YW - Drug Interactions II Flashcards
What variables influence absorption in pharmacokinetic interactions? (6)
Variables influencing absorption
- Altered concentration of free drug in gut lumen
- Competition for active transport
- Food (not really a drug - drug interaction)
- Gastro-intestinal motility
- Gut microflora – antibiotics
- First - pass metabolism in the gut wall
What interactions decrease the concentration of free drug in the gut lumen? (2)
i) Tetracyclines + di- or tri-valent cations
- e.g. calcium (milk), magnesium and aluminum (anti acid), iron
–> insoluble complex
ii) CHOLESTYRAMINE (ANION EXCHANGE RESIN, bile acid binding) interacts with acidic (anionic) drugs such as warfarin
–> decrease absorption
What interactions result in competition for active uptake processes?
Most drugs are absorbed by simple passive diffusion
- Both drugs must compete for the same transporter system
Relevant transporters exist for amino acids, for purines and for pyrimidine bases
Describe the interactions of drugs with food (2)
Interactions affecting absolute bioavailability
- for example milk (Ca 2+ ) and tetracyclines (see above)
Interactions affecting the shape of the plasma concentration
- time curve (due to altered gastric emptying)
What drugs alter gastrointestinal motility? (2)
Drugs taken after a meal are more slowly absorbed as progress to the small intestine is delayed
ANTICHOLINERGICS
- Slow gastric emptying
- Decrease G.I. motility
- Increase Tmax
- Decrease Cmax
- AUC not altered (usually)
METOCLOPRAMIDE
D2 antagonist used as antiemetic
- Increase gastric emptying
- Increase G.I. motility
- Decrease Tmax
- Increase Cmax
- AUC not altered (usually)
How do drugs affect the GI microflora?
Poorly absorbed broad-spectrum oral antibiotics
- Decrease gut flora numbers
- Decrease gut flora metabolism
How is biliary excretion involved in drug interactions?
The main interaction involves interference with entero-hepatic circulation of the drug in lower bowel
- Antibiotics reduce bacterial flora
- Decreased hydrolysis in the lower bowel
e.g. oestrogen in contraception - The conjugate is voided in the faeces
- The blood concentrations of drug decrease
How do drugs affect first-pass metabolism in the gut well?
Important interactions are when inhibition of an enzyme increases the bio-availability
cheese and wine reaction
- Patient given gruyere cheese while on an MAOI
- Increases BP
Hypertensive crisis
What interactions affect extent of drug distribution? (3)
Interaction only important if
- Displaced drug has a narrow therapeutic index e.g. warfarin
- Displaced drug is highly protein bound e.g. > 98%
- Displaced drug has a low apparent volume of distribution - so that plasma contains a significant proportion of the body load and so that the extra free drug “liberated” in the plasma produces a significant increase in drug at the site of action
Drugs affecting first-pass metabolism in the liver
CYP450 family is the major metabolising enzyme in oxidation process
What do P450 inducers and inhibitors do?
P450 – INDUCERS
- INCREASE METABOLISM
- Reduce bioavailability
P450 - INHIBITORS
- Decrease metabolism
- Enhance bioavailability
What are some possible mechanisms involved in enzyme induction?
↑ Transcription due to ↑ gene expression e.g CYP1A2 + CYP 4 + ?
↑ Translation of messenger RNA due to stabilisation of mRNA
↓ Degradation of enzyme due to decreased protease activity
What are some examples of Enzyme induction?
Paracetamol (normally metabolised to glucuronide or sulphate). When these enzymes are saturated (at high doses) it is metabolized by a cytochrome P450 to N-acetyl-p-benzoquinone imine (NAPQI, toxic). Chronic use of alcohol induces this enzyme.§
Phenobarbital can be given to premature babies to induce glucuronyl transferase, increasing bilirubin conjugation (Neonatal Jaundice).
When are clinical effects most important for in enzyme induction?
Clinical effects are most important when the drug has a narrow therapeutic index
- Clinical effects are slow to develop as more enzyme is synthesised and persist after treatment during which time the additional enzyme is slowly degraded
What are some examples of enzyme inhibition (3)?
Sildenafil (Viagra) metabolised by CYP3A4 - induced by barbiturates and rifampicin; inhibited by erythromycin and cimetidine
Disulfiram – inhibitor of aldehyde dehydrogenase, used to produce an adverse reaction to ethanol – also inhibits metabolism of other drugs e.g. warfarin which it potentiates
Methanol metabolised to formaldehyde – toxic. Poisoning treated with ethanol, which competes for aldehyde dehydrogenase and slows its metabolism
