Friday, March 22, 2013

ANS Receptors


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  
Spare receptor: 
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 

Autonomic  receptor 
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 . 
NM-R(nicotinic muscle);N2
NN-R(nicotinic neuronal):
Ganglia and CNS-R: N1

Cholinergic Receptor Mechanisms
Cholinergic receptors
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
Antagonist:
N1:hexamethonium
N2:decamethonium

Muscrinic receptors (M-receptor)
Locations:
smooth muscle, gland and cardiac muscle 
M--- smooth muscle,gland
M1-- ganglia,gland
M2--- heart

Muscarinic Agonists
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

Acetylcholinesterase Inhibitors
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"
D: Diarrhea
U: Urinaion
M: Miosis
B: Bradycardia
B: Bronchoconstriction
E: Excitation(Muscle & CNS)
L: Lacrimation
S: Salivation
S: Sweating

Antagonist

  • Atropine

Adrenergic Receptors
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

α1 Agonists

  • Phenylephrine (Nasal decongestant&opthalmologic use)
  • Methoxamine (Paroxysmal atrial tachycardia through vagal reflex)

α2 Agonists

  • Clonidine
  • Methyldopa

α Blockers
α1 non-selective blockers
  • Phentolamine
  • Phenoxybenzamine

α1 selective blockers

  • Prazosin
  • Doxazosin
  • Terazosin
  • Tamsulosin

α2 blockers:

  • Yohimbine:used in postural hypotension and impotence
  • Mirtazapine:used as antidepressant

β Agonists

  • Isoproterenol
  • Dobutamine
  • Salmeterol
  • Albuterol
  • Terbutaline
  • Ritodrine

β Antagonists:

  • propranonol(β)
  • atenolol(β1)
  • butoxamine(β2)

NOTE:
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
Full agonist
Strong affinity
Strong intrinsic activity
(a=1)
Partial agonist
Strong affinity
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
Emax decrease
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) . 

3 comments:

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    ReplyDelete
    Replies
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      Delete
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