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KINETICS OF DRUG INTERACTIONS
Presented byS.L.S(M. Pharm)
15AB1SO308
Under the esteemed guidance ofProf.Dr.G.KISHORE BABU.,
M.Pharm ., Ph.D.HOD, Department Of Pharmaceutics
VIGNAN PHARMACY COLLEGE(Approved by AICTE, PCI & Affiliated to JNTU KAKINADA)
VADLAMUDI, GUNTUR DIST, ANDHRA PRADESH, INDIA,PIN:522 2132015
10-12-2015
• Definition.
• Types of interactions.
• Factors contributing to drug interactions.
• Conclusion.
• Reference.
CONTENTS
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Drug interaction can be defined as the modifications of the effects of one drug by the
prior or concomitant administration of another drug.
Drug that precipitates the interaction - Precipitant drug
Drug whose action is affected - Object drug
DEFINITION
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Drugs likely involved in interactions
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Drugs highly bound to plasma
proteins
Used for long term
Enzyme inducers or inhibitors
Two drugs simultaneously given for
same disease
Precipitating drugs
• Narrow therapeutic index
• Zero order kinetics
Object Drugs
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Factors contributing to drug interactions:
1. Multiple drug therapy.
2. Multiple prescribers.
3. Multiple pharmacological effects of drug.
4. Multiple diseases/predisposing illness.
5. Poor patient compliance.
6. Advancing age of patient.
7. Drug-related factors.
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DI
Food
DrugDisease
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Drug -Food
Interactions
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Drugs effect food By
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Food intakeAlteration
in gut flora
Nutrient absorption
Nutrient metabolism
Nutrient excretion
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How food can effect drugs
Increase absorption
Decrease absorption
Irritation of digestive tract No effect
• Rifampicin- without food
• Rifabutin- with food
• Rifapentin- no effect of food
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Milk
Fruit juice
Tea/coffee
Alcohol
Swallowing of the
medicine
• Erythromycin
• Ketoconazole
• celiprolol
Tetrcayclines
Bisacodyl
Iron supplements
Mercaptopurin
• Wine-tyramine
reaction• iron absorbtion
• theophylline
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DRUG – ALCOHOL
INTERACTIONS
In the absence of alcohol
After moderate alcohol consumption
In chronic heavy drinkers who are sober
In chronic heavy drinkers who are intoxicated
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Class Names Interaction Effect1. Analgesics Aspirin
Acetaminophen Increase gastric emptying
Toxic metabolite of acetaminophen
Faster alcohol absorbtion
Liver damage
2. Anticonvulsant Phenytoin Induces phenytoin breakdown
Decrease effect
3. Antihistamines Chlorpheniramine Increase CNS effect sedation4. Antidiabetics Chlorpropamide
GlyburideMetformin
Increase risk of hypoglycemia
UnconsciousnessDisulfiram like reactionLactic acidosis
5. BZDs Diazepam Increase effect Sedation10-12-2015 Vignan pharmacy college
Table:1
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Drug Drug Interactions
DI
Outside the body
Syringe Iv fluids
Inside the body
Pharmacokinetic
Pharmacodynamic
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Also called as incompatibility. It is a physicochemical interaction that occurs
when drugs are mixed in i.v . Infusions causing precipitation or inactivation of active
principles .
Example:-
Ampicillin , chlorpromazine & barbituates interact with dextran in solutions
and are broken down or form chemical compounds.
Pharmaceutical interactions
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Interactions outside the body
• Mixing of the drugs in the same syringe
1. Thiopentone and succinylcholine.
2. Carbenicillin inactivate aminoglycosides.
3. Hydrocortisone inactivates penicillins.
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Fig:1
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• Giving drug in i.v infusion
1. Quinopristin and Dalfopristin.
2. Ampicillin, sodium salts of phenytoin, heparin.
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Fig:2
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Unstable Infuse within 2-
4hrs
Stable for 6-8 hrs
Stable for 12 hrs
Photosensitive drugs
Not infused after 6 hrs
Ampicillin Benzyl penicillin Fluoxacillin Amphoterecin Cephaloridine
Erythromycin Diazepam Tetracycline Dacarbazine colistin
Stability of drugs in Saline or Dextrose solution
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Table:2
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Prevention of Pharmaceutical Interactions
1. Give iv drugs by bolus.
2. Do not add infusion solutions.
3. Avoid mixing of drugs in the same infusion.
4. Mix the drug thoroughly in the infusion.
5. Use 2 separate infusion sites if drugs administered simultaneously .
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Fig:3
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“These interactions are those in which ADME properties of the object drug is
altered by the precipitant and hence such interactions are also called as ADME
interactions”.
• The resultant effect is altered plasma concentration of the object drug.
PHARMACOKINETIC INTERACTIONS
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Interactions inside the body
Absorbtion Distribution
Excretion Metabolism
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.Drug interactions can effect the rate and the extent of systemic
drug absorption (Bioavailability)from the absorption site, resulting in
increased or decreased drug bioavailability.
• Faster or slower drug absorption.
• More, or, less complete drug absorption.
Absorption interactions
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Fig:4
Surface area
Motility
Alter GI PH
Chelation & Complexation
AlterIntestinal
flora
Alter drug transporter
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Fig:5
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Drug-induced mucosal damage.
Antineoplastic agents: e.g., cyclophosphamide vincristine procarbazine
Inhibit absorptionof several drugseg., digoxin
Surface area
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Al 3+ , Mg 2+ + Prednisolone Insoluble Complexes Ca2+ + TC Formation of chelating compounds
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Chelation and Complexation
Fig:6
Fig:7
Fig:8
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Antacid (aluminum or magnesium hydroxide) Decrease absorption of
ciprofloxacin by 85%
due to chelation
Cholestyramine + Digoxin and Warfarin (Resin)
BA of Digoxin and Warfarin
Sodium polystyrene + cations Renal clearence of
bicorbonate resulting in
systemic acidosis
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The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does.
Alteration in pH
PH Absorption of weak acids
PH Absorption of weak bases
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Fig:9
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antiacids Decrease the tablet dissolution of Ketoconazole (acidic)
H2 antagonists
Therefore, these drugs must be separated by at least 2h in the time of administration of both .
Increases absorption of weak bases likeAnti coagulents, warfarin, phenyl butazone
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Forming an absorbtive layer Cholestyramine inhibits absorbtion of Digoxin,warfarin
Sucralfate interferes with absorbtion of Phenytoin
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Fig:10
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Altered Gut flora
Bacterial flora has a marked role in metabolization
of some drugs.
Long term antibiotics may kill normal flora and
affect drug absorption.
Ex : erythromycin and digoxin
40% or more of the administered digoxin dose is
metabolised by the intestinal flora. Coadministration of
antibiotics leads to increase in digoxin levels.
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Fig:11
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Metoclopramide (antiemitic)
Increase absorption of cyclosporine due to the increase of stomach empting time
Increase the toxicityof cyclosporine
Altered gastric emptying
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Fig:12
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Atropine/opiods reduce absorption of drugs
Purgatives decrease absorbtion of digoxin
Psyllium + Fibre + fluid Increase in gi motility & decrease the time
available for coadministered drugs to be
absorbed
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Alteration of drug transporters
Oral drug inhibitor transporterDigoxin quinidine P gp
Paclitaxel Cyclosporin P gp
Effect on Transporters
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Table:3Fig:13
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TCA
Antipsychotics
Corticosteroids
Sulfonylureas
Methylphenidate
Fenfluramine
Dexfenfluramine
Sibutramine
Orlistat
appetite
appetite
Alteration in appetite
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Beneficial absorbtion interactions
Metoclopramide
Increases gastric emptying
Increases absorbtion of analgesic in treatment of acute attack of migraine
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There is an important factor :
Vd
Protein binding interactions :
- unbound molecules remain free and pharmacological active.
- bound molecules are pharmacological inactive.
Some drugs may compete others for binding to protein depending on affinity
and concentration.
Distribution Interactions
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Displacement from tissue binding site
Displacement from protein binding site
Impaired renal excretion
Quinidine given to a patient on digoxin
1. Displacement from tissue binding sites
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2. Displacement from plasma protein binding
Can be clinically important if 2 criteria are fulfilled
Drug should be highly protein bound (>90%)
Low apparent volume of distribution
Precipitant drugs involved
1. Salicylates
2. Phenylbutazone
3. Sulfonamides
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Warfarin (99% bound) and Phenytoin (90% bound)
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Fig:14 Fig:15
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Metabolism (biotransformation) Interactions
• Most drugs are chemically altered within Liver to less
toxic and less lipid-soluble metabolites.
• Hepatic metabolism has two pathways :
– Phase 1 (modification)
– Phase 11 (conjugation)
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Fig:16
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Pathways of drug metabolism
CYP450
Pathways of drug metabolism
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• CYP450 most important isoenzymes responsible for liver metabolism.– CYP 3A4– CYP 2D6– CYP 2C8
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Fig:17
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MetabolismEnzyme Induction
S No. Precipitant drug Object drug1. Alcohol Warfarin, Phenytoin2. Barbiturates Chlorpromazine, Phenytoin3. Phenytoin Tolbutamide4. Rifampicin Warfarin, Tolbutamide5. St. John’s Wort Carbamazepine, SSRIs, Warfarin
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Table:4
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Metabolism
Enzyme Inhibition
S No. Precipitant Drug Enzyme Object drug1. Allopurinol Xanthine Oxidase Azathioprine2. Carbidopa Dopa decarboxylase L-Dopa3. Disulfiram Aldehyde dehydrogenase Alcohol4. MAO Inhibitors Monomine Oxidase Amine containing
foods
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Table:5
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S.no Precipitant drug Object drug Effect
1. Cimetidine Diazepam CNS effects
2. Macrolides Theophylline Cardiac toxicity
3. Metronidazole Alcohol Disulfiram like action
4. Chloramphenicol Tolbutamide Hypoglycemia
Enzyme Inhibition
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Table:6
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Alteration in nutrient metabolism
Ex:
Anticoagulant drug warfarin and vitamin K
Statins inhibit HMG –CoA Reductase inhibitor – precursor for
cholesterol and coenzyme Q10
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Excretion Interactions
• Most drug are excreted in Urine or Bile.
• Some drugs are reabsorbed from renal tubules or
enterohepatic recirculation.
• Some drugs are excreted in acidic urine, so changing
urine PH will affect there serum level.
• These interaction is rare.
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Fig:18
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Mechanisms :
• Altered urine PH Change in active tubular secretion.
Some drugs may compete for excretion.
E.g. probenecid and penicillin.
Enterohepatic recirculation.
E.g. penicillins and oral contraceptives.
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Excretion
S. No. Precipitant Drug Object Drug Result
1. Probenecid Penicillin Penicillin Retention
2. Quinidine Digoxin Digoxin Toxicity
3. Salicylates Methotrextate Methotrexate toxicity
4. Salicylates Uricosuric Drugs Reduced Uricosuria
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Table:7
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Fig:19
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Alteration in nutrient excretion
• D- penicillamine & EDTA binds metals Zn2+ and eliminates it via urine.
• Diuretics cause loss of ions such as Mg 2+ ,K+ ,Na+ , Ca 2+.
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Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
● Opiates with Naloxone
● Warfarin with Vitamin K
These interactions occur when the pharmacodynamic effect of the drug is alter by
another drug, chemical ,or food element, producing an antagonistic, synergistic , or
addtive effect
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Fig:20
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2. Synergism at same site
● Effects of depolarising skeletal muscle relaxants potentiated
by antibiotics like aminoglycosides, polymixin B
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Dihydropteroate diphosphate+ P-aminobenzoic acid(PABA)
Dihydropteroate synthetase sulfonamides
Dihydropteroic acid
Dihydrofolic acid
× trimethoprim
Tetrahydro folic acid
×
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Fig:21
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3. Summation of similar effects at different sites
● Effect of alcohol as a depressant potentiated by other
centrally acting drugs
● Effect of trimethoprim and sulfamethoxazole
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B) Indirect Pharmacodynamic Interactions
1. Cardiovascular system
Loss of Antihypertensive action of ACEI with NSAIDS
Bradycardia- beta blockers + verapamil
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2. Fluid and electrolyte imbalance Thiazide and loop diuretics - hypokalemia
3. CNS Sedation- BZD+ Alcohol
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DRUG HERB
INTERACTION
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HERBS
Betel NutsArea Catechu• Contains
arecoline• Extrapyramida
l symptoms
Ginkgo Biloba• Inhibits PAF• spontaneous
Subarachnoid hemorrhage
St. Johns WortHypericum perforatin
• Inducer of CYP3A4
• May elevate serotonin
GarlicAllium sativum• Increases INR• Post operative
bleeding
LiquoriceGlycyrrhizin• Inhibits
degradation of cortisol
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• Polypharmacy people (elder)
• Hepatic disorders
• Renal disorders
• Genetic factors
Patients in high risk of drug interactions
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Fig:22
Fig:23 Fig:24Fig:25
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PHARMACIST’S ROLE IN DRUG INTERACTIONS
Advising
Monitoring
Reporting
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Fig:26
Fig:27
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Health care professionals and pharmacists have to play an important role in giving
advisory knowledge on monitoring concurrent use of herbal and conventional
medicines and to collect data for suspected drug interactions.
We need to bring into lime light about the drug interactions
CONCLUSION
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REFERENCES
LEON SHARGEL, ALANH.MUTNICK, PAULF.SOUNEY, LARRY
N.SWANSON, Comprehensive Pharmacy Review, Eight edition,
Pg.no: 271-276
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ROGER WALKER & CATE WHITTLESEA, Clinical Pharmacy and
Therapeutics, 5th Edition, Pg.no: 52-59
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Online Drug Interaction Checker
http://reference.medscape.com/drug-interactionchecker,,,,,,,https://online.epocrates.com/u/1300/MultiCheck?ICID=search-DDI,,,,,,http://www.drugs.com/drug_interactions.html
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THANKS TO ALL
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