Pharmacology - Drug Interactions

Question 1

Describe different types of drug interaction

Answer 1

An interaction occurs when one drug affects the clinical effect of another drug, either to increase, or decrease its effects.

Physicochemical
As a result of interactions between the molecules themselves
Bicarbonate & calcium will precipitate if given together
GTN is absorbed by PVC & requires its own giving set
Gentamicin & penicillins will precipitate

Pharmacodynamic
Direct - both drugs act on the same receptor system
Flumazenil & Benzos
Naloxone & Opioids
Tamsulosin & metaraminol (particularly relevant for anaesthesia)

Indirect - A different mechanism affects the same outcome.
Neostigmine inhibits AChase, so more ACh can compete with rocuronium
MAOi increase noradrenaline, and pethidine prevents noradrenaline re-uptake, which can lead to a fatal excitatory interaction
MAOi also increase serotonin concentrations, interacting with SSRIs to predispose serotonins syndrome
Antihypertensives with different mechanisms work synergystically
Levosimendan & dobutamine both increase cardiac contractility

Pharmacokinetic
Absorption
Activated charcole adsorbs molecules in the stomach
Metoclopramide reduces gastric statis & increases aspirin absorption
P-glycoprotein transport protein inhibitors (such as verapamil) can greatly increase the bioavailability of drugs that are a substrate for this protein (Digoxin, cyclosporin and dabigatran)

Distribution
Chelation agents prevent drugs from leaving the blood (such as dicobalt edetate for cyanide)
Sugammadex encapsulates rocuronium
Any drugs with reduce CO will slow distribution of other drugs
Drugs with very high protein binding (such as phenytoin & warfarin) can be displaced by other drugs, leading to toxicity

Metablism
Inhibition - Amiodarone inhibits CYP2C9 - warfarin is more active
Induction - Dexamethasone induced CYP3A4, shortening duration of vecuronium, Broccoli induced 1A2, and EtOH induces 2E1, metabolising sevoflurane faster.

Excretion
Antibiotics that kill gut bacteria will reduce enterohepatic circulation (such as ciprofloxacin with diclofenac)
Bicarbonate causes urinary alkalization, which enhances aspirin excretion

Question 2

Explain summation, synergism, and potentiation. How might these be displayed graphically?

Answer 2

These terms describe the overall effect when two interacting drugs are co-administered

Summation
When the effect equals the sum total of giving them separately - giving a benzo at induction reduces the amount of induction agent required

Synergism
The effect is greater than the sum of individual parts - opioids and propofol work synergystically, hence their use in TIVA

Potentiation
One drug enhances the other, but doesn’t have any direct activity itself - Probenecid reduces renal penicillin excretion, increasing effective plasma concentration

An Isobologram can show these properties, with the curve showing equal clinical effect
For a summative relationship, this is a straight line. For a synergistic relationship, less of each drug is required. For an antagonistic relationship, more of both is required.

Question 3

Which drugs are known to cause hepatitis?

Answer 3

Valproate
Amiodarone
Methyldopa
Pyrazinamide
Isoniazid
Rifampicin
Phenytoin
Simvastatin

Question 4

Which drugs can trigger porphyric crises

Answer 4

Thiopentone
Barbiturates
Etomidate
Enflurane
Halothane
LAs - Cocaine, lidocaine, prilocaine
Clonidine
Metoclopramide
Hyoscine
Diclofenac
Ranitidine

Bupivacaine is considered safe to use

Question 5

What is an idiosyncratic response?

Answer 5

A usually undesirable response to a drug or metabolite seen in an individual patient, or small cohort of patients

Suxamethonium apnoea
Malignant hyperthermia
Codeine metabolism
Acetylator status (relevant for isoniazid, amongst others)

Question 6

What is an adverse effect, and how are they categorised?

Answer 6

An undesirable effect caused by a drug at a normal dose, rather than due to an overdose.

More common in young people, women (2x men), asthmatics, and pregnant women.

Type A Dose related response due to mechanism of action - Reproducible & predictable
Hypokalaemia with furosemide, and tachycardia with salbutamol

Type B Idiosyncratic, less common, and unpredictable. Not dependent on dose given, with a genetic component frequently implicated
Anaphylaxis/anaphylactoid reactions, stevens-Johnson syndrome, suxamethonium apnoea

Type C Accumulation or prolonged use - Dose and time-related.
Osteonecrosis with bisphosphonates, adrenal suppression with steroids

Type D Time related
Tardive dyskinesia from antipsychotics

Type E Withdrawal reaction

Type F Unexpected failure - Antibiotic resistance