Lecture 6 (refer to slides) Flashcards
True or False, no one biochemical model can explain the variety of pharmacological effects triggered by drugs
True - No one biochemical model can explain the bariety of pharmacological effects triggered by drugs.
Models such as occupancy mode, rate model, induction model, pertubation model and cooperativity model
Occupancy model
The intensity of the pharmacological effect is directly proportional to the number of receptor binding sites being occupied by the drug.
Rate model
The intensity of the pharmacological effect is directly proportional to the total number of encounters of the drug with its receptor binding sites per unit time.
Induction model
The pharmacological effect is induced by the drug via specific conformational changes in the active binding site of the receptor complex.
Pertubation Model
Pharmacological substances induce macromolecular perturbations, whereby agonists trigger relatively specific conformational changes as compared to antagonists.
Cooperativity Model
If pharmacological receptors exist in a dynamic equilibrium between activated and inactive states, agonists may shift the equilibrium to an active state and antagonists to an inactive state.
Type 1 ionotropic receptor: Ligand-gated ion channel
- Ligand binding domain
- Ion channel lining domain
- Membrane-spanning domain: hydrophobic a-helical region, approx. 20 amino acids long
- five subunit ion channel complex is a common structural arrangement found in many ionotropic receptors
- extremely fast response (milliseconds)
- membrane-bound
- direct coupling to ion channel
- oligomeric assembly of subunits surrounding central ion pore
Type 2 metabotropic receptor: G-protein coupled receptor
- Ligand binding domains
- G-protein coupling domain
- fast response (seconds)
- membrane-bound
- indirect coupling via G-protein to effector (enzyme or ion channel)
- monomeric assembly comprising seven trans-membrane helices
Type 3 receptor: Kinase-linked receptor
- Extracellular ligand binding domain
- Intracellular catalytic domain kinase activity
- slow response (hours)
- membrane-bound
- direct coupling to enzyme between receptor and kinase enzyme
Type 4 receptor: Nuclear receptor
- Receptor binding domain
- ‘zinc-fingers’ - DNA binding domain
- Slow response (hrs)
- intracellular
- coupling via DNA
- effect on gene transcription
- monomeric structure with seperate receptor and DNA binding domains
Describe Agonist - Nicotine
- Receptor type - nicotinic acetylcholine receptor
- alkaloid from tobacco plants
- Agonist of nicotinic acetylcholine receptor
- stimulating drug (Parasympathomimetic)
- Potential toxic side effects
Describe Agonist - Isoprenaline
- Receptor type: Beta-adrenoreceptor
- b-adrenergic agonist
- structural similarity to adrenaline
- treatment of slow heart rate [bradycardia]
Modulator
a modulator is a substance or compound that can alter the toxicity or the effects of a toxic substance.
Describe modulator - Lidocaine
- Ion channel : Voltage-dep. Na+ channel
- Local anesthetic
- Common usuage as: Injected form for dental anesthesia, injected form for minor surgery, topical form to relieve pain from skin inflammations
Describe agonist - Nifedipine
- Ion channel: Voltage-dep. Ca2+ channel
- Nifedipine
- Dipydropydrine
- L-type calcium channel blocker
- Usage as: Anti-anginal drug, antihypertensive agent
Describe inhibitor - Neostigmine
- Enzyme - Aceytlcholinesterase
- Reversible inhibitor of acetylcholinesterase
- Interference with the breakdown of physiological ligand acetylcholine
- Indirect stimulation of nicotinic and muscarinic receptors
- Usage in: Reversal of the effects of non-depolarizing muscle relaxants following anesthesis, Treatment of myasthenia gravis to increase NMJ stimulation
Describe the inhibitor Aspirin
- Enzyme cyclooxygenase
- Non-steroidal anti-inflammatory drug (NSAID)
- Inhibitor of the enzyme cyclooxygenase [COX-1>COX-2]
- Usage as: Analgesic, Anti-platelet drug
Describe the inhibitor Hemicholinium
- Carrier: Choline carrier
- Blocks choline uptake
- Not used clinically
- Neuromuscular blocking drug
Describe the inhibitor - Ouabain
- Carrier: Na+/K+ pump
- Cardiac glycoside
- Blocker of Na+/K+-ATPase
- Increases [Ca2+]i due to decreased NCX-Therapeutic usage in heart failure
- Potential toxicity
