternative or additional way of birth control
during or for at least 2-4 wks after inducer stop
P- Glycoprotein
substrate
INDUCERS
INHIBITORS
Important only for drugs which are excreted unchanged
Important
Drug Interactions
****************************************
Antibiotics
Macrolides : Clarithromycin , Erythromycin

Quinolones : Cipro. , Moxi. , Levofloxacin

Co-trimoxazole
Statins
Atorvastatin

Rosuvastatin
Azole Anifungals
Itraconazole

Fluconazole

Ketoconazole
Blood Thinners
Warfarin

Clopidogrel

Aspirin
Proton Pump Inhibitors
Esomeprazole

Rabeprazole

Lansoprazole

Pantoprazole
Antidepressants
Fluxetine

Paroxetine

Tricyclic A.D.
Rosuvastatin , fluvastatin , pravastatin
not metabolized by CYP3A4
All patients receiving statin therapy should be advised
to report any unexplained muscle pain or weakness particularly when accompanied by fever & dark urine or grossly elevated CK (10 times in some cases) .
Drug that incease risk of statin toxicity :
Gemfibrozil ,Azole antifungls , Amiodarone ,
Macrolide A.B. (except Azithromycin) , colchicine
Patients should be advised to notify their physician promptly if they experience any signs of excessive anticoagulation such as unusual or prolonged bleeding, bruising, vomiting, change in stool or urine color, headache, dizziness, or weakness.
Magdy Rashed
Ph. Magdy Rashed
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