Individual Variations Flashcards
what is intra-individual variation
variation in the same individual
what is inter-individual variation
variation between individuals
do drugs work for everyone
no
what are the two types of variability
pharmacodynamic = different physiological responses to the same drug conc. Due to different factors: disease, genetics DDI.
pharmacokinetic = different conc at target sites. Due to ADME.
what are the two effects of variation
quantitative (similar effect but larger/smaller/longer/shorter) and qualitative (entirely different effect) e.g., primaquine (an antimalarial) can induce haemolysis in individuals with deficit in G6PDH.
7 causes of variability
- Age
- Physiological factors
- Gender - Females
- Pregnancy
- Body weight/composition
- Disease
- Sociocultural factors (diet, habits)
- Ethnicity
- Drug interactions
- Genetic factors
variation with age: elderly
Elimination becomes less efficient in elderly people (main reason). GFR declines with age (at 75yrs declined by half) and so drugs have greater and more prolonged effects.
Metabolism decreases with age. Activity of hepatic microsomal enzymes (present in the liver, includes the Cytochrome P450 enzymes) declines → decreased clearance. (E.g., benzodiazepines).
-Body composition changes with age: Fat composition increases with age → distribution volume changes. Examples: increased serum levels of water soluble drugs like digoxin & increased half-life of lipid-soluble drugs like benzodiazepines.
- Variations in sensitivity: The same plasma conc. of a drug can cause different effects in younger people vs older. E.g., benzodiazepines cause more confusion and less sedation in elderly, also hypotensive drugs cause more postural hypotension and the response to opioid analgesics is increased.
- Increased frequency of polypharmacy: increased risk of drug-drug interactions and adverse drug effects.
variation with age: newborn
Renal excretion is less efficient (main cause): GFR is only 20% of the adult → longer plasma elimination half-lives of renally excreted drugs → greater risk of toxicity → greater and more prolonged effects of drugs. Higher effect in premature infants due to immature kidney. necessary to space out doses to avoid toxicity in babies.
Low activity of several important enzymes in liver and plasma: slow conjugation activity → accumulation → toxicity. E.g., Chloramphenicol: grey baby syndrome & Morphine: not used as analgesic in labour as it transfers to baby and accumulates causing prolonged respiratory depression
grey baby syndrome pathophys
Roughly half of serum chloramphenicol is bound to albumin and other plasma proteins. Elimination happens primarily in the liver through O-glucuronidation, which puts neonates with immature hepatic metabolism at risk for the grey baby syndrome.
physiological factors: pregnancy
effects on the mother:
* Reduced albumin → altered drug-protein binding
* Increased cardiac output → increased renal blood flow and GFR → increased renal elimination * Reduced gastric motility and acid secretion → reduced gastrointestinal absorption
effects on the foetus:
Some drugs are excluded by the placenta, e.g. low molecular weight heparins
* Lipophilic molecules traverse rapidly, hydrophobic drugs are slow. If transferred to foetus elimination is slower than from the mother due to immature kidneys
disease can cause what type of alterations
pharmacokinetic and pharmacodynamic
variation: ethnicity
caused by environmental factors (diet) and genetics.
BiDil used for congestive heart failure marketed for African-Americans.
Propranolol more effective in Chinese than other ethnicities.
Gefitinib works better in Japanese people who have advanced lung tumours.
Disease: pharmacokinetic alterations
disease can affect ADME.
A = pancreatic disease & absorption, oedema of ileal mucosae & absorption, migraine & gastric stasis.
D = meningitis & altered blood-brain barrier, chronic renal failure & altered plasma protein binding.
M = hypothermia & reduced clearance, hepatic cirrhosis/portal hypertension & reduced clearance.
E = renal failure & reduced excretion
Disease: pharmacodynamic alterations
1) myasthenia gravis = Increased sensitivity to drugs that influence neuromuscular transmission: e.g., like neuromuscular blocker vecuronium, aminoglycoside antibiotics
2) familial hypercholesterolaemia = Resistance to statins in homozygous individuals
3) Familial precocious puberty and hyperthyroidism = Resistance to hormones
first drug is called
object drug
second drug is called
precipitant drug
define drug interaction
= A clinically meaningful alteration in the effect of one drug (object drug) as a result of coadministration of another drug (precipitant drug).
3 mechanisms of drug interactions
1) pharmacokinetic = affects ADME and conc.
- St Johns Wort, Brussel sprouts and cigarettes induce the CYP3A4 enzyme → increasing drug metabolism
- Grapefruit juice inhibits the CYP3A4 enzyme → decreasing drug metabolism.
2) pharmacodynamic = does not affect conc.
e.g., warfarin and antiplatelet drugs.
sulfonamides and trimethoprim.
3) in vitro interaction = not in vivo. Drugs react when in contact with each other in the vial or syringe before application. Thiopental and Suxamethonium form a complex when in the same syringe.
codeine to morphine: by CYP2D6
CYP2D6 inhibitors such as fluoxetine can affect therapeutic effect
drug acetylation deficiency is a …
and what does it cause
pharmacogenetic disorder (balanced polymorphism)
some people are slow acetylators and some are fast.
delayed metabolism of isoniazid (used for Tb)
pharmacogenetic disorders are caused by
alterations in a single gene.
define pharmacogenomics
how genetic alterations affect drug function. study of variability in drug response determined by the genome.
is cyp2d6 polymorphic
yes. highly.
snps
Alternative sequences at a locus within the alleles that persist in a population through several generations.
haplotypes
combinations of SNPs at a locus
