Connecting Pharmacology with Therapeutics

Clive Roberts

Become wise!

What can be predicted from a drug’s pharmacological profile

• Pharmacological actions

• Some adverse effects

• Some contraindications

• Some drug interactions

• Acute toxicity risk

• Mode of administration possibilities

What can NOT be predicted?

• Therapeutic effect

• Appropriate usage in comparison with other drugs

• Some adverse effects

• Some drug interactions

What does the pharmacological profile consist of

• Pharmacodynamic data• Pharmacokinetic data• Physicochemical properties• Potential to induce or inhibit hepatic enzymes• Acute toxicity information• “The therapeutic ratio”• Usage history• Cost

Pharmacodynamic information

• What receptors does it block or stimulate

• Or what ionic channels or enzymes etc does it affect

• What is the hypersensitivity risk

• What unrelated toxicity occurs, how serious and how often

• What happens in acute overdose

Pharmacokinetic information

• How is it cleared from the blood – liver/kidney/lung etc

• First order / zero order process

• If liver, how high is the clearance rate

• What is the bioavailability

• If low is it due to pre-systemic hepatic clearance or poor absorption

Pharmacokinetic info. continued

• How is the drug distributed in the body

• What is the volume of distribution

• What is the extent of plasma protein binding

• What is the plasma half life

Patient groups at risk

• Liver disease

• Renal disease

• Heart disease

• Lung disease

• Elderly

• Those taking other drugs

• Pregnancy

So let’s take the example of

Phenytoin

?? Digoxin

Mrs Y.Y. Born 1912

• Admitted late Feb with general deterioration in health, nausea, anorexia, constipation

• At her EPH there had been an outbreak of D+V 4 weeks previous. She had never really got better.

• Dehydrated, hypotensive, pale, slow reg pulse

• Drugs – perindopril, digoxin, frusemide, aspirin, Isosorbide mononitrate

• Urea 31, creatinine 223

• ECG ……………

• Digoxin level 3.5

• What went wrong?

What is it about the patient with hepatic failure that puts them at

risk• Pharmacokinetic disturbance -

– Decreased clearance of some drugs– Increased bioavailability of some drugs– Altered distribution volume– Decreased protein binding

• CNS sensitivity

• Electrolyte abnormality

What is it about the patient with hepatic failure that puts them at

risk - continued

• Fluid retention

• Risk of bleeding – generally and specifically in gut

• Metabolic disturbance

• Encephalopathy risk

And the renal patient ?

• Pharmacokinetic disturbance – Mainly affecting drug clearance– Also protein binding

• Increased sensitivity

• Poor tolerance of adverse effects

• Decreased effectiveness of some drugs

Drugs in the elderly

• Multiple indications leads to polypharmacy

• Pharmacokinetic disturbance of metabolism, excretion, protein binding and drug distribution

• Increased sensitivity to the actions of drugs on CVS, CNS, GIT

• Poor tolerance of adverse effect

Drug interaction

• Pharmacodynamic mechanisms usually easy to predict

• Pharmacokinetic mechanisms – need to know / look up.

Le Fin

Profile of new drug for reflux oesophagitis

• Phenothiazine drug with powerful antigastric secretory action at low doses.

• Acts on both h2 receptors and the proton pump• Also blocks muscarinic receptors throughout the

body• Inhibits some hepatic enzymes• Causes a rise in transaminases in some patients• Limited experience in overdose

Profile of new drug for reflux oesophagitis

• High hepatic clearance with extraction ratio of 65%

• Widely distributed in tissues

• Plasma half life of 48 h

What might you predict about the adverse effects?

Who might be at greatest risk?What drug interactions might

occur?What about self harm doses?