DRUG COMBINATION

AND DRUG
INTERACTIONS -1
Dr Olayinka O.Ogunleye
MBBS(Ib), MSc(Epid &Med Stat), FMCP(Nig)
Department of Pharmacology, Therapeutics and Toxicology
LASUCOM, Ikeja
 Drug interactions
• Definition
• The modification of drug actions/effects or an individual’s
response produced by the co-administration of drugs
(together or in quick succession) or concomitant
exposure to drugs and other substances.
• Drug interactions may be intentional in order to provide
improved therapeutic response or to decrease adverse
effects.
• A precipitant drug is the drug, chemical or food element
causing the interaction.
• An object drug is the drug affected by the interaction.
• Response by the host may be quantitative i.e. increased or
decreased response to the effect of the drug(s) or
qualitative i.e. an abnormal or different response is elicited
Drug Interaction
• Several ailments are treated with more than one drug.
• Components of drug combinations are selected in order to
complement each other’s actions. E.g
• Adrenaline and lidocaine for Local anesthesia
• Probenecid and Penicillin
Types and Classifications of Drug
Interactions
• Types of Drug Interactions
• Drug-drug interaction
• Food-drug interaction
• Chemical-drug interaction
• Drug-laboratory test interaction.

• Classification of Drug Interactions

• Pharmacokinetic interaction
• Pharmacodynamic interaction
• Pharmaceutical interaction
Pharmacokinetic Interactions
• One drug alters the rate or extent of absorption, distribution,
metabolism or excretion of another drug.
• A change in blood concentration causes a change in the drug’s effect.
• Absorption
• Drug interaction can affect the rate and the extent of systemic drug absorption
(bioavailability).
• Apart from the gastrointestinal tract (GI), drug interaction can affect the absorption
from the skin.
• Precipitant drug may compete for the same carrier as the object drug
• Absorption may be delayed by administering the drug as an oily depot (Lipophilic
formulation). An example is Paracetamol)
• Absorption of an orally administered drug can be affected by other concurrently
administered drugs
• Examples of Alterations of Absorption through Interactions
• Change in gastrointestinal pH
• Ketoconazole needs acidic conditions in gut
• Drug binding in GI tract
Tetracycline and calcium
• Change in gastrointestinal flora
• Antibiotics with Oral Contraceptives
• Change in gastrointestinal motility
• Metoclopramide and digoxin
• Malabsorption caused by other drugs
• Orlistat (Xenical) and fat soluble vitamins
• Distribution
• Distribution of drug may be affected by plasma protein binding and
displacement interactions
• Valproic acid displaces Phenytoin from plasma protein binding sites and
increases hepatic Phenytoin clearance by inducing the liver metabolism of
Phenytoin
• Aspirin decreases protein binding and induces the metabolism of Valproic
acid
• Quinidine displaces digoxin from tissue binding sites leading to higher
plasma digoxin level
• Plasma protein binding
• Highly plasma protein bound drugs are largely confined to the vascular
compartment
• The bound fraction is pharmacologically inactive
• The unbound fraction is free to exert a pharmacologic effect
• Several drugs can compete on the same binding site leading to displacement
interactions and increased plasma concentration of the displaced drug
• Plasma protein binding
• Examples of displacement interactions
• Salicylates displaces Sulfonylureas and Methotrexate
• Indomethacin and Phenytoin displaces Warfarin
• Sulfonamides displaces bilirubin
Drug metabolism and hepatic clearance
• Can be affected by
• enzyme induction,
• enzyme inhibition,
• substrate competition for same enzyme
• change in hepatic blood flow
• Examples
• Phenytoin, Carbamazepine and Phenobarbital elevate levels of glucuronyl transferase, increasing the
clearance of valproate
• Grape fruit juice inhibit cyp3A4 and increases the blood levels of saquinavir when taken
together.
• A decrease in hepatic blood flow can decrease the hepatic clearance for drugs, such as
propranolol and morphine
• Renal drug clearance
• Can be affected by changes in glomerular filtration, tubular reabsorption, active drug secretion and
renal blood flow.
Excretion Interactions
• Drug A increases or reduces the excretion (usually renal) of Drug B.
• Blood levels of B fall below or rise above normal therapeutic range.
• Becomes either ineffective or toxic.
• Mechanisms of urinary excretion:
• - Simple filtration
• - Active secretion
• Mechanisms for active secretion
• - Acids
• - Bases
Excretion Interactions
• Active secretion mechanisms have limited capacity.
• One acid drug may saturate the acid drug active secretion mechanism.
• Another acid drug will then be secreted less efficiently
• Examples
• Lithium + Thiazides (Probable Mechanism)
• Thiazides cause diuresis and initial sodium loss
• Compensatory sodium retention in proximal tubules.
• Proximal tubules do not distinguish sodium from lithium
• Lithium also retained and accumulates.

• Methotrexate and NSAIDs

• NSAIDS can decrease renal blood flow by inhibition of renal prostaglandins
• Reduced clearance of MTX and active (toxic) metabolite
Pharmacodynamic interactions
• Drugs that have similar pharmacodynamic actions may produce an excessive
pharmacologic or toxic response.
• One drug causes a change in patient response to another drug without
altering that drug’s pharmacokinetics
• Examples:
• Combination of alcohol and antihistamines can produce increased drowsiness in the patient.
• Anticholinergic agent (promethazine) and antihistamines can cause dryness of the mouth,
blurred vision and urinary retention
• Aspirin increases the risk of bleeding in patients on anticoagulants
• Additive effects of alcohol and benzodiazepines
• increase toxicity of digoxin caused by diuretic induced hypokalaemia
• Beta-blocker given with beta-agonist
Pharmaceutical Interactions
• Interactions that occur prior to systemic administration of drugs.
• Examples:
• incompatibility between two drugs mixed in an IV fluid. These
interactions can be physical (e.g. with a visible precipitate) or chemical
with no visible sign of a problem
Some beneficial drug combinations
• Trimethoprim + sulfamethoxazole
• Amoxicillin + Clavulanic acid
• Hydrochlorothiazide + Enalapril
• Probenecid inhibits renal tubular secretion of penicillin, therefore
prolonging the plasma half-life.
Drug interaction Examples Effects

Complexation/chelation Calcium, magnesium, or Divalent cations, causing a

aluminum. decreased bioavailability.
Cations in antacids bind to
sodium poly styrene
sulfonate causing reduced
renal clearance of
biocarbonate resulting in
systemic acidosis

Adsorption Cholestyramine Decreased bioavailability of

digoxin, thyroxine

Kaolin bioavailability of digoxin

Activated charcoal bioavailability of many drg

Increased GI Laxatives, cathartics GI motility, bioavailability

for drugs that are adsorbed
motility slowly. May also affect the
bioavailability of drug form
controlled release

Decreased GI Anticholinergic agents Propatheline the gastric

emptying of acetaminophen
motility delaying absorption from the
small intestine
Drug interaction Examples Effects

Alteration of H-2 blockers and

antacids
Both H-2 blockers and
antacids increase the
gastric pH gastric pH. The
dissolution of
ketoconazole is reduced
causing decreased drug
absorption.

Alteration of Antibiotics (e.g.;

tetracyclines, penicillin)
Digoxin has better
bioavailability after
intestinal flora erythromycin.
Erythromycin
administration reduces
bacterial inactivation of
digoxin.

Inhibition of Monoamine oxidase

inhibitors (MAOIs)
Hypertensive crisis can
occur in patients treated
drug tranylcypromine, with MAOIs and foods
phenelzine containing tyramine.
metabolism in
intestinal cells
Drug interaction Examples Effects
Enzyme Smoking (polycyclic
aromatic hydrocarbons)
Smoking increases
theophyline clearance
induction barbiturates Phenobarbital increases
the metabolism of
warfarin

Enzyme Cimetidine, monoamine

oxidase inhibitors
Decreased theophyline
clearance, serious
inhibition mixed (MAOIs) (e.g. pargyline, hypertensive crisis can
tranylcypromin) occur following ingestion
function oxidase of foods with a high
other enzymes content of tyramine or
other pressor substances
(e.g., cheldar cheese,
red wines).
Drug interaction Example Effect
Glomerular Methylxanthine (e.g.
caffeine, theobromine)
Increased renal blood
flow and GFR will
filtration rate decrease time for
reabsorption of various
(GFR) and renal drugs leading to more
blood flow rapid urinary drug
excretion

Active tubular Probenecid Probenecid blocks the

active tubular secretion
secretion of penicillin and some
cephalosporin antibiotics

Tubular Antacids, sodium

biocarbonate
Alkalinisation of the urine
increases the reabsoption of
reabsorption amphetamine and
decreases its clearance.
and urinary pH Alkalinsation of the urine pH
increases the ionisation of
salicylates, decreases
reabsorption, and increases
its clearance
Enzyme Inhibitor Inducer
Fluoxetine Ciprofloxacin, Phenobarbital
CYP1A2 Nefazodone Carbamazepine
Phenytoin
Miconazole Rifampin
CYP2C9
Clopidogrel Carbama
Fluvastatin Phenytoin
Fluoxetine Rifampin
CYP2C
Ritonavir
Cimetidine None known
CYP2D
Quinidine
Fluoxetine
Ritonavir
Cimetidine Ritonavir
CYP2 E1
Isoniazid
Alcohol
Erythromycin Carbamazepine
CYP3A group
Ketoconazol Phenobarbital
Saquinavir Prednisone
Verapamil troglitazone
Omeprazole
Risk Factors for Drug Interactions
• High Risk Patients
• Elderly, young, very sick, multiple disease
• Multiple drug therapy
• Renal, liver impairment
• High Risk Drugs
• Narrow therapeutic index drugs ( e.g. Lithium, Carbamazepine,
Phenytoin, Theophylline, Digoxin, Cyclosporin, Phenobarbitone,
Warfarin)
• Recognized enzyme inhibitors or inducers