Lecture 10.2: Variation in Response to Drugs and Drug Interactions Flashcards by Purva Shegunshi

What can cause interindividual variability in the response to pharmacologic agents? (7)

Immunological Factors (allergies)
Genetics
Age (elderly, children)
Sex
Physiology (pregnancy)
Exogenous (other drugs, foods)
Disease States

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What is Pharmacogenomics/Pharmacogenetics?

Role of the components of the genome on the
response to a drug and pharmacogenetics role of genetic variation

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What are Epigenetic Changes?

Changes that affect genes without altering the gene
sequence
This may occur via changes in gene methylation or
histone modification (methylation, acetylation)
Both can influence the rate of transcription or
silencing of gene expression

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What is Pharmacokinetics?

What body does to drug, how it moves through the body

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What is Pharmacodynamics?

What drug does to the body

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Drug Metabolism: Phase 1

Polar groups added to lipophilic molecules by oxidation, reduction, or hydrolysis to make water-soluble
Catalysed by the cytochrome P450 superfamily of mixed function oxidases (CYPs)

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Drug Metabolism: Phase 2

Compounds not hydrophilic enough for excretion
Further processing
Conjugation with glucuronidation, glutathione, methyl
or acetyl group
Readily excretable, nontoxic substances

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How many genes code for CYP proteins?

60 genes

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What types of CYP proteins are responsible for Phase I drug metabolism?

Microsomal-Type
Located on the cytoplasmic side of the endoplasmic
reticulum membrane

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Hepatic metabolism of drugs and toxins is by which families of CYP proteins?

CYP1, CYP2, and CYP3

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What 5 isoenzymes are involved in 90 percent of all drug metabolism?

CYP3A4
CYP2D6
CYP2C9
CYP2C19
CYP1A2

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Enzymes are organised into..? (3)

Families (eg, CYP2)
Subfamilies (eg, CYP2D)
Isoenzyme (eg, CYP2D6)

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What effect can genetic polymorphisms in the CYP isoenzymes have on drug metabolism?

Diminished metabolism
Lack of metabolism
Excessive metabolism of a compound

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What effect can genetic polymorphisms in the phase II and the phase III enzymes have?

Decreased and increased activity
Variations in the hepatobiliary transporters (drug-
induced cholestasis)

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What is Clopidogrel?

It is a prodrug whose active metabolite prevents platelet aggregation

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What is the MOA of Clopidogrel?

Binds irreversibly to ADP receptor on the surface of
platelets
Independent of cyclooxygenase pathway
Synergistic with aspirin (Inhibit COX - reduced
thromboxane – reduce platelet aggregation)

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Codeine is a prodrug it is metabolised by …. to …. and codeine-6-glucuronide

CYP2D6
Morphine

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What is the Role of Thiopurine S-methyltransferase (TPMT)?

It is an enzyme that metabolises a class of drugs called thiopurines

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Examples of Thiopurines

Azathioprine
6-mercaptopurine
Thioguanine

What are Thiopurines used to treat?

Maintenance of remission in inflammatory bowel
disease (Crohn’s)
Disease modifying agent in rheumatoid arthritis
Prevent rejection in transplant patients

What is START in Elderly Patients?

Screening Tool to Alert to Right Treatment
Can be used to prevent omissions of indicated,
appropriate medicines in older patients with specific
conditions

What is STOPP in Elderly Patients?

Screening Tool of Older Persons’ potentially
inappropriate Prescriptions
Aims to reduce the incidence of medicines-related
adverse events from potentially inappropriate
prescribing and polypharmacy

Why may use of drugs in patients with reduced renal function give rise to problems for several reasons?

Reduced renal excretion of a drug or its metabolites
may cause toxicity
Many side-effects are tolerated poorly by patients with
renal impairment
Some drugs are not effective when renal function is
reduced
Problems can be avoided by reducing the dose or by
using alternative drugs

Why is Pregnancy a key factor to consider when prescribing medications?

Drugs can have harmful effects on the embryo or
foetus at any time during pregnancy
First trimester drugs can produce congenital
malformations
During the second and third trimesters drugs can
affect the growth or functional development of the
foetus

Can Liver Disease impact drug metabolism?

Liver metabolism is the main route of elimination for many drugs, but hepatic reserve is large and liver disease must be severe before important changes in drug metabolism occur

How does Hypoalbuminaemia affect drug metabolism?

* Reduced protein binding * Increased toxicity of highly protein-bound drugs such as phenytoin and prednisolone

What effect does reduced synthesis of blood-clotting factors have on drug metabolism?

Increased sensitivity to oral anticoagulants such as warfarin

What effect does severe liver disease have on drug metabolism?

* Drugs may precipitate hepatic encephalopathy * Sedative drugs, opioid analgesics, diuretics that produce hypokalaemia, and drugs that cause constipation

Oedema and ascites in chronic liver disease can be exacerbated by drugs that give rise to fluid retention such as...? (2)

* NSAIDs * Corticosteroids

What does the efflux transporter P-glycoprotein do?

P-glycoprotein actively transport drugs across membranes, transports absorbed drugs back into the gut

What drugs can inhibit P-glycoprotein? (3)

* Verapamil * Atorvastatin * Amiodarone

What drug can induce P-glycoprotein?

Rifampicin

What happens if P-glycoprotein is inhibited?

Increased bioavailability of the susceptible drug

What type of pump is an Organic anion transporting polypeptides (OATPs)? Where is it found?

* Influx pump * Gut wall and transporter portal system into liver cells

What drug is OATP in the liver inhibited by?

Rifampicin

What drug is OATP in the gut inhibited by?

* Grapefruit juice fexofenadine * Absorption is prevented

Which enzymes are most important in Phase I reactions?

* Cytochrome P450 family of isoenzymes * CYP3A4 is the most important

What drug is a potent inducer of CYP3A4?

Carbamazepine

...X... is substrate for CYP3A4, carbamazepine will reduce ...X... concentrations

Midazolam

What drug is potent inhibitor of CYP3A4?

Ketoconazole

Drug Interactions of Erythromycin and Warfarin

* Some warfarin is metabolised by CYP3A4 * Erythromycin is an inhibitor of CYP3A4 * Reduction in CYP3A4 activity leads to decreased warfarin metabolism * Increased INR and increased potential bleeding

What is the International Normalised Ratio (INR)?

A blood test called the prothrombin time (PT) that tells you how long it takes for your blood to clot

What can happen if 2 drugs are administered with similar pharmacological effects?

The effects can be additive

Factors to consider to help prevent adverse drug reactions? (10)

* Never use any drug unless there is a good indication * Pregnancy do not use a drug unless imperative * Allergies/Previous Reactions * Ask about taking other drugs (interactions) * Age * Hepatic/Renal Disease * Genetic factors in metabolism * Prescribe as few drugs as possible and give very clear instructions * Use a familiar drug, with a new drug, alert for adverse reactions * Consider excipients contributing to adverse reaction

What is the MHRA?

Medicines and Healthcare products Regulatory Agency