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?