drug safety in the clinic

What is the overarching principle that must be satisfied before prescribing any medicine?

The benefit to the patient must clearly outweigh the potential harms of the medicine

Name five patient-specific factors a prescriber must consider when prescribing

• current and recent medications

• known allergies

• previous ADRs

• age

• ethnicity

Why must a prescriber adhere to national guidelines and local formularies?

it ensures standardised, high-quality care

Define a drug allergy

An abnormal reaction of the immune system to a medication

Within what timeframe do serious drug allergy symptoms typically occur?

Often within one hour of taking the drug, though rashes and some reactions can appear hours, days, or weeks later.

Define anaphylaxis

A rare, life-threatening allergic reaction to a drug causing widespread dysfunction of multiple body systems

Name six signs or symptoms of anaphylaxis

• airway tightening/throat swelling

• difficulty breathing

• abdominal cramps

• vomiting/diarrhoea

• dizziness

• weak pulse

What is the first-line treatment for anaphylaxis?

Immediate administration of adrenaline via an epipen

Why is adrenaline the correct treatment for anaphylaxis? (Describe its mechanism.)

• Adrenaline acts on α-adrenoceptors to cause vasoconstriction (raising blood pressure)

• on β₁-adrenoceptors to increase heart rate and cardiac output

• on β₂-adrenoceptors to reverse bronchospasm

Define a pharmacodynamic drug interaction

An interaction where two drugs with similar or opposing pharmacological actions combine to produce additive or antagonistic effects.

Give an example of an additive pharmacodynamic drug interaction and explain the mechanism

• Benzodiazepines + alcohol — both are CNS depressants that enhance GABAergic inhibition.

• Combined use produces additive CNS depression that can cause severe respiratory depression, unconsciousness, and death.

How can antacids cause a pharmacokinetic drug interaction affecting absorption?

• By raising gastric pH, antacids alter the degree of ionisation of co-administered drugs

• affecting their solubility and ability to be absorbed.

• This can impair the absorption of drugs that require an acidic environment

How does metoclopramide cause a pharmacokinetic drug interaction affecting absorption?

Metoclopramide increases the rate of gastric emptying — drugs spend less time in the small intestine so less absorption

How does protein binding displacement cause a pharmacokinetic interaction?

Two highly protein-bound drugs can compete for albumin binding sites. One displaces the other → increased free (unbound) fraction of the displaced drug → increased pharmacological effect and potential toxicity.

For which drugs is protein binding displacement clinically important

Only drugs that are MORE than 90% protein-bound AND have a narrow therapeutic index

What is enzyme induction and what is its clinical effect on co-administered drugs?

• the increased expression of drug-metabolising enzymes, caused by certain drugs or substances.

• This accelerates the metabolism of co-administered drugs → lower plasma concentrations → reduced therapeutic effect

How quickly does enzyme induction take effect and how quickly does it reverse?

It takes days to weeks to take full effect (new enzyme protein must be synthesised).

It also takes days to weeks to reverse once the inducing agent is stopped.

What is enzyme inhibition and what is its clinical effect on co-administered drugs?

• Enzyme inhibition is blockade of drug-metabolising enzyme activity, caused by certain drugs or substances.

• This slows the metabolism of co-administered drugs → higher plasma concentrations → increased therapeutic effect and risk of toxicity.

How quickly does enzyme inhibition take effect compared to enzyme induction?

Enzyme inhibition starts almost immediately

Describe the clinically important interaction between erythromycin and statins

Erythromycin inhibits CYP3A4 → reduced metabolism of statins → elevated plasma statin levels → increased risk of myopathy

How do thiazide or loop diuretics interact with lithium, and why is this dangerous?

Thiazide and loop diuretics reduce renal excretion of lithium (by causing sodium depletion, which triggers compensatory lithium reabsorption in the proximal tubule) → elevated plasma lithium levels → risk of lithium toxicity.

What are the signs of lithium toxicity?

Nausea, tremor, confusion, cardiac dysrhythmias, seizures

Name four ways in which reduced renal function can cause problems with drug therapy.

• Reduced excretion → drug/metabolite accumulation → toxicity

• increased sensitivity to some drugs even when elimination is unaffected

• poor tolerance of drug side effects that are normally minor

• reduced efficacy of some drugs

Why should NSAIDs be avoided in patients with renal impairment?

NSAIDs can further reduce renal blood flow by inhibiting prostagladin synthesis → precipitate acute kidney injury (AKI) (when already impaired)

Why should prescribing be kept to a minimum in patients with severe liver disease?

The liver is the primary site of metabolism for many drugs. Severe liver disease impairs drug metabolism → drug accumulation → toxicity.

How does hypoalbuminaemia in liver disease affect drug pharmacokinetics

Reduced albumin synthesis → reduced plasma protein binding → increased free (unbound) fraction of highly protein-bound drugs → increased pharmacological effect and risk of toxicity.

What is the difference between a caution/precaution and a contraindication?

• A caution means the drug may be used but requires a risk assessment and careful monitoring

• A contraindication means the drug should be avoided

Define the therapeutic index (TI)

The TI is a ratio comparing the blood concentration at which a drug becomes toxic to the concentration at which it is effective