Drug-Drug interaction (Silent Epidemic)

By Mohie Aldien (MD)

Definitions and Terms • Side Effects: unintended, usually detrimental, consequences

• Adverse: untoward, unintended, possibly causing harm

• AE: Adverse Event, Effect or Experience

• ADE (AE associated with a Drug): an AE which happens in a patient taking a drug

• ADR (Adverse Drug Reaction): an ADE in which a causal association is suspected between the drug and the event

Unfortunately, these terms are frequently used interchangeably

•Drug Interactions:“ The pharmacologic or clinical response to the administration of a drug combination different from that anticipated from the known effects of the two agents when given alone ”

1Tatro DS (Ed.) Drug Interaction Facts. J.B. Lippincott Co. St. Louis 1992.

Why Are There So Many ADRs? • Two-thirds of patient visits result in Rx

• 3 BILLION outpatient Rx per year

• Specialists give 2.3 Rx per visit

• Medicare Patients (2003, before drug benefit)

– 89.2% take a prescription medicine daily

– 46.1% take ≥5 prescriptions chronically

– 53.6% take meds Rxed by 2 or more doctors

– 5% obtain an Rx from Canada/Mexico

• ADRs increase exponentially with ≥4 Rx

Leape LL et al. JAMA 1995;274(1):35–43.

Raschetti R et al. Eur J Clin Pharmacol 1999;54(12):959–963.

Contribution of Drug Interactions to the Overall Burden of Preventable ADRs

• Drug interactions represent 3–5% of preventable in-hospital ADRs

• Drug interactions are an important contributor to the number of ER visits and hospital admissions

0 10 20 30 40 50 60

Being Given the Wrong Drug

Being Given Drugs that Interact

Cost of Treatment

Complications of Treatment

Having Enough Information

Getting an Infection in the Office/Hospital

Side-Effects from a Medicine

Receiving too much Medicine

Suffering Pain

Cost of Prescriptions once discharged

% of Patients

Primary Worries in Primary Care: 1,008 Patients

Source: American Society of Health Systems Pharmacists.

ASHP Patient Concerns National Survey Research Report, 1999.

Prescriber’s Knowledge

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Patient Education

Monitoring

ADR

Drug Interaction Defenses

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

Drug Administration

Pharmacogenetics

Drug A + Drug B

Latent Failures

Defenses

Drug-Drug Interactions classification:

•According to effect:

A-Harmful Effects (potentiating/antagonism)

B- Beneficial Effects (Additive or Synergistic)

II) According to site of interaction:

A) In-vitro:

1-Drug-laboratory tests interaction:

Mixture Mixing into Result

•Thiopentone+ suxamethonium

•Heparin + hydrocortisone

•Kanamycin + hydrocortisone

•Kanamycin + pencillin

•Soluble insulin + PZ insulin.

•Penicillin + hydrocortisone

•B-lactam antibiotic + gentamycin

•Pz insulin +Heparin (Acid)

•Thiopentone (Alkaline) +

Succinylcholine (Acid)

•Same syringe •Precipitation(ppt)

•Inactivation of heparin

•Inactivation of kanamycin

•Inactivation of pencillin

•Ppt of soluble insulin.

•Inactivation of penicillin

•Mutual inactivation

•Neutralization

•Neutralization

•Na salt of barbiturate, phenytoin,

sulphonamide ,heparin ,peniciline,

Diazep. Amamphotricin,

Hydrocortisone .

•Ampicillin, Barbiturates &

Ascorbic acid (Vit C)

•IV adr.,erythrocin, cephalothin .

•Almost all drugs

•Iv fluid e.g 5%

dextrose.

•Dextran

•Aminophyline IV

solution

•In blood , plasma

aminoacid,manitol

or heparin IVI.

•Precipitation in acidic pH

of dextrose.

•Precipitation

•Decompose in alkaline

PH ofAminophyline .

•Precipitation or

inactivation

2) Mixing 2 drugs prior injection:

Drug-Drug interaction inside the body

Drug interaction Includes:

1.Drug-drug

2.Drug-allergy

3.Drug-nutrient

4.Drug-alternative medicine

5.Drug-food

Features:

1.Identify drug interactions and minimize adverse events

2.Ranked by severity

3.Description of each interaction

4.No redundant information

5.Customized alerts

•Onset of drug interaction It may be seconds up to weeks for example in case of enzyme induction, it needs weeks for protein synthesis , while enzyme inhibition occurs rapidly.

The onset of action of a drug may be affected by the half lives of the drugs e.g., cimitidine inhibits metabolism of theophylline. Cimitidine has a long half life, while, theophylline has a short one. When cimitidine is administered to a patient regimen for Theophylline, interaction takes place in one day.

Factors Influencing Drug Interaction Outcomes

PATIENT FACTORS

CLINICAL

OUTCOME

OF

DRUG

INTERACTIONS

DRUG ADMINISTRATION

•Genetics •Diseases(malignant cases, diabetic patients, patients with liver or kidney , disorders.)

•pregnant women •Diet/Nutrition

•Environment

•Smoking

•Alcohol

•Dose

•Duration

•Dosing Times

•Sequence

•Route

•Dosage Form

•lowTherapeutic index Phenytoin, Cyclosporine Theophylline

•Sharp response curve Phenytoin, Aminoglycoside Vancomycin

•Dose dependent , Michalis-Menten Kinetic.

Phenytoin

HIGH

VARIABILITY

Therapeutic Index : Ratio = LD50 / ED50 - LD50 = Lethal dose in 50% of animals - ED50 = Effective dose in 50% of animals *Theophylline *Quinine *Lithium *Digoxin *Anticoagulants (Warfarin) *Antibiotics (Aminoglycosid, rifampicin) *Anticonvulsants (carbamazepine, lithium, phenytoin, phenobarbital *Cytotoxic and Immunosuppresants *Oral Contraceptives, ciclosporin,

MTC

MEC

Time

Plas

ma d

rug

conc

entra

tion

Need to keep concentration of drug withinthe therapeutic range

Pharmacokinetic interactions

1) Altered GIT absorption.

•Altered pH • Altered bacterial flora • formation of drug chelates or complexes, • drug induced mucosal damage • altered GIT motility.

•Gastric acidity : -Infection Absorption of weak acid drugs eg Aspirin & Phenobarbitone. •Antiacids ,H2 antagonists , PPIs, atazanavir, itraconazole (gastric alkalinity) →↓absorbtion of weak acid (Aspirin,barbiturate,Ketoconazole

,quinolones and fluoroquinolones , tetracyclin) and ↑absorption weak base.

•Intestinal Alkalinity Absorption of weak base drugs e.g. Ephedrine

Therefore, these drugs must be separated by at least 2h in the time of administration of both .

a)Altered pH; The non-ionized form of a drug is more lipid soluble and more readily absorbed

from GIT than the ionized form does.

b)Interactions during absorption 1. Chelation chelating agent:1. a compound that combines with metal ions to form stable ring structures.

2. a substance used to ↓the concentration of free metal ion in solution by complexing it.

Usually separating administration of chelating drugs by 2+h decreases interaction effect

*Antacids (Ca2+, Mg2+, Al3+), iron salts (Fe2+) and

milk (Ca2+) inhibit the absorption of

tetracyclines through chelation

*Bile acid binding resins: cholestyramine,

cholestipol adsorps and inhibits the

absorption of thyroxine, cardiac glycosides

(digoxin, digitoxin), warfarin, corticosteroids,

thiazides and (Immunosuppressants?)

*Kaolin-pectin decrease the absorption of digoxin

*Tetracyclines and Quinolones chelate metals and

form an insoluble complex that reduces their

absorption.

* EDTA chelates toxic metals such as lead and

reduces toxicity..

b)Interactions during absorption(cont.)

Usually separating administration of chelating drugs by 2+h decreases interaction effect

2-Adsorption is the nonspecific binding

of a drug to another agent: •Cholestyramine adsorbs many drugs such as dicumarol, methotrexate and digitoxin and decreases their absorption. • Antacids decrease digoxin and iron absorption by adsorption

An enzyme inhibition interaction

The chloramphenicol inhibited the metabolism of the phenytoin in this patient so that the

serum levels climbed into the toxic range and intoxication developed (indicated by

nystagmus). The problem was solved by stopping the phenytoin and later re-starting at a

lower dosage (after Ballek RE et al., Lancet (1973) i, 150, with permission).

C) E p i t h e l i a l S t r u c t u r e o f G u t W a l l: •Phenytoin Absorption of Folic acid •Para-amino-salicylic acid (PASA) & Colchicine Absorption of Vit B-12 •Neomycin Absorption of digitalis & Penicillins . •Antineoplastic agents e.g., cyclophosphamide , vincristine, procarbazine mucosal damage Inhibit absorption of several drugs eg., digoxin

D) Altered motility;Gastric emptying time (GET) is the time required to

empty the stomach.

• GET is increased by food , morphine, Metoclopramide (antiemitic) →

Gastric emptying ↑ absorption of rapid dissolution drugs e.g

Paracetamol & Propranolol but ↓absorption of delay dissolution drugs e.g.

Digoxin.

GET is decreased by fasting ,antacids, opioid, antimuscarinic : (propantheline atropine), antidiarrhoeal →↓ Gastric emptying:

- ↓ absorption of paracetamol - Decreased bioavailability of drugs that

are degraded in the intestine (levodopa) - Increased bioavailability of lipid soluble drugs

•The Reverse.

•Laxatives will cause drugs to move through

The intestine so rapidly that they are poorly

absorbed

E)Interactions at the GIT may be indirect and complex: Antimicrobials: Chloramphenicol, tetracyclines alter gut flora.

• Causing decreased synthesis of vit K by bacteria, thus prolonged the effects of oral anticoagulants which compete with vit K.

• Inhibit the enterohepatic recycling of estrogens, thus decrease the efficacy of oral contraceptives

• Increase the absorption of drugs that are metabolized by gut bacteria e.g. digoxin

F) Altered intestinal bacterial flora ; - In 10% 0f patients receive digoxin….. 40% or more of the administered dose is metabolized by the intestinal flora

- Antibiotics (Chloramphenicol, tetracyclines) kill a large number of the normal flora of the intestine,

• Causing decreased synthesis of vit K by bacteria, thus prolonged the efects of oral anticoagulants which compete with vit K.

• Inhibit the enterohepatic recycling of estrogens, thus decrease the efficacy of oral contraceptives

• Increase the absorption of drugs that are metabolized by gut bacteria e.g. digoxin

Increase digoxin conc. and increase its toxicity

G) Increases in blood flow will increase drug absorption whereas a decrease in blood flow will decrease drug absorption. . Epinephrine reduces blood flow and is used in combination with local anesthetics [lidocaine and procaine] to decrease their absorption into the blood (rapidly hydrolyzed) and to prolong their duration of action.

Efflux (to intestinal lumen): • P-glycoprotein (P-gp, MDR1, ABCB1) • Breast Cancer Resistance Protein (BCRP, ABCG2)

G) Transport alteration

They Can Occur in the GI Tract • Sucralfate, some milk products,

antacids, and oral iron preparations

• Omeprazole, lansoprazole,

H2-antagonists

• Didanosine (given

as a buffered tablet)

• Cholestyramine

Block absorption of quinolones, tetracycline, and azithromycin

Reduce absorption of ketoconazole, delavirdine

Reduces ketoconazole absorption

Binds raloxifene, thyroid hormone, and digoxin

Drug affected Interacting drugs Effect of interaction

Digoxin

Metoclopramide Reduced digoxin absorption

Propantheline Increased digoxin absorption (due to changes in gutmotility)

Digoxin

Colestyramine Reduced absorption due to binding/complexation with colestyramine

Levothyroxine

Warfarin

Ketoconazole Antacids Reduced ketoconazole absorption due to

reduced dissolution H2-blockers

Penicillamine Antacids containing Al3+, Mg2+, iron preparations, food

Formation of less soluble penicillamine chelates resulting in reduced absorption of penicillamine

Penicillin Neomycin Neomycin-induced malabsorption state

Quinolone antibiotics

Antacidscontaining Al3+, Mg2+, milk, Zn2+ (?), Fe2+

Formation of poorly absorbed complexes

Tetracyclines Antacids containing Al3+, Ca2+, Mg2+, Bi2+, milk, Zn2+, Fe2+

Formation of poorly soluble chelates resulting in reduced antibiotic absorption

Some drug absorption interactions

Graphic depiction of a theoretical drug distribution interaction

PK interaction associated with Protein binding

• The major plasma proteins to which most drugs bind are albumin and a1-acid glycoprotein; the former typically binds acidic, anionic drugs whereas the latter typically favors basic drugs

• Competitive protein binding by another drug will result in increase concentration of free drug, and that will yield more drug response

f) Displaced protein binding

It depends on the affinity of the drug to plasma protein. The most likely bound drugs is capable to displace others. It is clinically important if displaced drug is highly PP binding , with LONG T ½, small Vd, narrow therapeutic range. The free drug is increased by displacement by another drug with higher affinity.

Aspirin, Phenylbutazone, Clofibrate & Sulfa Displace: a-Oral Anti-coagulants (Dicumarol, Warfarin) Bleeding b-Oral Hypoglycemics (Tolbutamide) Hypoglycemia c-Bilirubin in Neonate Jaundice & Kernictrus. D-phenytoin

Free drug

Bound drug

Transporters in Drug Distribution, Uptake and

excreation –important liver transporters

metabolism

Determinants of Drug Disposition and Interaction

Efflux

Enterocyte

Drug/Metabolite

Drug Systemic Circulation

Intestinal Lumen

Biliary and Renal Elimination

Uptake

Transport

Transport

Transport

Uptake

Transport

Hepatocyte,

Kidney tubule cells

metabolism

Efflux

Efflux

Examples of Clinically Significant Drug interactions Associated with Inhibition of Transporters Other Than PgP

Bauer B, Hartz AM, Fricker G, Miller D. Modulation of p-Glycoprotein Transport Function at the

Blood-Brain Barrier. Experimental Biology and Medicine Feb. 2005;230:118-27.

P-Glycoprotein (PGP) Substrates

OATP and CYPs

CYP3A P-gp

OATP*

CYP3A P-gp OATP*

P-gp

OATP*

A

B

C

Intestine

Liver

Blood-Brain

Barrier

The effects of drug A on drug B through (A) direct induction/inhibition of enzymes; (B)

indirect induction/inhibition of transcription factors that regulate the drug-metabolizing

enzymes.

Tari L et al. Bioinformatics 2010;26:i547-i553

NEDMDG, March 2010 43

Ieiri et al. (2009) Expert Opinion in Drug Metabolism and Toxicology, 5: 703-729.

Transporter Interaction Redundancy:

Drugs that are shown to interact with one transporter typically interact with multiple transporters.

Thus, multiple pathways for clearance are possible for transporter substrates.

Slide courtesy of Dr. Mitchell Taub

Drug affected Interacting drugs Results of interaction

Clonidine Tricyclic antidepressants

Antihypertensive effects

opposed, possibly due to

interference in CNS with

clonidine uptake

Guanethidine-like

antihypertensives

(debrisoquine,

guanoclor, etc.)

Tricyclic antidepressants

Antihypertensive effects

opposed, due to

inhibition of uptake into

adrenergic neurones.

Chlorpromazine

Haloperidol

Tiotixene (Thiothixene)

Indirectly-acting

sympathomimetics

Noradrenaline

(norepinephrine) Tricyclic antidepressants

Pressor effects

increased due to

inhibition of

noradrenaline uptake

into adrenergic neurones

Interactions due to changes in drug transport mechanisms

OATP and CYPs

CYP3A P-gp

OATP*

CYP3A P-gp OATP*

P-gp

OATP*

A

B

C

Intestine

Liver

Blood-Brain Barrier

Transport Proteins in the liver

BCRP

canalicular

membrane

basalateral

membrane

MDR1

BSEP

MDR3

MRP2

NTCP

Na + Bile acids

OCT1 OAT2

OATP-C OATP-B OATP-8

Estrone-3-sulfate

BSP

pravastatin

E217G, Estrone-3-sulfate

LTC4, thyroid hormones

bile acids, pravastatin

digoxin

DPDPE, BSP

Estrone-3-sulfate

PGE2

AZT

MTX

phospholipids

Bile acids

Drug Efflux Transporters in the Liver

MDR1/ABCB1 MRP2/ABCC2 BCRP/ABCG2

Tissue

distribution

BBB, GI, liver, etc Liver, proximal part

of GI.

GI, liver, BBB,

placental, etc

MW (Kd) 170 190 70

Function Dramatic impact on

CNS exposure

Oral absorption

Maintain basal bile

flow

Biliary excretion

Oral absorption,

Biliary exretion

Typical

Substrates

Diverse

hydrophobic

xenobiotics:

vinblastine

GSH, GSH-

/glucuronide-

conjugates, organic

anions

mitoxantrone,

methotrexate

topotecan, E23-

sulfate

P-Glycoprotein (MDR1) Actively Transports Drugs Out of Cell Wall

Cell Wall

• Efflux pump: exposure to xenobiotics

• Found in numerous tissues: - Intestinal Epithelium - Biliary canaliculi

• -Renal proximal tubules - Blood-brain barrier - Tumor cells

• Promiscuous: interacts with wide variety of chemical structures

Inhibitors: cyclosporine, verapamil, erythromycin, Itraconazole,retoniver , ketocon-azole, verapamil ,itraconazole ,quinidine azrythromycin Inducers: phenobarbital, rifampin, phenytoin, St. John’s wort. Substrate:digoxin, fexofenadine, indinavir, vincristine, colchicine, topotecan, paclitaxel, talinolol, loperamide.

= Lipophilic Drug Inside Cell

Outside Cell

Entry via passive diffusion

PGP

Primary drug Interacting drug effect Result of interaction

•Digoxin

•Lignocaine

•Diuretics

•Tubocurarine

•Lithium

•Angiotensin-

converting

enzyme

inhibitor

•Diuretic-induced hypokalemia

•Diuretic-induced hypokalemia

•NSAID-induced salt and water

retention

•Diuretic-induced hypokalemia

•Thiazide-induced reduction in

renal clearance

•Potassium chloride and/or

patassium-retaining diuretic-

induced hyperkalemia

•Digoxin toxicity

•Antagonism of

antiarrhythmic effects

•Antagonism of diuretic

effects

•Prolonged paralysis

•Raised plasma lithium

•Severe hyperkalemia

Interactions secondary to drug-induced alterations of

fluid and electrolyte balance.

Drug affected Interacting drugs Results of interaction

Digitalis Potassium-depleting diuretics

Digitalis toxicity related to changes in ionic balance at the myocardium

Lithium chloride

Dietary salt restriction Increased serum lithium levels; intoxication possible

Increased salt intake Reduced serum lithium levels

Lithium chloride Thiazide and related diuretics

Increased serum lithium levels; intoxication possible

Guanethidine Chlorothiazide

Kebuzone Phenylbutazone

Antihypertensive effects opposed due to salt and water retention

Interactions due to disturbances in fluid and electrolyte balance

Liver

Induction

Drug A induces the body to produce more of an enzyme to metabolized Drug B

This reduces the amount of Drug B and may lead to loss of Drug B’s effectiveness

Inhibition

Drug A inhibits the production of enzymes to metabolize Drug B

This increases the amount of Drug B in the body and could lead to an overdose or toxic effects

a-HME Inducers: Phenytoin, Phenobarbitone, Rifampicin, Testosterone &

Tobacco smoking Their own metabolism & Other drugs.

b-HME Inhibitors: MAO-I, Cimetidine, Estrogen, Na Valproate & Chloramphenicol

Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.

CYP3A

CYP2D6

CYP2C

CYP1A2 CYP2E1

Relative Importance of

P450s in Drug Metabolism

CYP450 Activity in the Liver

CYP3A

CYP2C

CYP1A2

CYP2E1

?

CYP2D6

Relative Quantities

of P450s in Liver

Drug affected Inducing agent(s) Effect of interaction

Anticoagulants (oral)

Aminoglutethimide

Anticoagulant effects reduced

Barbiturates

Carbamazepine

Dichloralphenazone

Glutethimide

Phenazone

Rifampicin (rifampin)

Contraceptives (oral)

Barbiturates,Carbamazepine, Phenytoin, Primidone, Rifampicin

Contraceptive effects reduced. Break-through bleeding, contraceptive failures

Corticosteroids

Aminoglutethimide

Corticosteroid effects reduced

Barbiturates

Carbamazepine

Phenytoin

Primidone

Rifampicin (rifampin)

Haloperidol Tobacco smoke Haloperidol effects reduced

Pentazocine Tobacco smoke Pentazocine effects reduced

Phenytoin Rifampicin (rifampin) Phenytoin effects reduced. Seizure-risk increased

Theophylline Barbiturates

Theophylline effects reduced Rifampicin (rifampin) Tobacco smoke

Interactions due to enzyme induction

Drug affected Inducing agent(s) Effect of interaction

Anticoagulants (oral)

Aminoglutethimide

Anticoagulant effects reduced

Barbiturates

Carbamazepine

Dichloralphenazone

Glutethimide

Phenazone

Rifampicin (rifampin)

Contraceptives (oral) Barbiturates,Primidone,Carbamazepine, Phenytoin,Rifampicin

Contraceptive effects reduced. Break-through bleeding, contraceptive failures

Corticosteroids

Aminoglutethimide

Corticosteroid effects reduced

Barbiturates

Carbamazepine

Phenytoin

Primidone

Rifampicin (rifampin)

Haloperidol Tobacco smoke Haloperidol effects reduced

Pentazocine Tobacco smoke Pentazocine effects reduced

Phenytoin Rifampicin (rifampin) Phenytoin effects reduced. Seizure-risk increased

Theophylline Barbiturates

Theophylline effects reduced Rifampicin (rifampin) Tobacco smoke

Interactions due to enzyme induction

Drug affected Interacting drugs Results of interaction

Anticoagulants Vitamin K Anticoagulant effects opposed

Carbenoxolone Spironolactone Ulcer-healing effects opposed

Hypoglycaemic agents Glucocorticoids Hypoglycaemic effects opposed

Hypnotic drugs Caffeine Hypnosis opposed

Levodopa Antipsychotics (those with Parkinsonian side effects)

Antiparkinsonian effects opposed

Opposing or antagonistic interactions

a-Competition for A c t i v e Tubular Excretion: •Probenecid Excretion of penicillin Prolongs its duration of action •Probenecid Excretion of Frusemide Antagonize its diuretic effect •Quinidine Excretion of Digoxin Its plasma concentration

Competitive interaction between drugs for active tubular

secretion.Probenecid ( • ) is able successfully to compete with some

of the other drugs ( o ) for active secretory mechanisms in the

kidney tubules which reduces their loss in the urine and raises

serum levels. The probenecid is later passively reabsorbed

Reabsorption of drugs

Bases: antihistamines and amphetamines ↑by Na Hco3 and ↓by ammonium chloride.

Acids: aspirin ,phenobarbital ,salicylate ,lithium ↑ by ammoniumchloride and ↓ by

Na bicarbonate.

Active secreation

Acid : Penicillin, cephalosporin,Frusemide, Nalidixic acidNSAIDs, methotrexate, salicylates, probenecid, PASA (Amino salicylic acid),acetohexamide. Base : Digoxin & Quinidine, histamine, morphine, atropine, acetylcholine

Drug Excretion Interactions

Passive reabsorbtion ,lipid-soluble,nonionized

Passive reabsorption , lipid-soluble ,nonionized

b- p H C h a n g e s: Acidification of urine (NH4Cl) Excretion of Weak base drugs e.g. Ephedrine Alkalinization of urine (NaHCO3) Excretion of weak acid drugs e.g. Aspirin

Competitive interaction between drugs

for active tubular secretion

Probenecid ( • ) is able successfully to

compete with some of the other drugs ( o )

for active secretory mechanisms in the

kidney tubules which reduces their loss in

the urine and raises serum levels. The

probenecid is later passively reabsorbed

Common Inducers, Inhibitors, and Substrates of Select CYP450 Isozymes

Drugs Result of interaction

•Anticholinergics + anticholinergics (anti-parkinsonian agents, butyrophenones, phenothiazines, tricyclic antidepressants, etc.)

•Increased anticholinergic effects; heat stroke in hot and humid conditions; adynamic ileus; toxic psychoses

•Antihypertensives + drugs causing hypotension (anti-anginals, vasodilators, phenothiazines)

•Increased antihypertensive effects; orthostasis

•CNS depressants + CNS depressants (alcohol, anti-emetics, antihistamines, hypnosedatives, etc.)

•Impaired psychomotor skills, reduced alertness, drowsiness, stupor, respiratory depression, coma, death

•QT prolonging drugs + other QT prolonging drugs (Amiodarone + Disopyramide)

•Additive prolongation of QT interval, increased risk of torsade de pointes

•Methotrexate + co-trimoxazole •Bone marrow megaloblastosis due to folic acid antagonism

•Nephrotoxic drugs + nephrotoxic drugs (gentamicin or tobramycin with cefalotin (cephalothin)

•Increased nephrotoxicity

•Neuromuscular blockers + drugs with neuromuscular blocking effects (e.g. aminoglycoside antibacterials)

•Increased neuromuscular blockade; delayed recovery, prolonged apnoea

•Potassium supplements + potassium-sparing diuretics (triamterene)

•Marked hyperkalaemia

Additive, synergistic or summation interactions

Drugs Result of interaction

Anticholinergics + anticholinergics (anti-parkinsonian agents, butyrophenones, phenothiazines, tricyclic antidepressants, etc.)

Increased anticholinergic effects; heat stroke in hot and humid conditions; adynamic ileus; toxic psychoses

Antihypertensives + drugs causing hypotension (anti-anginals, vasodilators, phenothiazines)

Increased antihypertensive effects; orthostasis

CNS depressants + CNS depressants (alcohol, anti-emetics, antihistamines, hypnosedatives, etc.)

Impaired psychomotor skills, reduced alertness, drowsiness, stupor, respiratory depression, coma, death

QT prolonging drugs + other QT prolonging drugs (Amiodarone + Disopyramide)

Additive prolongation of QT interval, increased risk of torsade de pointes

Methotrexate + co-trimoxazole Bone marrow megaloblastosis due to folic acid antagonism

Nephrotoxic drugs + nephrotoxic drugs (genta-micin or tobramycin with cefalotin (cephalothin)

Increased nephrotoxicity

Neuromuscular blockers + drugs with neuromuscular blocking effects (e.g. aminoglycoside antibacterials)

Increased neuromuscular blockade; delayed recovery, prolonged apnoea

Potassium supplements + potassium-sparing diuretics (triamterene)

Marked hyperkalaemia

Additive, synergistic or summation interactions

Drug affected Interacting drugs Results of interaction

Anticoagulants Vitamin K Anticoagulant effects opposed

Carbenoxolone Spironolactone Ulcer-healing effects opposed

Hypoglycaemic agents Glucocorticoids Hypoglycaemic effects opposed

Hypnotic drugs Caffeine Hypnosis opposed

Levodopa Antipsychotics (those with Parkinsonian side effects)

Antiparkinsonian effects opposed

Opposing or antagonistic interactions

Interactions at adrenergic neurones

* Prevention of drug interaction

1) Monitoring therapy and making adjustments

2) Monitoring blood level of some drugs with narrow therapeutic index e.g., digoxin, anticancer agents…etc 3) Monitoring some parameters that may help to characterize the the early events of interaction or toxicity e.g., with warffarin administration, it is recommended to monitor the prothrombin time to detect any change in the drug activity. 4) Increase the interest of case report studies to report different possibilities of drug interaction

Drug–Drug Interaction Observed Adverse Outcome ACE inhibitors + K-sparing diuretics Hospitalization for hyperkalemia ACE inhibitors + co-trimoxazole Hospitalization for hyperkalemia Benzodiazepines + CYP3A4 inhibitors Hospitalization for hip fracture Calcium channel blockers + macrolides Hospitalization for hypotension or shock Digoxin + macrolides Hospitalization for digoxin toxicity Lithium + ACE inhibitors, loop diuretics Hospitalization for lithium toxicity Phenytoin + co-trimoxazole Hospitalization for phenytoin toxicity Glipizide or glyburide + CYP2C9 inhibitors Hospitalization for hypoglycemia Tamoxifen + paroxetine Death from breast cancer Theophylline + ciprofloxacin Hospitalization for theophylline toxicity Warfarin + co-trimoxazole or fluconazole Hospitalization for GI bleeding Warfarin + NSAIDs Hospitalization for GI bleeding .

ACE = angiotensin-converting enzyme; CYP = cytochrome P450; GI = gastrointestinal; K = potassium; NSAIDs =nonsteroidal anti-inflammatory drugs

Important Drug Interactions in the Elderly

Thank you

Drug–Drug Interaction Observed Adverse Outcome ACE inhibitors + K-sparing diuretics Hospitalization for hyperkalemia ACE inhibitors + co-trimoxazole Hospitalization for hyperkalemia Benzodiazepines + CYP3A4 inhibitors Hospitalization for hip fracture Calcium channel blockers + macrolides Hospitalization for hypotension or shock Digoxin + macrolides Hospitalization for digoxin toxicity Lithium + ACE inhibitors, loop diuretics Hospitalization for lithium toxicity Phenytoin + co-trimoxazole Hospitalization for phenytoin toxicity Glipizide or glyburide + CYP2C9 inhibitors Hospitalization for hypoglycemia Tamoxifen + paroxetine Death from breast cancer Theophylline + ciprofloxacin Hospitalization for theophylline toxicity Warfarin + co-trimoxazole or fluconazole Hospitalization for GI bleeding Warfarin + NSAIDs Hospitalization for GI bleeding .

ACE = angiotensin-converting enzyme; CYP = cytochrome P450; GI = gastrointestinal; K = potassium; NSAIDs =nonsteroidal anti-inflammatory drugs

Important Drug Interactions in the Elderly

Common Diabetes, Hypertension, and Lipid Drug Interactions

Common Inducers, Inhibitors, and Substrates of Select CYP450 Isozymes

Cytochrome P450 Nomenclature, e.g., for CYP2D6

• CYP = cytochrome P450

• 2 = genetic family

• D = genetic sub-family

• 6 = specific gene

• NOTE: This nomenclature is genetically based; it does not imply chemical specificity

Major Human CYP450 Isoforms

• CYP2D6

• CYP2E1

• CYP3A4

• CYP3A5

• CYP3A6

CYP1A2

CYP2B6

CYP2C8

CYP2C9

CYP2C19

Overactive metabolism can cause adverse events

“Normal” Activity

Morphine Enzyme

Pro-Drug (Codeine)

Morphine

Morphine

Morphine

Enzyme

Enzyme

Enzyme

“Ultra-rapid” Activity

Pro-Drug (Codeine)

Morphine

Morphine

Drug-Drug interaction (Silent Epidemic)

By Mohie Aldien (MD)

Drug Metabolism Interactions: Induction

Adapted from Urquhart et al J Clin Pharm 2007;47:566-78

First-pass metabolism: Oral administration increases the chance for liver and GIT metabolism of drugs leading to the loss of a part of the drug dose decreasing its action. This is more clear when such drug is an enzyme inducer or inhibitor.

EX., Rifampin lowers serum con. of verapamil level by increase its first pass . Also, Rifampin induces the hepatic metabolism of verapamil

Phase I - Drug Oxidation

Both PGP and CYP3A4

• Inhibitors

– Verapamil

– Clarithromycin

– Erythromycin

– Itraconazole

– Ritonavir

– Cyclosporine

• Inducers

– Rifampicin

– St. John’s Wort

– Phenobarbital

– Reserpine

*These programs are not endorsed by the FDA

Drug-Drug Interaction Prevention: A Stepwise Approach

1. Take a medication history

(AVOID Mistakes mnemonic)

2. Remember high-risk patients

• Any patient taking ≥ 2 medications

• Patients Rxed anticonvulsants, antibiotics, digoxin, warfarin, amiodarone, etc.

3. Check pocket reference or PDA

4. Consult pharmacists or drug info specialists

5. Check up-to-date computer program

• Medical Letter Drug Interaction Program*

• www.epocrates.com* and others

Marchietti S, et al. Clinical relevance of drug-drug and herb-drug interactions mediated by the

ABC transporter ABCB1 (MDR1, P-glycoprotein). The Oncologist 2007;12:927-41.

P - Glycoprotein Tissue Distribution

Bauer B, Hartz AM, Fricker G, Miller D. Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier. Experimental

Biology and Medicine Feb. 2005;230:118-27.

P-Glycoprotein (PGP) Substrates

Uptake proteins: focus on OATP (also OCT, OAT) Transport numerous amphipathic compounds Some present only in the liver Many present at the BBB, lung, heart, intestine, kidney etc. Facilitate the influx of compounds Fexofenadine and digoxin are well-defined OATP substrates Fruit juices(grapefruit juice, apple juice, and orange juice) inhibit OATPs, along with

quinidine, nelfinavir, saquinavir, and ketoconazole

Recently, increased

NEDMDG, March 2010 97

Tables of Substrates and Inhibitors

NEDMDG, March 2010 99

Lack of selective inhibitors of drug transporters

1. Dantzig et al. (1999) JPET 290, 854-862 2. Hsiang et al. (1999) J Biol Chem 274, 37161-8 3. Abe et al. (1999) J Biol Chem 274, 17159-63 4. Konig et al. (2000) Am J Physiol Gastrointest Liver Physiol 278, G156-64 5. Hagenbuch. & Meier (2003) Biochim Biophys Acta 1609, 1-18 6. Oostendorp et al. (2009) DMD 37, 917-923

1999 1999 – 2003 2009

• LY 335979 (zosuquidar) is a potent inhibitor/modulator of P-gp, but does not inhibit MRP1 or MRP2. • Selectivity over inhibition of CYP3A4 is ~60-fold. [Reference 1]

• Discovery, cloning, and publication of OATP superfamily of uptake transporters [References 2-5]

• OATP1B1-mediated uptake of anticancer drugs gimatecan and BNP1350 were inhibited by zosuquidar. • The effect of modulators on the plasma pharmacokinetics of OATP1B1 substrate drugs may not be solely ascribed to inhibition of P-gp [Reference 6]

Slide courtesy of Dr. Mitchell Taub

Drug Interactions: Transport Proteins

Drugs metabolised by these cytochrome P450 isoenzymes

CYP450 isoenzyme

Drugs metabolised

CYP1A2 Caffeine, Clozapine, Imipramine, Maprotiline, Phenacetin, Propranolol, R-warfarin, Ropinirole, Theophylline

CYP2D6

Amitriptyline, Amfetamine (Amphetamine), Captopril, Clomipramine, Codeine, Desipramine, Dextromethorphan, Dihydrocodeine, Diphenhydramine, Flecainide, Fluoxetine, Haloperidol, Hydrocodone, Imipramine, Labetalol, Maprotiline, Metoprolol, Mexiletine, Nortriptyline, Ondensatron, Oxycodone, Papaverine, Paroxetine, Penbutolol, Perphenazine, Propafenone, Propranolol, Thioridazine, Timolol, Trimipramine, Venalfaxine, Yohimbine

CYP2C9 Diclofenac, Dofetilide, Fluvastatin, Ibuprofen, Mefenamic acid, Naproxen, Phenytoin, Piroxicam, S-warfarin, Tolbutamide

CYP2C19 Clomipramine, Diazepam, Hexobarbital (Hexobarbitone), Imipramine, Mephobarbital, Omeprazole, Phenytoin, Propranolol, Proguanil, S-mephenytoin

CYP3A4

Amiodarone, Amitriptyline, Alprazolam, Astemizole, Carbamazepine, Ciclosporin (Cyclosporin), Cisapride, Clindamycin, Clomipramine, Clonazepam, Dapsone, Dexamethasone, Dextromethorphan, Diazepam, Diltiazem, Erythromycin, Ethyl estradiol, Felodipine, Hydrocortisone (Cortisol), Imipramine, Indinavir, Lidocaine (Lignocaine), Lovastatin, Midazolam, Nefazodone, Nelfinavir, Nevirapine, Nifedipine, Nimodipine, Nisoldipine, Propafenone, Quinidine, R-warfarin, Ritonavir, Saquinavir, Sertraline, Simvastatin, Tamoxifen, Terfenadine, Testosterone, Triazolam, Venlafaxine, Verapamil, Zolpidem

This list is not exhaustive and is derived from several sources.

Cy P450 isoenzyme Inhibiting drugs

CYP1A2 Enoxacin, Cimetidine, Ciprofloxacin, Fluvoxamine, Furafylline, Grapefruit juice, Grepafloxacin

CYP2D6 Fluoxetine, Haloperidol, Paroxetine, Quinidine, Ritonavir, Sertraline, Thioridazine

CYP2C9 Fluconazole, Fluoxetine, Fluvoxamine, Ritonavir

CYP2C19 Fluoxetine, Fluvoxamine, Omeprazole

CYP3A4

Cimetidine, Clarithromycin, Erythromycin, Fluvoxamine, Grapefruit juice, Itraconazole, Ketoconazole, Miconazole, Nefazodone, Nelfinavir, Remacemide, Ritonavir

Drugs that inhibit these cytochrome P450 isoenzymes

Cytochrome P450 isoenzyme Inducing drugs

CYP1A2 Barbiturates, Omeprazole, Phenytoin, Tobacco smoke

CYP2D6 ?

CYP2C9 Barbiturates, Rifampicin (Rifampin)

CYP2C19 ?

CYP3A4 Barbiturates, Carbamazepine, Dexamethasone, Phenytoin, Rifabutin, Rifampicin (Rifampin)

Drugs that induce these cytochrome P450 isoenzymes

1 in 10 7

1 in 10 6

1 in 10 5

1 in 10 4

1 in 10 3 1 in 10 2

Lightning

Plane crash Murder

Auto-cash

Fatal, unexpected drug reaction

Increasing risk of death

Distribution

Harmful Effects (potentiation/antagonism)

Additive or Synergistic/ Beneficial Effects

Altered pH

Altered motility Chelation

Chelation

CYPP450 isoenzyme

Drugs metabolised

CYP1A2 Caffeine, Clozapine, Imipramine, Maprotiline, Phenacetin, Propranolol, R-warfarin, Ropinirole, Theophylline

CYP2D6

Amitriptyline, Amfetamine (Amphetamine), Captopril, Clomipramine, Codeine, Desipramine, Dextromethorphan, Dihydrocodeine, Diphenhydramine, Flecainide, Fluoxetine, Haloperidol, Hydrocodone, Imipramine, Labetalol, Maprotiline, Metoprolol, Mexiletine, Nortriptyline, Ondensatron, Oxycodone, Papaverine, Paroxetine, Penbutolol, Perphenazine, Propafenone, Propranolol, Thioridazine, Timolol, Trimipramine, Venalfaxine, Yohimbine

CYP2C9 Diclofenac, Dofetilide, Fluvastatin, Ibuprofen, Mefenamic acid, Naproxen, Phenytoin, Piroxicam, S-warfarin, Tolbutamide

CYP2C19 Clomipramine, Diazepam, Hexobarbital (Hexobarbitone), Imipramine, Mephobarbital, Omeprazole, Phenytoin, Propranolol, Proguanil, S-mephenytoin

CYP3A4

Amiodarone, Amitriptyline, Alprazolam, Astemizole, Carbamazepine, Ciclosporin (Cyclosporin), Cisapride, Clindamycin, Clomipramine, Clonazepam, Dapsone, Dexamethasone, Dextromethorphan, Diazepam, Diltiazem, Erythromycin, Ethyl estradiol, Felodipine, Hydrocortisone (Cortisol), Imipramine, Indinavir, Lidocaine (Lignocaine), Lovastatin, Midazolam, Nefazodone, Nelfinavir, Nevirapine, Nifedipine, Nimodipine, Nisoldipine, Propafenone, Quinidine, R-warfarin, Ritonavir, Saquinavir, Sertraline, Simvastatin, Tamoxifen, Terfenadine, Testosterone, Triazolam, Venlafaxine, Verapamil, Zolpidem

This list is not exhaustive and is derived from several sources.

1.6 Drugs metabolised by these cytochrome P450 isoenzymes