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Membranes and Receptors > Lecture 10.2: Variation in Response to Drugs and Drug Interactions > Flashcards

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

1
Q

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

A
  • Immunological Factors (allergies)
  • Genetics
  • Age (elderly, children)
  • Sex
  • Physiology (pregnancy)
  • Exogenous (other drugs, foods)
  • Disease States
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2
Q

What is Pharmacogenomics/Pharmacogenetics?

A

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

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3
Q

What are Epigenetic Changes?

A
  • 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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4
Q

What is Pharmacokinetics?

A

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

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5
Q

What is Pharmacodynamics?

A

What drug does to the body

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6
Q

Drug Metabolism: Phase 1

A

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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7
Q

Drug Metabolism: Phase 2

A
  • Compounds not hydrophilic enough for excretion
  • Further processing
  • Conjugation with glucuronidation, glutathione, methyl
    or acetyl group
  • Readily excretable, nontoxic substances
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8
Q

How many genes code for CYP proteins?

A

60 genes

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9
Q

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

A
  • Microsomal-Type
  • Located on the cytoplasmic side of the endoplasmic
    reticulum membrane
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10
Q

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

A

CYP1, CYP2, and CYP3

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11
Q

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

A
  • CYP3A4
  • CYP2D6
  • CYP2C9
  • CYP2C19
  • CYP1A2
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12
Q

Enzymes are organised into..? (3)

A
  • Families (eg, CYP2)
  • Subfamilies (eg, CYP2D)
  • Isoenzyme (eg, CYP2D6)
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13
Q

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

A
  • Diminished metabolism
  • Lack of metabolism
  • Excessive metabolism of a compound
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14
Q

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

A
  • Decreased and increased activity
  • Variations in the hepatobiliary transporters (drug-
    induced cholestasis)
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15
Q

What is Clopidogrel?

A

It is a prodrug whose active metabolite prevents platelet aggregation

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16
Q

What is the MOA of Clopidogrel?

A
  • 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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17
Q

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

A
  • CYP2D6
  • Morphine
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18
Q

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

A

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

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19
Q

Examples of Thiopurines

A
  • Azathioprine
  • 6-mercaptopurine
  • Thioguanine
20
Q

What are Thiopurines used to treat?

A
  • Maintenance of remission in inflammatory bowel
    disease (Crohn’s)
  • Disease modifying agent in rheumatoid arthritis
  • Prevent rejection in transplant patients
21
Q

What is START in Elderly Patients?

A
  • Screening Tool to Alert to Right Treatment
  • Can be used to prevent omissions of indicated,
    appropriate medicines in older patients with specific
    conditions
22
Q

What is STOPP in Elderly Patients?

A
  • Screening Tool of Older Persons’ potentially
    inappropriate Prescriptions
  • Aims to reduce the incidence of medicines-related
    adverse events from potentially inappropriate
    prescribing and polypharmacy
23
Q

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

A
  • 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
24
Q

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

A
  • 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
25
Q

Can Liver Disease impact drug metabolism?

A

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

26
Q

How does Hypoalbuminaemia affect drug metabolism?

A
  • Reduced protein binding
  • Increased toxicity of highly protein-bound drugs such
    as phenytoin and prednisolone
27
Q

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

A

Increased sensitivity to oral anticoagulants such as warfarin

28
Q

What effect does severe liver disease have on drug metabolism?

A
  • Drugs may precipitate hepatic encephalopathy
  • Sedative drugs, opioid analgesics, diuretics that
    produce hypokalaemia, and drugs that cause
    constipation
29
Q

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

A
  • NSAIDs
  • Corticosteroids
30
Q

What does the efflux transporter P-glycoprotein do?

A

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

31
Q

What drugs can inhibit P-glycoprotein? (3)

A
  • Verapamil
  • Atorvastatin
  • Amiodarone
32
Q

What drug can induce P-glycoprotein?

A

Rifampicin

33
Q

What happens if P-glycoprotein is inhibited?

A

Increased bioavailability of the susceptible drug

34
Q

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

A
  • Influx pump
  • Gut wall and transporter portal system into liver cells
35
Q

What drug is OATP in the liver inhibited by?

A

Rifampicin

36
Q

What drug is OATP in the gut inhibited by?

A
  • Grapefruit juice fexofenadine
  • Absorption is prevented
37
Q

Which enzymes are most important in Phase I reactions?

A
  • Cytochrome P450 family of isoenzymes
  • CYP3A4 is the most important
38
Q

What drug is a potent inducer of CYP3A4?

A

Carbamazepine

39
Q

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

A

Midazolam

40
Q

What drug is potent inhibitor of CYP3A4?

A

Ketoconazole

41
Q

Drug Interactions of Erythromycin and Warfarin

A
  • 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
42
Q

What is the International Normalised Ratio (INR)?

A

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

43
Q

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

A

The effects can be addictive

44
Q

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

A
  • 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
45
Q

What is the MHRA?

A

Medicines and Healthcare products Regulatory Agency

Membranes and Receptors (19 decks)

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