Receptor occupancy model
The first model put forward by Clark to explain the activity of drugs at receptors quantified the relationship between drug concentration and observed effect.
1. Drug + receptor = effect
2. The response is directly depend on the proportional to the amount of drug bound receptor
how much effect = how many receptor occupied
3. The maximum response would be elicited once all receptors were occupied at equilibrium.
Drug + 100%receptor = efficacy
Another basal theory of agonist and antagonist
Not occupied receptors. Maximal effect can be elicited by an agonist at a concentration that not result in occupancy of the full complement of available receptor.
Available receptor and spare receptor are not hidden or unavailable and when they are occupied they can be coupled to response.
The type of receptors
Historically , structure-activity analyses , with careful cpomparisons of the potency of series of autonomic agonist and antagonist analogs , led to the definition of different autonomic receptor subtypes , including Muscarinic and nicotinic cholinoceptors and a, ß and dopamine adrenoceptors .
The model of ACh –receptor
1. Muscarinic –R ; there are subtypes M1,M2,M3 and so on , All of the parasympathetic postganglionic fibers ------ in the target organ the acetylcholine interacts with muscarinic receptor
2. Nicotinic -R: There are at least two types of nicotinic receptors ,they are found at the motor end plate , in all autonomic ganglia , and in the CNS--receptor .
Ganglia and CNS-R: N1
Cholinergic Receptor Mechanisms
Nicotinic receptors (N-receptor)
Locations: skeletal muscle-- motor ending-plate (N2 N2), ganglia-postsynaptic membrane(N1),
Effect: N2:exciting skeletal muscle ,
N1 exciting the postsynaptic neuron in ganglia
Muscrinic receptors (M-receptor)
smooth muscle, gland and cardiac muscle
M--- smooth muscle,gland
Properties of direct-acting Cholinomimetics
- ACh: Short half life-no clinical use
- Bethanechol: Rx-ileus(postOP/neurogenic),urinary retention
- Methacholine: Dx-bronchial Hyperreactivity
- Pilocarpine: Rx-glaucoma (Topical),xerostomia
Properties of indirect-acting cholinomimetics
- Edrophonium: Short acting, Dx-myasthania
- Physostigmine: Tertiary amine(enters CNS),Antidote in atropine overdose
- Neostigmine: No CNS entry. Rx-ileus,urinary retention,
- Donepezil: Lipid soluble(CNS entry).Rx-Alzheimer disease
- Organophosphates: Lipid soluble,irreversible inhibitors.Rx-glaucoma(Ecothiophate), can be used as Insecticides (malathion,parathion)
Side effects of Acetylchoninesterase Inhibitors
Remember the word "DUMBBELSS"
E: Excitation(Muscle & CNS)
There are two types of the adrenergic receptors binded with norepinephrine and epinephrine. They are divided into a and ß receptors .Each of these receptors is further subdivided into a1 a2, and ß 1 ß 2 and ß 3 ,respectively
Mechanisms used by Adrenergic Receptors
Distribution of Adrenoceptor sub-types
- Phenylephrine (Nasal decongestant&opthalmologic use)
- Methoxamine (Paroxysmal atrial tachycardia through vagal reflex)
α1 non-selective blockers
α1 selective blockers
- Yohimbine:used in postural hypotension and impotence
- Mirtazapine:used as antidepressant
The heart is main site for ß1-receptor
Activation of ß2-receptor relaxes smooth muscle
Activation of a receptors causes contraction or constriction , mostly vasoconstriction
α2 adrenergic receptors is listed--negative feedback loop
- Regulate release of neurotransmitters
- Control epinephrine, nor-epinephrine release
- Modulate sympathetic response “negative feedback loop”
Classification of agonist
Strong intrinsic activity
Weak intrinsic activity
( 0 <a< 1 )
Competitive (reversible ) antagonist:
Because antagonism is competitive, the presence of antagonist increases , the agonist concentration required for a given degree of response, and so the agonist concentration-effect curve shifts to the right.
Emax is not changed.
Noncompetitive (Irreversible) antagonist
Affinity & intrisic activity
concentration-effect curve shifts to the right.( not parallel)
For example :
Atropine has a greater affinity for the muscarinic –R than does acetylcholine but lacks efficacy in initiating activity.
Thus the resultant effects depends upon their relative concentrations and atropine blockade can be overcome by increasing the concentration of acetylcholine ( for example by a cholinesterase inhibitor) .