Lecture 55 – toxicology, adverse effects and tolerability Flashcards
Rule 1 of pharmacology
o All drugs have more than one action
o Ever drug can act non-selectively
Yohimbine
o An a2-adrendoceptor-selective antagonist
o Blocks a2-adrenoceptors from 10-8M
o But other receptors at lower concentrations thus selective, but not specific
Non-selectivity
o Can lead to side effects and adverse outcome
o Drug is selective but concentration is too high = use the right dose
o Drug has same affinity for two targets = choose (or develop) a more selective drug
o Drug is selective for target but target exists in several tissues = selective administration
Action of digitalis
o Inhibition of N+/K+ ATPase
Increases intracellular Na+
Which decreases Ca++ extrusion
Which increasers cardiac contractile force
Digitalis toxicity
o Cardiac arrhythmias
o Exacerbated by low K+
Some diuretics cause hypokalaemia
What is the right dose?
o Enough to do some good
o Not enough to do much harm
The right dose
o Identical therapeutic and toxic mechanisms e.g. digitalis
Good = inhibition of cardiac Na/K ATPase
Bad = inhibition of cardiac Na/K ATPase
o Different therapeutic and toxic mechanisms e.g. paracetamol
Good = inhibition of PG synthesis in brain, allegedly
Bad = liver cell necrosis after depletion of glutathione
Undesired actions
o On-target effects – too much of a good thing
o Off target effects – lack of specificity
o Drug interactions – don’t mix your drugs
o The ABCD classification of ADR
The trouble with grapefruit
o Off target effect
o Contains a CYP3A4 inhibitor
o Makes terfenadine bioavailable if taken together
o Terfenadine inhibits hERG the human ether-a-go-go related gene product, a delayed rectifier potassium channel
CYP3A4
o More than 60 drugs are metabolised by CYP3A4
o These drugs can be affected by grapefruit juice
o And by competition, each other
ABCD classification of adverse drug actions
o Type A = augmented
o Type B = bizarre
o Type C = continuous
o Type D = delayed
Type B ADRs
o Often due to phenotypic variation in metabolic rates and pathways
o Or allergy e.g. penicillin
Type C ADRs
o Often involve physiological adaptations to prolonged drug exposure tolerance and dependence to opioids
o Adrenal insufficiency after corticosteroids
Type D ADRs
o Cancers, infertility
o Do not always directly involve the patient
Morphine as ABCD example
o Type A = respiratory depression, constipation
o Type B = allergic-like mast cell reactions
o Type C = addition
o Type D = withdrawal syndrome
