Lecture 10.2: Variation in Response to Drugs and Drug Interactions Flashcards
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
What is Pharmacogenomics/Pharmacogenetics?
Role of the components of the genome on the
response to a drug and pharmacogenetics role of genetic variation
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
What is Pharmacokinetics?
What body does to drug, how it moves through the body
What is Pharmacodynamics?
What drug does to the body
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)
Drug Metabolism: Phase 2
- Compounds not hydrophilic enough for excretion
- Further processing
- Conjugation with glucuronidation, glutathione, methyl
or acetyl group - Readily excretable, nontoxic substances
How many genes code for CYP proteins?
60 genes
What types of CYP proteins are responsible for Phase I drug metabolism?
- Microsomal-Type
- Located on the cytoplasmic side of the endoplasmic
reticulum membrane
Hepatic metabolism of drugs and toxins is by which families of CYP proteins?
CYP1, CYP2, and CYP3
What 5 isoenzymes are involved in 90 percent of all drug metabolism?
- CYP3A4
- CYP2D6
- CYP2C9
- CYP2C19
- CYP1A2
Enzymes are organised into..? (3)
- Families (eg, CYP2)
- Subfamilies (eg, CYP2D)
- Isoenzyme (eg, CYP2D6)
What effect can genetic polymorphisms in the CYP isoenzymes have on drug metabolism?
- Diminished metabolism
- Lack of metabolism
- Excessive metabolism of a compound
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)
What is Clopidogrel?
It is a prodrug whose active metabolite prevents platelet aggregation
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)
Codeine is a prodrug it is metabolised by …. to …. and codeine-6-glucuronide
- CYP2D6
- Morphine
What is the Role of Thiopurine S-methyltransferase (TPMT)?
It is an enzyme that metabolises a class of drugs called thiopurines
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
