kinetics of drug interactions

Vignan pharmacy college 1

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


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


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


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


• Giving drug in i.v infusion

1. Quinopristin and Dalfopristin.

2. Ampicillin, sodium salts of phenytoin, heparin.

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Fig:2


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


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


“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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


PHARMACIST’S ROLE IN DRUG INTERACTIONS

Advising

Monitoring

Reporting

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Fig:26

Fig:27


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


THANKS TO ALL

10-12-2015

kinetics of drug interactions

Health & Medicine