Drug interactions make up only a small proportion of all ADRs but

account for disproportionate nos of deaths.

Clinically important drug interactions are most likely to occur.
Drugs having a steep dose response curve and drugs having a small
therapeutic window. (Dose intended for therapeutic action is close to
dose resulting in adverse drug affect)
Drug drug interactions can be divided into pharmacodynamics and
pharmacokinetic interactions.
Pharmacodynamics occur when both drugs act on the same target
site of clinical effect. Eg alcohol + benzodiazepines (such as valium).
Have an effect on the brain.
Pharmacokinetic interacitons occur when drugs interact remotely
from the target site (distance from), so that the amount of drug at
the target site of clinical affect is altered eg rifampicin + warfarin
(enzyme induction by rifampicin). Rifampicin indused the breakdown
of warfarin by triggering certain enzymes. You lose anticoagulant
effect of warfarin
Can occur at a number of sites:
Outside the body within an infusion bottle.
At the site of entry to the body infusion line or the syringe. Mixing
drugs to give only 1 injection.
At the binding site on plasma proteins
At the site of metabolism most important mechanism of drug-drug
interaction lies. Site of metabolism is in the liver (nephron).
During excretion
Dynamic interactions
Result from a combination of drugs with similar pharmacological
effects which are likely to be additive.
The most important examples concern drugs that affect bleeding or
coagulation eg NSAIDs, aspiring and anti-coagulants.
Elderly women (joint pain, rheumatoid arthritis therefore require
long term analgesics) appear to be at a disproportionately high risk
of GI haemorrhage because of drug interactions
Other examples include drugs that act to depress the CNS or act on
the renal tubule to affect electrolyte and H2O reabsorption.
Classification of interactions by severity of rxn:
Major life threating or involving permanent damage
Moderate requiring additional treatment to deal with complication

Minor unnoticeable or not sufficient to affect the therapeutic

outcome.
Most kinetic interactions can be attributed to impaired drug
elimination particularly through the interference with hepatic
metabolism, transcellular transport or renal excretion. of
mechanisms underlying drug-drug interactions.
It used to be thought that the most important mechanisms in drug
drug interaction was that involving 2 drugs altering their linkage
with a carrier protein. When you swallow a drug and its absorbed,
some attach themselves to carrier protein (usually albumen), the
rest circulates freely without circulatory system. The free moiety is
pharmacologically active. Part attached to serum albumen is
inactive. Drug A could result in dissociated of the drug B attached to
carrier protein thereby increasing pharmacological effect of drug B.
it does occur within the body but it is not the main mechanism
involved. Interference with hepatic metabolism is the most
important. In addition also transcellular transport or renal excretion.
Areas of maximum danger anticoagulant therapy
Antidiabetic therapy
Digoxin therapy
Cytotoxic drug therapy
MAOI therapy mono amino oxidase inhibitor
^ 5 areas that should alert about possibility of drug-drug
interactions.
Common adverse effects resulting from drug interactions: 2 affect
brain, 2 blood pressure and 1 the GI:
CNS depression
Severe hypotension
GI bleeding
Psychotic behavior
Hypertensive crisis
Examples of drug interactions commonly leading to hospital
admission:warfarin and aspirin GI haemorrhage
NSAIDS and aspirin GI adverse affects including bleeding
Warfarin and interacting drugs bleeding
Diuretic combinations renal failure
Diuretics and ACEIs - (renal failure)
Digoxin and interacting drugs digoxin toxicity
These are most commonly interactions are kinetic in nature,
resulting in an increase or decrease exposure to one or other drug.
The outcome will depend on the steepness of the dose response

curve for the agent and the relation between drug concentration
and effect.
Mechanisms underlying drug interactions
Effects on hepatic metabolism:
Drug interactions that affect hepatic metabolism (way liver is going
to break drugs) can be predicted from an understanding of the
function of specific microsomal isoenzymes of cytochrome P450
(CYP). They affect the enzymes by inducing or inhibiting reactions.
CYP= a drug metabolizing enzyme system.
^ main mechism
these enzymes of which CYP3A4 is by far the most abundant are
subject to:
1. relatively specific induction by other drugs, increasing the amount
of enzyme, therefore reducing the plasma conc of inducing drug
(more enzyme available level of liver, the more the drug will be
metabolized)
2. inhibition, where the plasma conc of the inhibited drug rises
In general the consequence of a drug interaction that involves
metabolism depends on the dosage of the inducing or inhibiting
agent.
An important inhibition interaction is an example of a food-induced
drug interaction. This involves grapefruit juice and drugs that are
substrates for the CYP3A4 enzyme system. Extent of interaction
varies. Doesnt seem to occur with freshlu squeezed uice
Effects of inhibition usually short lived once inhibitor is withdrawn
except where there is irreversible binding of an enzyme system for
eg by MAOIs it may take several weeks for effect to dissipate for
formation of new enzymes
Induction by contrast requires new enzyme formation and so onset
of effect is usually more gradual and may not be maximal for 1-2
weeks. Similarly when inducer is withdrawn effect of induction can
take a week or more to dissipate.
CYP3A4 is not the only microsomal enzyme system in the liver. It is
the most abundant.
CYP2C9 number of substrates, inducers and inhibitors is less than
the ones in CYP3A4.
CYP1A2 :

Most interactions resulting form inhibition fo metabolism occur

relatively early after taking te combination of drugs, reaching their
max effect after an interval determined by the elimination half life of
the affected drugs. It takes 4-5 half lives to reach a new steady state
plasma conc.
2nd mechanism - Transcellular transport:
Drug interactions also affect the function of P-glycoprotein, the
recently discovered xenobiotic transport system involved in drug
absorption from the GI tract, transport within the liver and
elimination by the kidneys as well as within the brain or target
tissues. EFFLUX.
The complexity of this system is becoming apparent, with the
recognition that it too exhibits genetic polymorphism and is subject
to both induction as well as inhibition interactions just like the CYP
drug metabolizing enzyme system and involving a similar range of
inducers and inhibitors.
P glycoprotein Pgp
Part of a larger family of efflux transporters found in the brain, gut
kidneys, biliary system, testes, ovaries and other organs.
Are 170KD cell membrane associated proteins that transport a
variety of drug substrates
Using atp as an energy source they transport hydrophobic
substances in the following directions:
Into the gut, out of the brain, into urine, into bile, out of gonads, out
of other organs.
Have been implicated as a primary cause of multi drug resistance in
tumors.
Block absorprtion in the gut & act as gtae keepers for late p-450
cytochrome actions. Ketoconazole (anti fungal), erythromycin
(antibiotic) inhibit pgp in the gut.
Prevent entry into the brain. Loperamide (opiate anti-diarrheal) is
normally kept out of the brain by the blood brain barrier due to
transport away from the brain by p-gp. If quinidine (antimalarial), is
given concurrently it will inhibit p-gp, more loperamide enters the
brain and cause respiratory depression.
Transport various substrates across the cell membrane including:
Glucocorticoids and other steroids
Cardiac glycosides such as digoxin
Immunosuppressive agents

Chemotherapeutic agents such as vinblastine

Lipids, peptides and bilirubin
Protein binding displacement:
Drug interactions SELDOM occurs solely because of protein binding
displacement. Those interactions ocne ascribed to this mechanism
eg between certain NSAIDs and warfarin ad are in fact usually the
result of impared metabolism or enhanced effect
Renal excretion:
Relatively few drugs undergo predominantly renal elimination. For
those with a low therapeutic index eg lithium, digoxin and
aminoglycosides an increase in plasma concentrations is often
associated with the drug toxicity.
NSAIDs compete with methotrexate for renal excretion and resultant
toxicity has been fatal. NSAIDs, thiazide, loop diuretics and to a
certain extent ACE inhibitors and angiotensin receptor antagonists,
reduce renal excretion of lithium.