Factors affecting ADME
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80 Terms
What is the Peter Perfect principle?
Drug behaviour can be predicted using pharmacokinetic rules but real patients vary greatly.
Why do drugs not work the same in all people?
Because intrinsic and extrinsic factors alter ADME processes.
What are intrinsic factors in pharmacology?
Internal patient factors such as genetics age sex and body composition.
What are extrinsic factors in pharmacology?
External influences such as diet environment disease and other drugs.
What does ADME stand for?
Absorption Distribution Metabolism Excretion.
Why are many drugs designed to be lipophilic?
To improve diffusion across cell membranes.
What happens to lipophilic drugs in adipose tissue?
They can accumulate and remain stored for long periods.
Why can adipose tissue increase drug toxicity?
Because drugs may accumulate to toxic levels in fat stores.
How much can adipose tissue vary between individuals?
Approximately 5% to over 45%.
What specialised barriers protect organs from drugs?
The placenta and blood-brain barrier.
What forms the blood-brain barrier?
Tightly connected endothelial cells with tight junctions.
Why does the blood-brain barrier restrict many drugs?
Because it limits aqueous diffusion and drug transport.
What property strongly affects blood-brain barrier permeability?
Octanol/water partition coefficient K.
How does lipophilicity affect BBB penetration?
More lipophilic drugs cross the BBB more easily.
Why does sucrose have poor membrane permeability?
Because it contains many polar groups.
Why does caffeine cross membranes well?
Because it is relatively non-polar.
Why does vincristine poorly cross the BBB?
Because it is large and contains hydrophilic regions.
What is the Lipinski Rule of 5 used for?
Predicting oral drug absorption and permeability.
How can drug formulation affect absorption?
It controls release site and release timing.
How does food usually affect drug absorption?
Food generally decreases absorption.
How can light meals affect absorption?
They may increase absorption of some drugs.
How does gastric pH affect absorption?
It alters drug ionisation and dissociation.
Why is gastric motility important for absorption?
Drugs must remain in the GI tract long enough to be absorbed.
How can GI tract damage affect absorption?
It reduces membrane efficiency and absorption.
What is plasma protein binding?
Binding of drugs to plasma proteins in blood.
Which form of a drug is pharmacologically active?
The free unbound drug.
How does polypharmacy affect plasma protein binding?
Drugs may compete for protein binding sites.
Why is tissue blood flow important for distribution?
Drugs need adequate blood supply to reach tissues.
How does heart disease affect drug distribution?
Reduced circulation decreases tissue delivery.
Why do lipophilic drugs distribute into adipose tissue?
Fat dissolves lipophilic drugs.
Why are ointments useful for tendons?
Tendons have poor blood supply.
How does age affect drug metabolism?
Hormonal changes can alter enzyme expression.
How can sex affect drug metabolism?
Hormonal differences influence metabolism.
How does nutrition affect drug metabolism?
Diet alters drug metabolising enzyme expression.
How does liver disease affect pharmacokinetics?
It impairs drug metabolism.
How does kidney disease affect pharmacokinetics?
It impairs drug excretion.
What organ is mainly responsible for drug metabolism?
The liver.
What organ is mainly responsible for drug excretion?
The kidney.
What organ is important for drug distribution?
The heart.
What is polypharmacy?
The use of multiple drugs simultaneously.
Why can polypharmacy be dangerous?
Drugs may interact with enzymes transporters or receptors.
What is a perpetrator drug?
A drug that alters another drug’s metabolism or transport.
What is a victim drug?
A drug affected by another drug interaction.
What is enzyme induction?
Increased enzyme expression or activity.
How does enzyme induction affect drug levels?
It usually lowers drug concentration.
Name an example of an enzyme inducer.
Rifampicin.
What herbal medicine induces drug metabolism and transport?
St John’s Wort.
What is enzyme inhibition?
Reduced enzyme activity causing slower metabolism.
How does enzyme inhibition affect drug levels?
It usually increases drug concentration and toxicity risk.
Name an example of an enzyme inhibitor.
Gemfibrozil.
How does grapefruit juice affect drug metabolism?
It inhibits intestinal CYP3A4 and P-glycoprotein.
Why can grapefruit juice cause toxicity?
It increases blood concentrations of some drugs.
What is pharmacogenetics?
The study of genetic influences on drug responses.
What is a mutation?
An error in DNA copying.
What is genetic migration?
Exchange of genes between neighbouring populations.
What is a founder population?
A small population with limited genetic diversity.
What is random genetic drift?
Random changes in allele frequency in small populations.
What is selection in genetics?
Advantageous alleles becoming more common.
What is P-glycoprotein PgP?
A drug transporter that pumps drugs out of cells.
Where does PgP act in the GI tract?
It pumps drugs back into the intestinal lumen.
What is the role of PgP in the body?
It acts as a protective defence against xenobiotics.
How much variation in ciclosporin A oral clearance is due to PgP?
About 17%.
What effect does St John’s Wort have on PgP?
It induces PgP activity.
What effect does verapamil have on PgP?
It inhibits PgP.
What is CYP3A4?
A major drug metabolising enzyme.
Why is warfarin clinically challenging?
It has a narrow therapeutic window.
Which enzyme mainly metabolises S-warfarin?
CYP2C9.
What metabolite is formed from S-warfarin by CYP2C9?
7-hydroxy S-warfarin.
Which drugs prolong warfarin action by inhibiting CYP2C9?
Gemfibrozil fluorouracil and amiodarone.
Which drugs reduce warfarin effect by enzyme induction?
Carbamazepine and clozapine.
How can metabolites affect enzymes?
Some metabolites strongly inhibit CYP enzymes.
What happens to gemfibrozil after phase II metabolism?
It becomes a potent CYP2C8 inhibitor.
Name drugs metabolised by CYP2C8.
Repaglinide rosiglitazone pioglitazone paclitaxel and cerivastatin.
What is tacrolimus used for?
Immunosuppression in transplant patients.
Which transporter strongly affects tacrolimus handling?
P-glycoprotein.
What is personalised medicine?
Tailoring treatment to individual patient characteristics.
What factors are considered in personalised medicine?
Genetics environment lifestyle and organ function.
What limits personalised medicine currently?
Complex interactions between genetics and environmental factors.
Why is predicting drug response difficult in populations?
Because people vary widely in ADME and genetics.
Why is making an effective drug delivery system difficult?
The drug must reach the correct tissue in sufficient amounts.