Lecture 5- Variability In Drug Response Flashcards
What are the factors affecting Drug Metabolism?
Drug Interaction Age Gender
Genetic differences
Diet (components/status) Environment Disease state
Self-serving
A drug inducing it’s own breakdown enzymes
Half life
Time it takes to reduce a drug circulating concentration to one half of that when the drug concentration was initially assayed
What do clear majority of drugs have?
Exponential decay
What is Rifampicin inducing?
Enzymes responsible for the metabolism of warfarin
What are the 2 drugs used for the treatment of depression?
Fluvoxamine Cimetidine
Where is CYP3A4 most ubiquitously found?
Liver
Age
Hepatic function is lower at birth and in old age
What does the use of Chloramphenicol cause?
Grey baby syndrome
What does Diazepam cause in the elderly?
Significant confusing effect
What is total body water a component of?
Total body fluid (consider total body fat)
What toxicants alter cytochrome P450 function?
Inducers/Inhibitors
What are some examples of toxicants that alter cytochrome P450 function?
Tobacco Heavy metals Industrial pollutants
Solvents (polychlorinated biphenyls)
Pesticides/Herbicides
What are 2 examples of liver disease?
Hepatitis or biliary cirrhosis
What happens if microsomal oxidases are markedly affected?
Decreased capacity to Metabolise drugs
What does migraine cause?
Gastric stasis
What does Kinsey problem cause?
Affected renal function and the level at which drug can be excreted (urine production) Chronic disease: heart failure, nephrotic syndrome
What did Bailey et al first note?
Grapefruit juice altered the oral bioavailability of felodipine
What has GFJ been used for?
Mask the taste of ethanol (efficacy of felodipine)
What did the plasma concentration of felodipine show?
5-cold higher after oral administration If taken with grapefruit juice
What enzymes does the basis of GFJ-felodipine Interaction appear?
CYP3A4
What is GFJ affecting?
The absorption of felodipine or the break down of felodipine
What does statins work to reduce?
Circulating levels of Lipids in bloodstream - reducing the risk of atherosclerosis
What do Brussel sprouts do?
Diminish the drug effect instead of prolonging it
Where does Furanocoumarins act on?
Cytochrome P450 to slow down its activity
What can activity of certain cytochrome P450 be increased by?
Presence of glucosinolates
What is pharmacogenomics?
The branch of genetics concerned with determining the likely response of an individual to therapeutic drugs
What are genetic differences often due to?
Single nucleotide polymorphisms
Nortriptyline
Treatment of depression
What are the 4 phenotypes identifies within European population?
- Poor metabolisers 2. Intermediary Metabolizers 3. Extensive metabolizers 4. Ultra-rapid metabolizers
Poor metabolizers
Such individuals lack the functional enzyme Drugs can have more than one route of elimination Elevated levels or drug
Intermediary metabolizers
Such individuals are heterozygous for one functional allele or have two partially defective alleles encoding the enzyme
Extensive metabolizers
Have two normal alleles
Ultra-rapid metabolizers
Carry duplicates or multi-duplicated functional CYP2D6 genes
Majority of population (80-65%)
Dose range between 100-200mg
5-10% poor metabolizers
Dose range will be low between 20-50mg because Nortriptyline hangs around in the body for a longer period
What does Warfarin have?
Narrow therapeutic window Wide variation in dose requirements High incidence of adverse events
What patient genotype does gene-guided dosing consider?
CYP2C9 and VKORC1
What is vitamin K involved in?
Coagulation process
What is N-acetyltransferase 2 responsible for?
Metabolism of Isoniazid - can enhance effect of drug
How does Isoniazid metabolism occur?
Acetylation
Fast Acetylators
UK 40%
Slow acetylators
UK 60%
What is Isoniazid?
Inherited characteristics
Isoniazid
Bi-modal distribution depending if you are fast or slow acetylators
What is salicylate?
Compound related to aspirin Used as anti-inflammatory (treatment of fever) Unimodal distribution - less variation in metabolic processes
What can affect drug response?
Receptor polymorphism
What receptor is associated with weight gain?
5-HT2C - affect patient compliance
What can sex hormones change?
Expression pattern
