Drug Interactions - Absorption and Excretion

Question 1

What is a drug interaction?

Answer 1

A drug interaction occurs when an effect of one drug alters the effect of another
The result is usually adverse, although it can sometimes be beneficial

Question 2

What are the different mechanisms of drug interaction ?

Answer 2

Pharmaceutical
Pharmacokinetic
Pharmacodynamic

Question 3

What is a pharmaceutical interaction?

- basic description

Answer 3

Pharmaceutical

• occurs before administration
• where drugs interacts (mixed) physicochemically in vitro (in solution) so that one or both are inactivated
• no pharmacological principles are involved but simple chemistry

Question 4

What is a pharmacokinetic interaction?

Answer 4

Pharmacokinetic
- where drug A alters the concentration of drug B that reaches its site of action

• occur when the absorption, distribution or elimination (metabolism or excretion) of drug A is altered by drug B
  = this can result in drug toxicity or loss of effect

Question 5

What is a pharmacodynamic interaction?

Answer 5

Pharmacodynamic
- the effect the drug has on the body/response it causes

• where drug A modifies the pharmacological effect of drug B without altering its concentration in the tissue fluid

Question 6

What are pharmaceutical interactions?

Answer 6

occur when 2 drugs interact physiochemically in solution (in vitro)

• physical and chemical incompatibilities may occur with loss of potency, increase in toxicity or other adverse effects

physical incompatibility (how it looks/can be seen)
=  precipitation, haziness, crystallisation, emulsions ‘cracking’)
- occur as a result of pH, concentration changes, ‘salting out’ effects

chemical incompatibility
= degradation, inactivation, complexation, a new compound formed
- occur as a result of a chemical reaction between the drugs after mixing (in vitro)

Question 7

How can pharmaceutical interactions be avoided?

Answer 7

do not add drugs to infusion solutions other than dextrose or saline
avoid mixing drugs in the same infusion solution, unless you know the mixture to be safe

solutions should be thoroughly mixed by shaking and checked for visible changes
- turbidity, precipitation or colour change (physical)
= absence of these signs is no guarantee of compatibility

ready-made solutions should be used whenever possible
avoid the need for mixing
drugs can be given via a different route
drugs can be given ay different times

Question 8

What is NATO?

Answer 8

N - necessary
A - alternative route
T - timing
O - other drugs

must try all possible ways to avoid mixing of drugs

Question 9

What are the mechanism for absorption interactions?

- pharmacokinetic

Answer 9

Change in pH of GI fluids
Effects on gastric emptying and GI motility
Binding or chelation of drugs
Competition for active absorption mechanisms
Toxic effects on the GIT
Changes in gut bacterial flora

Question 10

How do changes in the pH of GI fluids affect absorption?

Answer 10

passive diffusion across GIT is determined by ionisation state, solubility and lipophilicity of drug
- ionisation state depends on drug pKa and gastric pH

basic drugs are more soluble in acid GI content
- tend to be ionised and less lipid soluble so are absorbed less rapidly

acidic drugs are more soluble in alkaline fluids
- are unionised and absorbed rapidly

drugs which alter pH may have complex and unpredictable effects on the absorption of other drugs
- antacids should not be taken at the same time s other drugs as it may impair absorption

Question 11

How do changes in GI motility affect absorption?

Answer 11

drugs are absorbed more rapidly from the small intestine (larger SA + membrane is more permeable) than from the stomach

agents which increase or decrease the rate of gastric emptying may influence the absorption of other drugs given at the same time

vomiting and persistent severe diarrhoea can interfere with the absorption of combined oral contraceptives
- if vomiting occurs within 2 hours of taking a combined oral contraceptive another pill should be taken as soon as possible

Question 12

How do binding and chelation of drugs affect absorption?

Answer 12

Ca2+, Mg2+ , Al3+ containing antacids and iron form an insoluble complex with tetracycline and slow/reduce its absorption

cholestyramine, a bile-acid binding resin, binds several drugs preventing their absorption if administered simultaneously

binding and chelation of drugs can reduce their absorption

Question 13

How do changes in bacterial gut flora affect absorption?

Answer 13

some drugs are metabolised extensively or in part by the gut bacterial flora
- from pro-drug to metabolite (active form)

suppression of the gut bacterial flora by antibiotics might limit the metabolic conversion of sulphasalazine to its active component

Question 14

What are the main mechanisms for excretion interactions?

Answer 14

altering protein binding and hence filtration
inhibiting tubular secretion
altering urine pH and/or urine flow

Question 15

How do changes in urine pH affect absorption?

Answer 15

non-ionised drugs/metabolites can be passively re-absorbed from the tubule into plasma
- hence prolonging drug action

basic drugs are more rapidly excreted in the acid urine,

• low pH within the tubule favours ionisation and thus inhibits reabsorption
• acidic drugs are more rapidly excreted if the urine is alkaline as it will favour ionisation

Question 16

How does urinary alkalinisation and acidification affect absorption of basic and acidic drugs?

Answer 16

urinary acidification accelerates excretion of weak bases and retards that of weak acids

urinary alkalinisation reduces the excretion of weak bases and increases excretion of weak acids

Question 17

How do changes in urine flow affect absorption?

Answer 17

diuretics tend to increase the urinary excretion of other drugs
- move sodium into urine by increasing pores on the collecting duct

Question 18

How does inhibition of tubular secretion affect absorption?

Answer 18

many acidic drugs and metabolites share the same distal tubular active transport system
- can compete with each other for secretion from blood into kidney tubules

• one drug may therefore interfere with the renal excretion of another and can cause accumulation and toxicity

co-administration of probenecid competes with penicillin for active secretion
- increases penicillin serum level therefore prolonging its action