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Connecting Pharmacology with
Therapeutics
Clive Roberts
Become wise!
What can be predicted from a
drug’s pharmacological profile
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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
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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
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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
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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 –
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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?