Sesh 7: Individual Variations Flashcards
What is variability ?
Is the potential or the actual difference either quantitative or qualitative in the phenotype among individuals?
What are main causes of variability ?
Age Sex Pregnancy Disease Drug interactions Genetic factors
Why is age one of the main reasons drug action is affected ?
The main reason that age affects drug action is that elimination becomes less efficient. This is because glomerular filtration rate declines slowly with ages
For example chronic administration over the years of the same daily rise of digoxin to an individual as they age will lead to progressive increase in plasma concentration. This is common cause of glycoside toxicity in elderly patients .
What important factors change with age ?
Metabolism and body composition.
metabolism: The activity of hepatic microsomal enzymes declines slowly with age resulting in decreased clearence
Body composition: the distribution volume of lipid soluble drugs increases because the proportion of the body that is fat increases with advancing age.
The activity of hepatic microsomal enzymes decline with ages which then decreases clearance for example benzodiazepines
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An effect of benzodiazepines ?
Class of psychoactive drugs
Can cause more confusion and less sedation
Hypotensive drugs
Treatment for low blood pressure
Can cause postural hypotension more commonly
Variability in newborn ;
Rates of drug absorption in the infant are lower than absorption rates in children and adults.
Prolonged affects results in risk of toxicity . Situation is more severe in premature infants due to immaturity of the kidney.
Gentamicin plasma half life:
Premature - >18h
Newborn - 10h
Adult -1-4h
The half-life of a drug is the time taken for the plasma concentration of a drug to reduce to half its original value
Why isn’t morphine used in labour ?
It is transferred to the fetus and accumulates there causing prolonged respiratory depression
What can accumulation of chloramphenicol cause ?
the low conjugation activity may result in accumulation of drugs in tissues, causing toxic effects, like in the case of the gray baby syndrome due to accumulation of the antibiotic chloramphenicol
How can pregnancy influence drug pharmacokinetics ?
Pregnancy causes physiological changes. Plasma albumin concentration is reduced influencing drug binding to circulating proteins.
Drug absorption and elimination are also affected by changes in the GI and cardiovascular physiology.
Drugs transferred to the fetus are eliminated more slowly due to immaturity of liver and kidney function
Some drugs like LMW heparins are effectively excluded by the placental barrier and can be administered chronically to the mother
Pharmacokinetic alterations
Absorption -
Pancreatic disease - malabsorption
Distribution-
Chronic renal failure - altered plasma protein binding.
Meningitis - altered blood brain barrier
Metabolism -
Hepatic cirrhosis - reduced clearance
Hypothermia- reduced clearance
Excretion -
Renal failure - reduced excretion
Myasthenia gravis
pharmacodynamic alterations
Myasthenia gravis (MG) is a chronic autoimmune disorder in which antibodies destroy the communication between nerves and muscle, resulting in weakness of the skeletal muscles
For example myasthenia gravis, an autoimmune disease where the patient develops antibodies against the nicotinic acetylcholine receptors, results in increased sensitivity to drugs that influence neuromuscular transmission, like the neuromuscular blocker vecuronium.
Ethnicity can play a role in drug responsiveness ?
Hydralazine and nitrate for heart failure increases life expectancy of African Americans but not white Americans
Chinese subjects are more sensitive to the cardiovascular effects of propranolol than white Europeans
Environmental factors involved such as dietary habits
What is a drug interaction?
Clinically meaningful alteration in the effect of one drug as a result of a co-administration of another drug.
What is an object drug and a precipitant drug ?
The drug affected by interaction is called an object drug
The drug causing interaction it called precipitant drug
What is thiopental?
Thiopental is used to induce general anesthesia and reduce intracranial pressure.
Why shouldn’t thiopental and suxamethonium be mixed in the same syringe ?
mixing thiopentone and suxamethonium in the same syringe can form a complex
Why shouldn’t ciprofloxacin and iron be taken at the same time ?
Ciprofloxacin and ferrous sulfate should not be taken orally at the same time. Products that contain magnesium, aluminum, calcium, iron, and/or other minerals may interfere with the absorption of ciprofloxacin into the bloodstream and reduce its effectiveness.
Results in decreased absorption
metoclopramide Increases GI motility and this can decrease cefprozil absorption
Metoclopramide is a medication used for stomach and esophageal problems.
Cefprozil is a second-generation cephalosporin antibiotic. It can be used to treat ear infections, skin infections, and other bacterial infections
Alkalinisation by omeprazole a drug used to treat conditions caused by excess stomach acid may decrease absorption of the anti fungal ketocanazole
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Decreased GI bacterial flora caused by antibiotic administration could decrease bacterial production of vitamin K , increasing the anticoagulant effect of warfarin
If too much warfarin can lead to severe bleeding
Displacement of a drug
Displacement from a receptor site diminishes drug activity,
but displacement from plasma or tissue proteins increases the effect by making more unbound drug available at the receptor site.
Example of Displacement from plasma proteins?
Displacement of methotrexate from plasma proteins by NSAIDS may increase risk of methotrexate toxicity .
methotrexate treats cancer
Another example ;
Phenylbutazone (NSAID) displaces warfarin from albumin resulting in increased bleeding
Enzyme inhibition resulting in reduced drug effect
Analgesic and toxic effects of codeine result from its conversation to morphine by CYP2D6 . This CYP2D6 inhibitors can impair therapeutic effect of codeine
Enzyme inhibition resulting in increasing risk of toxicity ;
Inhibitors if CYP2C9 can increase risk of toxicity from warfarin
Enzyme induction resulting in reduced drug effect -
Rifampicin reduced effect of warfarin as an anticoagulant
Enzyme induction resulting in toxic metabolites ?
A small amount of paracetomol is converted to a cytotoxic metabolite. Enzyme inducers can increase formation of toxic metabolites and increase risk of hepatotoxicity
Excretion ;
Inhibition of tubular secretion;
Digoxin is eliminated through renal excretion and drugs such as amiodarone can inhibit this . Digoxin toxicity results x
Probenecid was developed expressly to inhibit penicillin secretion and this prolong its action
Probenecid is used in the treatment of chronic gout or gouty arthritis.
Drug interactions ;
Warfarin and anti thrombotic drugs; increased risk of bleeding by two mechanisms, anti coagulation and inhibition of platelet function.
Sulphonamides and trimethoprim - synergistic antibacterial action by inhibiting different steps of tetrahydrofolate synthesis
NSAIDs and anti hypertension drugs - NSAIDs block the hypotensive effects of various anti-hypertensive drugs by inhibiting the synthesis of renal vasodilator
Promethiazine and alcohol - promethiazine is a histamine H1 receptor antagonist that causes drowsiness . This is increased if taken with alcohol
What are slow acetylators ?
Slow acetylators are people whose liver cannot completely detoxify reactive drug metabolites.
What are SNPs?
Single Nucleotide Polymorphisms (SNPs) holds the key in defining the risk of an individual’s susceptibility to various illnesses and response to drugs.
SNPS and drug metabolism : CYP2D6
The cytochrome P450 2D6 metabolises numerous drugs
CYP2D6 is highly polymorphic.
Genetic tests could predict levels of CYP2D6 activity and Inform prescription . Individuals can be classified according to their CYP2D6 activity in ultra rapid , extensive and poor metabolisers.
E.g codeine is metabolised to the active drug morphine by CYP2D6. If the genetic tests tells us an individual might be an ultra rapid metaboliser this would inform codeine should be avoided due to toxic levels of morphine
Poor metaboliser - avoid codeine due to lack of efficacy
Extensive metaboliser - use age and weight specific dosing.
Pharmocogenomic tests
Carbamazepine and other anticonvulsants can provoke severe adverse effects and this is associated with a particular HLA allele found in Asian patients . Screening Chinese patients for this allele is recommended before starting therapy .
Testing
Testing for DPYD deficiency would be useful before antitumoral therapy with 5-fluorouracil.
DPYD metabolises the drug and when missing toxic levels of 5FU can be reached
Drug target related test ;
Trastuzumab (Herceptin) is a monoclonal antibody that targets the EGF receptor HER2. This receptor is normally expressed at low levels but in some tumours there is over expression causing cells to hyperproliferate.
Trastuzumab antagonises epidermal growth factor by binding to receptor HER2
HER2 occurs in tumour tissue of some patient as a result of mutation
only cancer patients whose tumour over expresses HER2 will benefit
It is possible to obtain tumour biopsy and determine if there’s overexpression of HER2. In which case trastuzumab would be a useful therapy
