Sesh 7: Individual Variations

Question 1

What is variability ?

Answer 1

Is the potential or the actual difference either quantitative or qualitative in the phenotype among individuals?

Question 2

What are main causes of variability ?

Answer 2

Age 
Sex 
Pregnancy 
Disease 
Drug interactions
Genetic factors

Question 3

Why is age one of the main reasons drug action is affected ?

Answer 3

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 .

Question 4

What important factors change with age ?

Answer 4

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.

Question 5

The activity of hepatic microsomal enzymes decline with ages which then decreases clearance for example benzodiazepines

Answer 5

X

Question 6

An effect of benzodiazepines ?

Answer 6

Class of psychoactive drugs

Can cause more confusion and less sedation

Question 7

Hypotensive drugs

Answer 7

Treatment for low blood pressure

Can cause postural hypotension more commonly

Question 8

Variability in newborn ;

Answer 8

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

Question 9

Why isn’t morphine used in labour ?

Answer 9

It is transferred to the fetus and accumulates there causing prolonged respiratory depression

Question 10

What can accumulation of chloramphenicol cause ?

Answer 10

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

Question 11

How can pregnancy influence drug pharmacokinetics ?

Answer 11

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

Question 12

Pharmacokinetic alterations

Answer 12

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

Question 13

Myasthenia gravis

pharmacodynamic alterations

Answer 13

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.

Question 14

Ethnicity can play a role in drug responsiveness ?

Answer 14

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

Question 15

What is a drug interaction?

Answer 15

Clinically meaningful alteration in the effect of one drug as a result of a co-administration of another drug.

Question 16

What is an object drug and a precipitant drug ?

Answer 16

The drug affected by interaction is called an object drug

The drug causing interaction it called precipitant drug

Question 17

What is thiopental?

Answer 17

Thiopental is used to induce general anesthesia and reduce intracranial pressure.

Question 18

Why shouldn’t thiopental and suxamethonium be mixed in the same syringe ?

Answer 18

mixing thiopentone and suxamethonium in the same syringe can form a complex

Question 19

Why shouldn’t ciprofloxacin and iron be taken at the same time ?

Answer 19

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

Question 20

metoclopramide Increases GI motility and this can decrease cefprozil absorption

Answer 20

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

Question 21

Alkalinisation by omeprazole a drug used to treat conditions caused by excess stomach acid may decrease absorption of the anti fungal ketocanazole

Answer 21

X

Question 22

Decreased GI bacterial flora caused by antibiotic administration could decrease bacterial production of vitamin K , increasing the anticoagulant effect of warfarin

Answer 22

If too much warfarin can lead to severe bleeding

Question 23

Displacement of a drug

Answer 23

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.

Question 24

Example of Displacement from plasma proteins?

Answer 24

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

Question 25

Enzyme inhibition resulting in reduced drug effect

Answer 25

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

Question 26

Enzyme induction resulting in reduced drug effect -

Answer 26

Rifampicin reduced effect of warfarin as an anticoagulant

Question 27

Enzyme induction resulting in toxic metabolites ?

Answer 27

A small amount of paracetomol is converted to a cytotoxic metabolite. Enzyme inducers can increase formation of toxic metabolites and increase risk of hepatotoxicity

Question 28

Excretion ;

Answer 28

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.

Question 29

Drug interactions ;

Answer 29

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

Question 30

What are slow acetylators ?

Answer 30

Slow acetylators are people whose liver cannot completely detoxify reactive drug metabolites.

Question 31

What are SNPs?

Answer 31

Single Nucleotide Polymorphisms (SNPs) holds the key in defining the risk of an individual’s susceptibility to various illnesses and response to drugs.

Question 32

SNPS and drug metabolism : CYP2D6

Answer 32

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.

Question 33

Pharmocogenomic tests

Answer 33

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 .

Question 34

Testing

Answer 34

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

Question 35

Drug target related test ;

Answer 35

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