Pharmacology Flashcards
Which of the following does NOT affect the bioavailability of an orally administered drug?
A. First pass metabolism B. Rate of GIT transit C. Presence of other drugs in the GIT D. Dose of the drug E. Lipid solubility of the drug
Answer: D - Dose of the drug
Bioavailability, when administered by an extravascular route, is the fraction of the dose that reaches the systemic circulation as an intact drug (usually less than 1).
The main determinants are how much drug is absorbed and how much is removed by the liver before reaching the systemic circulation (first pass metabolism).
Physical drug properties (lipid or hydro solubulity, formulation e.g. slow release), the presence of food/other drugs and intestinal motility will all affect absorption.
Oral Bioavailability = AUC (oral) / AUC (IV)
Acidic drugs, such as phenytoin, bind primary to which one of the following plasma proteins?
A. Alpha-fetoprotein (AFP) B. Lipoprotein C. Albumin D. Alpha-acid gylcoprotein (AAG) E. Gamma globulin
Answer: C - Albumin
The main drug-binding proteins in plasma are albumin, apha1-acid glycoprotein and lipoproteins.
Albumin binds drugs and ligands, reducing serum concentration of these compounds. An example is serum calcium, the free (ionised) fraction needs to be corrected for albumin.
Drugs that are important for albumin binding are warfarin, digoxin, NSAIDs and benzodiazepines.
Which of the following does NOT interact with ligand-gated ion channels?
A. Benzodiazepines B. Glutamate C. Glycine D. Insulin E. Serotonin
Answer: D - Insulin
Ligand-gated ion channels are a group of transmembrane ion channels that open or close in response to the binding of a chemical messenger (a ligand) such as neurotransmitters.
Insulin binds the extracellular portion of the alpha subunits of the insulin receptor, causing a conformation change and activating the kinase domain in the intracellular portion.
Which one of the following drugs in 100% renally cleared and has a narrow therapeutic index?
A. Amoxicillin B. Oxypurinol C. Ceftriaxone D. Lithium E. Atenolol
Answer: D - Lithium
Lithium is 100% renally cleared and has a narrow therapeutic index.
Oxypurinol is the metabolite of allopurinol and is 100% renally cleared but has an intermediate therapeutic index.
Amoxicillin is 100% renally cleared but has a wide therapeutic index
Which of the following pharmacodynamic factors is the most important in determining efficacy of lincosamides?
A. Renal clearance
B. Concentration above the minimum inhibitory concentration
C. Maximum plasma drug concentration after dosing
D. Tissue penetration
E. Time the concentration is above the minimum inhibitory concentration
Answer: E - Time the concentration is above the minimum inhibitory concentration (MIC)
Lincosamides = Clindamcyin, Lincomycin
Antibiotic dosing is dependent on the 3 pharmacological properties of the drug: 1. concentration-dependent killing, 2. total exposure and 3. time-dependent killing
The time the drug is above the MIC is the factor most correlated with efficacy in these. Free drug levels of lincosamides should exceed the MIC for at least 40-50% of the dosing interval. Beta-lactams (penicillins, cephalosporins, carbapenems) share this property.
Aminoglycosides and Quinolones are dependent on the maximum plasma drug concentrate to eradicate bacteria.
Vancomycin depends on the total body exposure to the antibiotic - as indicated by the ratio of the area under the concentration-time curve during a 24 hour period (AUC 0-24) to MIC
Which of the following is most likely to inhibit the metabolism of warfarin?
A. Oral contraceptive B. Omeprazole C. Aspirin D. Rifampicin E. Amlodipine
Answer: B- Omeprazole
Warfarin metabolism is complex and done by multiple cytochrome P450 enzymes, but notably CYP2C9.
Omeprazole, metronidazole, Cimetidine, Amiodarone all inhibit CYP2C9 and would exacerbate the anti-coagulant effects of warfarin.
Rifampicin induces Cytochrome P450 and would reduce effect.
Oestrogen can reduce the anticoagulant effec through non cytochrome P450 mechanism (pro-oestrogenic effect?)
The proportion of drug reabsorbed in the renal tubule depends on the:
A. Volume of distribution B. Urine pH C. Glomerular filtration rate D. Extent of drug secretion into the renal tubule E. Serum creatinine
Answer: B - Urine pH
Renal drug clearance is the net result of filtration clearance (at the glomerulus) plus clearance by active secretion (in the PCT) minus reabsorption (along the entire tubule).
Passive tubular reabsorption is determined by the magnitude of concentration gradient (which depends on the extent of water reabsorption) and the ease with which the drug can move through membranes. Only non-ionised drugs can pass through the lipid membrane readily and the ease with which this occurs depends on the lipid solubility. The ionised vs non-ionised component depends on the pH of the urine and the acid dissociation constant (pKa) of the drug. Therefore, for drugs that are lipid soluble enough to be reabsorbed and can ionise to an anion or a cation, renal clearance varies with the urine pH.
What is the mechanism of Ivabradine in the treatment of stable angina?
A. Coronary artery vasodilation B. Blood pressure reduction C. Decreased cardiac contractility D. Reduction in heart rate E. Increased myocardial efficiency
Answer: D - Reduction in heart rate
Ivabradine is a direct sinus node inhibitor without negative effects on LV function.
During a constant rate of IV infusion of Piperacillin/Tazobactam, which one of the following determine the steady-state drug concentration?
A. Bioavailability B. Dose rate C. Half-life D. Loading dose E. Volume of distribution
Answer: B - Dose rate
Steady state concentration (CPss)
= Dosing rate/Clearance
Volume of distribution determines half-life and helps to calculate loading doses but no effect on steady state concentration.
Beta-lactams exhibit time dependent killing - correlated with the time above the minimum inhibitory concentration (MIC)
A 25-year old man presents after intentionally taking a large dose of paracetamol (in excess of 20g) about 6 hours prior to presentation. On the Rumack-Matthew nomogram, his plasma paracetamol places him at risk of hepatic injury. He is commenced on N-acetylcysteine infusion after initial assessment. How does N-acetylcysteine prevent hepatic injury in paracetamol overdose?
A. Inhibits glucoronidation of paracetamol
B. Enhances sulphation of paracetamol
C. Inhibits Cytochrome p450 2E1
D. Reduces paracetamol absorption in the GIT
E. Restores hepatic glutathione
Answer: E - Restores hepatic glutathione
Normal paracetamol metabolism progresses down 2 pathways:
- > 90% glucoronidated and suphation to non-toxic metabolites
- 5% metabolised by cytochrome P450 2E1 to NAPQI
- Extremely hepatotoxic
- Normally rapidly detoxified by glutathione
- If Glutathione depleted, NAPQI causes hepatocyte injury and death
- Cysteine is the rate limiting factor in glutathione synthesis
- Oral absorption is poor but NAC readily absorbed
Which one of the following pharmacodynamic factors is important in determining the efficacy of aminoglycosides?
A. Ratio of the maximum concentration over the minimum inhibitory concentration
B. Renal clearance
C. Total exposure of the body to the drug
D. Tissue penetration
E. Time the concentration is above the minimum inhibitory concentration
Answer: A -Ratio of the maximum concentration over the minimum inhibitory concentration
Aminoglycoside primary site of action is the 30S subunit of the prokaryotic ribosome, interrupting bacterial protein synthesis.
Aminoglycosides (and Quinolones) are dependent on the maximum plasma drug concentrate to eradicate bacteria.
EMQ - diuretics
A. Amiloride B. Acetazolamide C. Chlothalidone D. Eplenerone E. Furosemide F. Indapamide G. Mannitol H. Spironolactone
- Which diuretic inhibits renal potassium secretion at the distal nephron by a mineralo-corticoid independent mechanism?
- Which is an osmotic diuretic that is freely filtered by the glomeruli and remains in the tubular lumen?
- Which diuretic inhibits the sodium-potassium-chloride transport in the thick ascending limb of the loop of Henle?
- Which diuretic inhibits the apical distal convoluted tubule epithelial sodium-chloride co-transporter and decreases peripheral vascular resistance?
- Answer: A - Amiloride
Amiloride is a K-sparing diuretic that inhibits renal potassium secretion at the distal nephron (mineralocorticoid-independent mechanism). It acts on the luminal side blocking sodium entry, reducing H and K excretion.
- Answer: G - Mannitol
- Answer: E - Furosemide
- F - Indapamide
A woman with Liddle syndrome presents with severe symptomatic hypokalaemia and her GP starts her on 50mg/day of spironolactone. Four days later, repeat potassium measurement shows persistent severe hypokalaemia. The ongoing hypokalaemia is best explained by:
A. Underprescribing B. Poor compliance C. Prescription writing error D. Inappropriate prescribing E. Drug-drug interaction
Answer: D - Inappropriate prescribing
Liddle syndrome is a disorder of the epithelial sodium channels (ENaC)
- Autosomal dominant
- Manifests as mineralocorticoid excess with 1. hypertension, 2. hypokalaemia, 3. metabolic alkalosis
- Apparent mineralocorticoid excess (low renin, low aldosterone)
Although Spironolactone is a K sparing diuretic it acts via aldosterone receptors (low aldosterone anyway) and is ineffective. Amiloride, which acts via the ENaC is effective.
Which one of the following best describes the pharmacologicalD properties of Azithromycin?
A. Azithromycin is bactericidal
B. Half-life of Azithromycin ins 12 hours
C. Azithromycin is a strong cytochrome p450 enzyme, CYP3A3 inhibitor
D. Azithromycin inhibits formation of the bacterial cell wall
E. Azithromycin is safe for use in pregnancy
Answer: E - Azithromycin is safe for use in pregnancy
Azithromycin acts via binding bacterial 50S ribosomal subunit to inhibit translocation of peptide-tRNA and inhibit protein synthesis.
A. - bacteriostatic B. long half life of 60h C. few drug interactions D. See above E. True
Which one of the following increases the risk of liver toxicity from Izoniazid therapy?
A. Increasing age B. Use of NSAIDs C. Co-administration of ethambutol D. Co-administration of phenytoin E. Co-administration of pyridoxine
Answer: A - Increasing age
Risk of lsoniazid liver toxicity increases with age, particularly in females >60yrs.
Isoniazid related hepatitis presents insidiously usually at 4-6 months after initiation. Commonly there are flu-like symptoms.
Abnormal AST and ALT in up to 20% of all patients on Isoniazid but often subsides.
Pyridoxine is given concurrently to prevent peripheral neuropathy.
Which one of the following best describes the mechanism of action of Caspofungin?
A. Forms artificial pores by binding to Ergosterol in fungal membranes, thereby disrupting membrane permeability
B. Prevents synthesis of Ergosterol from Lanosterol by inhibiting cytochrome P450 dependent demethylation
C. Inhibits the synthesis of glucan in fungal cell walls
D. Deposits in newly formed keratin and disrupts microtubule structure
E. Inhibits ergosterol synthesis by inhibiting squalene epoxidase
Answer: C - Inhibits the synthesis of glucan in fungal cell walls
Caspofungin = Echinocandin class anti-fungal Non-competitively inhibits synthesis of B(1-3) - D- Glycan Neither P-glycoprotein of CYP interaction.
Amphotericin B forms artificial pores by binding Ergosterol in fungal membranes and disrupts permeability.
Azole anti-fungal = prevent synthesis of Ergosterol from Lanosterol by inhibiting Cytochrome P450 dependent 14a-demethylation
Griseofulvin is only active against dermatophytes. Deposits in newly formed keratin and disrupts microtubule structure
Terbinafine prevents Ergosterol synthesis by inhibiting squalene epoxidase.
Which one of the following types of study for an investigational new drug involves each subject receiving a sequence of all the different treatments?
A. Cross-over study B. Double blind study C. Head to head study D. Placebo controlled study E. Single blind study
Answer: A - Cross over study
Which one of the following is true of the pharmacokinetics and metabolism of paracetamol?
A. Rate of absorption from the GIT is age-dependent
B. Volume of distribution of paracetamol increases with increasing age
C. Total paracetamol clearance is not affected by age
D. Metabolism in the liver involves conjugation to glucuronide and sulphate metabolites
E. Metabolism in the liver involves N-demethylation
Answer: D - Metabolism in the liver involves conjugation to glucuronide and sulphate metabolites
Paracetamol is rapidly/completely absorbed from the GIT - no evident age dependence
Vd generally decreases with age
Clearance and metabolism may change with age but do not seem to have therapeutic indications given paracetamol has a wide therapeutic index.
A 38 year old man with epilepsy has been taking carbamazepine for the past 6 years and his seizures are well controlled. He commenced a new medication a week ago and presents with recurrent episodes of seizures. Which one of the following drugs is most likely to be responsible?
A. Amoxicillin B. Fusidic acid C. Rifampicin D. Tetracycline E. Voriconazole
Answer: C - Rifampicin
Enzyme inducers including phenytoin, carbamazepine (autoinduces), phenobarbitone, Rifampicin, alcohol, sulphonamides, increase the metbolism of carbamazepine.
A 54 year old woman presents with pancytopaenia for investigation. Her medical history is significant: a 2 year history of well-controlled autoimmune hepatitis for which she is on Azathioprine 75mg daily and prednisolone 2mg daily. She developed a second episode of acute gout attack 3 months before this presentation. She was found to be hyperuricaemic and was started on allopurinol 300mg daily upon resolution of the acute gout. what is the most likely explanation for this patient’s pancytopaenia?
A. Idiosyncratic allopurinol toxicity B. Autoimmune pancytopaenia C. Bone marrow suppression D. CMV infection E. Folate deficiency
Answer: C
Allopurinol interaction with Azathioprine
Allopurinol is a xanthine oxidase inhibitor that blocks uric acid synthesis.
Azathioprine (and 6-mercaptopurine 6-MP) are both inactive pro-drugs. Aza is converted to 6-MP which is then metabolised via 3 different routes.
6-thioguanine nucleotides (6TGNs) are responsible for the majority of immunosuppressant activity but are associated with bone marrow suppression at high concentrations.
Xanthine oxidase inhibition increases 6-TGN production through preferential metabolism along this pathway.
Which one of the following is true about cytochrome p450 enzymes?
A. Cytochrome P450 enzymes are not known to exhibit polymorphism
B. Individuals with 2 copies of wild-type alleles for a cytochrome P450 enzyme are poor metabolisers
C. Individuals with 2 copies of variant alleles for a cytochrome P450 enzyme are normal metabolisers
D. Individuals with 2 copies of wild-type alleles for a cytochrome P450 enzyme will have severely reduced enzyme activity
E. Cytochrome P450 enzymes are required for corticosteroid synthesis
Answer: E - Cytochrome P450 enzymes are required for corticosteroid synthesis
Cytochrome P450 (CYP450) enzymes are essential for production of cholesterol, steroids, prostacyclin and thromboxane A2.
They also detoxify foreign chemicals and metabolise drugs. CYP450 enzymes exhibit polymorphism , influencing drug metabolism.
Variant alleles usually encode an CYP450 enzyme with reduced or no activity. Two variant alleles typical result in ‘poor metabolisers’.
Which receptor is involved in opioid-induced dysphoria, hallucination and psychosis?
A. GABA receptor B. Kappa receptor C. Mu receptor D. Nociceptin receptor E. Sigma receptor
Answer: E - Sigma receptor
There are 4 opioid receptors - the main being mu and kappa
Mu receptor - analgesia, respiratory depression, euphoria, miosis
Kappa - analgesia, miosis, sedation, respiratory depression
Two other receptors:
Sigma receptor - dysphoria, hallucinations, psychosis
Delta receptors - ? unknown ? dysphoria
EMQ Immunosuppression
A. Anthi-thymocyte globulin B. Azathioprine C. Basiliximab D. Ciclosporin E. Leflunomide F. Mycophenolate mofetil G. Sirolimus H. Tacrolimus
- Which immunosuppressive drug binds FK506-binding protein 12 (FKBP12) to form a complex that inhibits T cell activation?
- The use of which immunosuppressive agents is associated with cytokine release syndrome?
- The use of which immunosuppressive agent is associated with pneumonitis?
- Which immunosuppressive agents binds to and blocks CD25 on activated T cells
- Which immunosuppressive agent can be used to treated BK-related polyoma virus nephropathy?
- Answer: H - Tacrolimus
Tacrolimus binds FKBP12 and forms a complex inhibiting calcineurin and T-cell activation. Calcineurin usually induces transcription factors and IL2/related cytokine expression. Ciclosporin also engages calcineurin. Both cause nephrotoxicity, Tacrolimus induces more diabetes but less lipid/HTN. Both are metabolised via CYP3A4
- Answer: A - Ant-thymocyte globulin
- Answer: G - Sirolimus
- Answer: C - Basiliximab
- Answer: E - Leflunomide
Anti-metabolite with immunosuppressive and antiviral activity. It exerts an anti-viral effect on CMV by disrupting virion assembly. Its effect on BK virus has an unknown mechanism.
Cyp450 inducers (name 5)
Makes you CRAPS out the drugs
Carbamazepine (auto-induces its own metabolism) Rifampicin bArbituates Phenytoin St Johns wort
1 .Cyp450 inhibitors
- What antidepressant interferes with Tamoxifen and which enzyme pathway?
‘Some Certain Silly Compunds Annoyingly Inhibit Enzymes, Grrrr…….’
Sodium valproate Ciprofloxacin Sulphonamides Cimetidine/Omeprazole Azole antifungals, Amiodarone Isoniazide Erythromycin/Clarithromycin Grapefruit juice
Others: Verapamil (always comes up)
Ritonavir - boosts HIV protease inhibitors
Fluoxetine/Paroxetine - inhibit Tamoxifen metabolism/efficacy (CYP2D6)
What is P-glycoprotein?
Common inhibitors?
Common inducers?
What are 2 major drugs affected by changes in PGP metabolism?
P glycoprotein is a drug efflux transport designed to pump drugs back out of cells. First described in cancer research as reducing action of cytotoxic drugs.
PGP inhibitors: erythromycin, ritonavir, verapamil
PGP inducers: Rifampicin, St John’s wort
Remember:
- Digoxin - major mechanism for drug interactions is PGP related
- Dabigatran is a major PGP substrate - inhibitors such as ketoconazole/amiodarone/verapamil can increase drug concentration significantly
