Corticosteroids

Question 1

FIVE examples of anti-inflammatory gene targets increased by corticosteroids.

Answer 1

1. Annexin‐A1: A PLA2 inhibitor
2. β2‐adrenoceptor
3. IL‐1 Receptor Antagonist
4. IL‐1R2 (decoy receptor)
5. Neutral endopeptidase (NEP)
6. Endonucleases
7. IκB‐α (Inhibitor of NF‐κB)
8. MAPK Phosphatase‐1 (MKP‐1)

Question 2

Anti-inflammatory actions of corticosteroids

Answer 2

1. Decrease circulating inflammatory cells; except neutrophils
2. Have more effects on cellular imunity than humoral immunity
3. Decrease size & lymphoid content of lymph nodes
4. Increase macrophage efferocytosis & promotion of resolution of inflammation
5. Decrease type IV delayed hypersensitivity reaction (Eg. transplantation reaction)
6. First-line immunosuppressant in solid organ & hematopoietic stem cell transplantation

Question 3

Factors which limit drug entry into enterocyte from GI tract

Answer 3

P glycoprotein (active transport efflux transporter) pumps drugs from inside of a cell to the outside

Absorption of orally administered drug → metabolism of drug via CYP3A4 → transport of parent compound or metabolite back into the gut lumen via PGP

tumour cells have high expression of PGP, and hence they pump anti-cancer drugs (eg doxorubicin) out of the cell

Question 4

Drug factors affecting absorption (and hence bioavailability)

Answer 4

Physico-chemical properties

• Aqueous/lipid solubility
• pKa/degree of ionisation
• Molecular weight

Type of dosage form

• injections: intravenous, intramuscular, subcutaneous
• suspensions, solutions
• tablets, capsules → must be in solution before absorption

Question 5

concentration

Answer 5

target concentration to be achieved in the patient

Question 6

Products of drug metabolism + clinical implications of the metabolites

Answer 6

Active parent drug → inactive metabolite → drug elimination (end of drug effects)

Inactive parent drug (prodrug) → active metabolite (required for drug action and effects to happen)

Active parent drug → active metabolite (cumulative effects if metabolites are active)
eg biotransformation of codeine to morphine via CYP450

Active parent drug → reactive intermediate (may induce toxicity)
eg oxidation of acetaminophen to reactive metabolite (accumulates due to limited GSH) which leads to hepatic necrosis

Question 7

phase II of drug biotransformation

Answer 7

conjugation (glucuronic acid, sulphate, acetyl CoA, gluthathione)

enzymes involved

• microsomal glucuronyltransferase
• non-microsomal conjugating enzymes (eg sulfotransferases)

Question 8

Factors affecting drug excretion

Answer 8

Urine pH and properties of drugs
Urine flow
Plasma protein binding
Competition for tubular secretion
State of renal function

Question 9

Examples of idiosyncratic ADRs

Answer 9

G6PD deficiency: hemolysis with maloprim (antimalarial drug) due to increased oxyhaemoglobin formation → depletion of GSH

HLA-B 1502 allele & carbamazepine-induced Steven-Johnson syndrome and toxic epidermal necrosis

Question 10

Examples of type A ADRs

Answer 10

Bleeding
- NSAIDS: inhibits COX1 & 2, anti-thromboxane effects and gastric mucosa erosion
- warfarin
Sedation: anti-histamines, morphine, benzodiazepine
Hypoglycemic coma: insulin
Tremors: sabutamol (beta-adrenergic receptor agonists)
Respiratory depression: alcohol, morphine
Gastro-intestinal pain: NSAIDS
Hearing loss: gentamicin

Question 11

Factors affecting Glomerular filtration

Answer 11

Protein binding (only free drugs will enter the kidney tubules)
Molecular size (filtered when molecular weight <500 daltons)
Number of functional nephrons

Question 12

Factors affecting secretion

Answer 12

Affinity of drug for transport protein
Rate of delivery of drug to the secretory site
Rate of transfer of drug across the tubular membrane
Competition between drugs (2 drugs which are secreted by the same active process will compete for the available transport proteins)

Question 13

Factors affecting reabsorption: pH of urine

Answer 13

Weak acids - as pH increased, ionised component increased, reabsorption decreases → increased drug excretion
Weak bases - as pH increases, ionised component decreases, reabsorption increases → decreased drug excretion

Question 13

Factors affecting reabsorption: pH of urine

Answer 13

Weak acids - as pH increased, ionised component increased, reabsorption decreases → increased drug excretion
Weak bases - as pH increases, ionised component decreases, reabsorption increases → decreased drug excretion

Question 14

Factors affecting drug metabolism - Pharmacological factors (enzyme induction)

Answer 14

Induction: increases protein synthesis → increases enzyme levels → increases Vmax

• Eg. [drugs] phenytoin, carbamazepine, phenobarbital, rifampin / [others] alcohol, tobacco, charcoal-broiled food etc
• Clinical implications
• • Decrease concentration of parent drug → decreased effect
• • Increase concentration of metabolite which may be toxic
• Pharmacokinetic consequences
• • Decreased plasma drug concentration
• • Decreased AUC
• • Decreased elimination half-life

Question 15

Factors affecting drug metabolism - Pharmacological factors (enzyme inhibition)

Answer 15

Eg. cimetidine, ketoconazole, erythromycin, ciprofloxacin
- Clinical implications:
increased concentration of parent drug → prolong effect/result in toxicity
- pharmacokinetic consequences
– increased plasma drug concentration
– increased AUC
– increased elimination half-life

Question 16

Factors affecting first pass effect

Answer 16

GIT: poor absorption, metabolism, efflux (reverse transport) at intestinal enterocytes

Liver: drugs with high first pass metabolism (ie. low hepatic ER drugs) in the liver before reaching systemic circulation

Note - intravenous administration of drug bypasses first pass effect

Question 17

Metabolism-related DDIs

Answer 17

CYP enzyme inducers → increases clearance of drugs

• Antiepileptics: phenobarbitone, carbamazepine, phenytoin
• Anti-TB: rifampicin

CYP enzyme inhibitors → decreases clearance of drugs

• H2 blocker: cimetidine
• Antimicrobials: ciprofloxacin, erythromycin, ketoconazole, isoniazid
• Antidepressants: SSRIs fluoxetine, fluvoxamine
• Food: grapefruit juice

Question 18

Absorption related DDIs

Answer 18

Oral route, leads to altered bioavailability

Eg. antacids containing Ca, Fe, Al, Mg bind to drugs → decreases absorption of many drugs (eg antibiotics)

Question 19

PD-related DDIs

Answer 19

Agonist-antagonist interactions
- Salbutamol (β-adrenergic receptor agonist) & propranolol (β-adrenergic receptor blocker)

Synergism/potentiation
- Eg. alcohol + benzodiazepines/narcotic analgesics (depressants) → oversedation

Question 20

What is the drug receptor theory

Answer 20

A precise fit of the drug to its respective receptor is required for full agonist effect

Question 21

Reduced expression of pro-inflammatory genes

Answer 21

Reduced expression of pro-inflammatory genes:

• Cytokines e.g., TNF‐α,IL‐1β, IL‐2,IL‐4,IL‐5,IL‐13,IL‐33,IFNγ
• Chemokines e.g., RANTES,Eotaxin,MIP‐1α,MCP‐1
• Inflammatory enzymes e.g., Cyclooxygenase‐2(COX‐2), 5‐Lipoxygenase (5‐LOX), Phospholipase A2 (PLA2)
• Adhesion Molecules e.g., ICAM‐1, VCAM‐1, E‐Selectin
• Receptors e.g., IL‐2R (αchain), T‐CellReceptor (βchain)

Question 22

Vd =

IV calculation

Answer 22

Vd = (dose x F)/Co

Question 23

Definition of apparent volume of distribution (Vd)

Answer 23

Proportionality constant that relates the dose to the plasma drug concentration

Question 24

Drug inducers affecting drug metabolism

Answer 24

phenytoin, carbamazepine, phenobarbital, rifampin / [others] alcohol, tobacco, charcoal-broiled food etc

Question 25

Drug inhibitors affecting drug metabolism

Answer 25

cimetidine, ketoconazole, erythromycin, ciprofloxacin