HUF 2-75 Mechanisms of drug interactions

Question 1

Drug interactions

Answer 1

• Effects of one drug are altered by effects of another drug
  1. Pharmaceutical interactions (physiochemical rxn)
  2. PK interactions (ADME)
  3. PD interactions (therapeutic/observed outcome)

Question 2

Object drug

Answer 2

The drug whose action is affected

• Only really important if it has steep dose-response curve and narrow therapeutic window
  (i. e. small change in conc. => dramatic change in drug action)

Question 3

Precipitant drug

Answer 3

The drug tat precipitates an interaction

Question 4

Pharmaceutical interactions

Answer 4

1. Reaction with infusion fluid
   - Diazepam/Phenytoin + infusion fluid => Precipitation
2. Chemical reaction of 2 drugs in solution
   - Thiopentone + Suxamethonium => Precipitation
   - Penicillin + Hydrocortisone => Inactivation of Penicillin

• Outcome: loss of activity or potential toxicity
• Useful interactions:
• Activated charcoal for GI detoxification; Antibodies for Digoxin

Question 5

Plasma/tissue binding sites

Answer 5

• Precipitating drugs displace object drug from binding sites on plasma albumin or w/i tissues
• High protein bound (>90%) with low apparent volume of distribution (e.g. <35L)
• Object drug displaced
  => Compensatory ↑ in clearance
  => ↑ in free drug may be transient (several days; NOT long term)
• ***Precipitating drug concurrently prevents metabolism/excretion of object drug

e. g. Salicylates, Chloral hydrate, Phenybutazone, Valproate displacing
1. Warfarin (potential bleeding)
2. Phenytoin (headache, ataxia, confusion)
3. Tolbutamide (hypoglycemia)

Question 6

Interactions involving metabolism

Answer 6

• Interaction at Phase I enzymes
• Object drugs differentially metabolised by isoforms 1A2, 3A4, 2C9, 2C19, 2D6
• ** Precipitating drugs induce or inhibit isoforms

Question 7

Stereoselective specificity

Answer 7

• S-warfarin: biologically important stereoisomer
• Metabolism inhibited by Phenylbutazone. Metronidazole. Sulphinpyrazone
  => ↑ Prothrombin time
• R-warfarin metabolism inhibited by Cimetidine, Omeprazole
  => Minimal effect on prothrombin time
• Amiodarone has non-specific effects on both stereoisomers
  => ↑ Prothrombin time

Question 8

Interactions due to inhibition of other enzymes

Answer 8

1. Xanthine oxidase
   - Azathioprine
   (-) Allopurinol
   => ↑ Azathiprine level
2. DOPA decarboxylase
   - L-dopa
   (-) Carbidopa or Benserazide
   => ↑ CNS L-dopa level
3. Alcohol dehydrogenase
   - Acetaldehyde
   (-) Disulfiram
   => abdominal colic, flushing, tachycardia, vomiting

Question 9

Excretion interactions

Answer 9

• Common transport mechanism in proximal tubules

=> Mutually affect one another’s excretion by competition

Question 10

PD interactions

Answer 10

• Modification of object drugs action results w/o modifying plasma conc.

1. β blocker + bronchodilators
   => ↓ Bronchodilator effectiveness
2. Opioid + Naloxone
   => ↓ Opioid effectiveness
3. Warfarin
   + Inhibitors of Vit K synthesis / function (antibiotics, liquid paraffin)
   => Bleeding
4. Ethanol, antihistamine, barbiturates
   + other sedative-hypnotics
   => Additive sedation, ataxia, depression
5. Drugs causing K+ loss
   + Cardiac glycosidase, antiarrhythmic drugs
   => ↑ Effects
6. Drugs causing GI ulceration
   + Anticoagulants
   => ↑ Risk of bleeding

Question 11

Drug-food interactions (excessive amounts)

Answer 11

1. Grapefruit juice: 3A4 inhibitor
   + Terfenidine
   => Risk of arrhythmia
2. Banana (high K+)
   + ACEI
   => Risk of hyperkalaemia
3. Tyramine in cheese/red wines
   + Non-selective MAOI
   => Hypertensive crisis
4. Ginkgo, garlic, dong quai, danshen
   + Warfarin
   => Bleeding
5. St John’s wort
   + ↓ Bioavailability of Digoxin, Theophylline, Cyclosporin, Phenprocoumon
   => ↓ Action of object drug
6. Xiao chai hu tang
   + Prednisolone
   => ↓ plasma levels of Prednisolone