Pharmacology



Pharmacology





Neurotransmitters and Receptors


I. Acetylcholine



  • Synthesis: occurs in the nerve terminal


    This is the rate-limiting step in production of acetylcholine (ACh).

    The supply of choline is the rate-limiting factor in production.


  • Release: Voltage-dependent calcium (Ca) channels open with depolarization, causing an influx of Ca.

    This results in fusion of the synaptic vesicles and release of neurotransmitter.


  • Degradation: occurs in the synaptic cleft



  • Reuptake: Choline is recycled by the presynaptic terminal.


  • Receptors



    • Muscarinic (M) receptors (in brain, muscarinic > nicotinic )



      • All subtypes linked to G-proteins


      • M 1,3,5 activate phosphytidyl inositide hydroxylase


      • M 2,4 inhibit adenyl cyclase


      • Muscarinic agonists (cholinergic, parasympathomimetic)



        • Bethanechol—bladder (not degraded by esterase), carbechol—gut


        • Pilocarpine—eye


        • Methacholine


      • Muscarinic antagonists (anticholinergic)



        • Atropine, scopolamine, tricyclic antidepressants


        • Pupils dilate, tachycardia, reduced secretions, decreased sweating, increased intraocular pressure


        • May help control tremor and rigidity in Parkinson disease


    • Nicotinic receptors (N1 through N4)



      • Neuromuscular junction (NMJ) and nerve receptors differ in pharmacology.


      • Nicotinic antagonists



        • Tubocurare—competitive blocker at NMJ causes hypotension by blocking autonomics



        • Succinylcholine—depolarizing blocker


        • Atracurium—short half-life at in vivo pH


  • Central nervous system (CNS) sources



    • Nucleus basalis of Meynert


    • Diagonal band of Broca


    • Caudate


  • Locations



    • Nicotinic and muscarinic



      • All preganglionic synapses (sympathetic and parasympathetic)


      • CNS (M>N)


    • Muscarinic



      • All postganglionic parasympathetic


      • Postganglionic sympathetic at sweat glands. (The rest of the postganglionic sympathetic synapses use epinephrine and/or norepinephrine.)


    • Nicotinic



      • NMJ


      • Adrenal medulla


  • Disease states



    • Acetylcholine deficiency



      • NMJ release blockade (presynaptic disorders)



        • Botulinum toxin—blocks presynaptic vesicle mobility


        • Lambert-Eaton syndrome—blocks presynaptic calcium channels


        • Tick paralysis


        • Sea snake toxin


      • NMJ receptor blockade (postsynaptic disorders)



        • Myasthenia gravis—ACh receptor antibodies


        • Depolarizing blockade—succinylcholine


        • Nondepolarizing blockade—curare, procainamide, aminoglycosides


        • α-Bungarotoxin—irreversible ACh receptor blockade


      • Alzheimer disease



        • Degradation of ACh nuclei in nucleus basalis


        • Basal forebrain atrophy


    • Acetylcholine excess



      • Anticholinesterases (acetylcholinesterase inhibitors)



        • Prevent breakdown of ACh at the synaptic cleft and increase amount of ACh available in the cleft. Some examples:



          • Pyridostigmine (Mestinon)—used in myasthenia gravis


          • Physostigmine


          • Edrophonium (Tensilon)


          • Tacrine, donepezil—used in Alzheimer disease


          • Organophosphates, diisopropyl fluorophosphate, sarin, soman—irreversible action at the receptors


      • Black widow spider venom



        • Causes explosive release of ACh


      • β-Bungarotoxin



        • Promotes release of ACh



II. Norepinephrine (NE)



  • Synthesis




    • Rate-limiting step is mediated by tyrosine hydroxylase.


    • NE is a feedback inhibitor of tyrosine hydroxylase.


    • L-aromatic amino acid (LAA) decarboxylase requires a vitamin B6 cofactor.


    • Dopamine β-hydroxylase is a copper-containing enzyme and requires oxygen and vitamin C as cofactors.


    • NE is converted to epinephrine by phenylethanolamine-N-methyl transferase in the adrenal medulla only.


  • Storage



    • Dopamine (DA) and NE are transported into the vesicles by a magnesium (Mg) and ATP-dependent process.


    • Transport into vesicles is inhibited by reserpine and tetrabenazine.


    • Oxidation of DA to NE occurs in the vesicles.


    • NE is displaced from the vesicles by amphetamines and ephedrine.


  • Release



    • Vesicles are released after depolarization results in calcium influx.


    • Catecholamines in the synaptic cleft then inhibit further vesicle release.


    • Amphetamines increase release.


  • Metabolism

    Metabolism of catecholamines occurs more slowly than does ACh metabolism. Catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO) are the two major enzymes in catecholamine metabolism.




    • MAO



      • Found on the outer surface of presynaptic mitochondria and on the postsynaptic cell membrane. MAOb is found primarily in the CNS.


      • MAOa is blocked by clorgyline and pargyline.


      • MAOb is blocked by selegiline and pargyline.


    • COMT



      • Found only on the postsynaptic cell membrane


      • COMT is blocked by tropolone.


  • Reuptake



    • Reuptake is the primary mode of NE termination.


    • Reuptake is mediated by sodium (Na)/ATP channel.


    • Reuptake is inhibited by cocaine, nortriptyline, amitriptyline, imipramine, and desipramine.


  • Receptors



    • All receptors work via G-proteins.


    • α1-Receptor is most sensitive to epinephrine and blocked by prazosin and clonidine. It is postsynaptic



    • α2-Receptor inhibits adenyl cyclase and is inhibited by yohimbine and clonidine. It is presynaptic.


    • Phentolamine and phenoxybenzamine—block both α1-receptors and α2-receptors


    • Labetalol—blocks both alpha and beta receptors


  • Location



    • Locus ceruleus


    • Hypothalamus


    • Reticular activating system


III. Dopamine



  • Synthesis


    Tyrosine hydroxylase (TH) mediates the rate-limiting step.

    LAA decarboxylase is a vitamin-B6-dependent enzyme.

    DA is a feedback inhibitor of TH and of the release of vesicles.


  • Release: action potentials cause calcium influx, which results in the fusion of vesicles.


  • Metabolism: after reuptake, presynaptic intraneuronal MAO converts DA to DOPAC (dihydroxyphenylacetic acid). Extraneuronal postsynaptic COMT and MAO convert DA to homovanillic acid (HVA).


  • Reuptake: presynaptic terminals contain high-affinity DA transporters.


  • Receptors



    • D1,5



      • Postsynaptic linked to G-protein


      • Excitatory


      • Stimulates cAMP (cyclic adenosine monophosphate)


    • D2,3,4



      • Presynaptic—inhibitory (high affinity)


      • Postsynaptic—inhibitory (low affinity)


  • DA Pathways



    • Nigrostriatal—substantia nigra to striatum


    • Tuberoinfundibular


    • Mesolimbic—ventral tegmentum to limbic areas/nucleus accumbens


    • Mesocortical—ventral tegmentum to prefrontal cortex


  • Medications



    • Antipsychotics



      • Dopamine blockers (D2). The antipsychotics block the inhibitory D2-receptors with a resultant excitatory effect. D2-receptor affinity correlates with efficacy.


    • Amphetamines



      • Increase release and decrease reuptake of dopamine


    • MAO inhibitors—antidepressants



      • Increase DA by decreasing metabolism


      • Examples: selegiline, pargyline


    • Cocaine and tricyclic antidepressants



      • Block reuptake


    • Reserpine and tetrabenazine



      • Prevent uptake of DA and NE into vesicles



  • Model of Parkinson disease (MPTP)



    • MAO converts MPTP to MPP+ (toxic to dopaminergic cells). This is the basis for using selegiline to treat Parkinson disease.


IV. Serotonin



  • Synthesis


    Tryptophan hydroxylase mediates the rate-limiting step.

    Increasing the level of L-tryptophan increases the production of 5-hydroxy tryptamine (5-HT).

    Amino acid decarboxylase requires a vitamin B6 cofactor.


  • Storage



    • 5-HT complexes with proteins, divalent cations, and adenosine diphosphate in granules.


    • Storage is disrupted by reserpine and tetrabenazine.


  • Release



    • Amphetamine and fenfluramine cause the release of 5-HT.


    • Clomipramine and amitriptyline both increase release and block reuptake of 5-HT.


  • Metabolism



  • Reuptake: is the primary mechanism of inactivation; is blocked by clomipramine, amitriptyline, sertraline, and fluoxetine.


  • Receptors



    • 5-HT1a



      • Linked to G-protein, inhibiting adenyl cyclase


      • Agonist—buspirone


    • 5-HT1b/d



      • Linked to G-protein, inhibiting adenyl cyclase


      • Both act as autoreceptors


      • Agonist—sumatriptan (5-HT 1d)


    • 5-HT1c



      • Only type 1 receptor that has an antagonist; really more like a 5-HT2


      • Linked to G-protein, activating PLC to increase DAG and IP3


      • Agonist—α-methyl-5-HT, (LSD)


      • Antagonist—retanserine, pizotofen, clozapine. Note: This is the exception to the no antagonist rule for 5-HT1 receptors.


    • 5-HT2



      • Linked to a G-protein activating PLC to increase DAG and IP3


      • Agonist—alpha-methyl-5-HT, (LSD)


      • Antagonists—ketanserine, pizotifen, clozapine


    • 5-HT3



      • Agonists—2-α-5-HT


      • Antagonists—metoclopramide, cocaine (weak), ondasetron (potent)


  • CNS Source: midline raphe nuclei


V. Glutamate



  • Excitatory amino acid neurotransmitter



  • Receptors



    • N-methyle-D-aspartate (NMDA)



      • Activates mainly calcium channels


      • Five binding sites alter channel opening



        • Glutamate—increases


        • Glycine—increases


        • Polyamine—increases


        • Mg—decreases flow


        • Zinc—decreases flow


      • Glutamate and glycine are required for channel opening.


      • Voltage-dependent blockers—phencyclidine, ketamine, Mg, MK-801


      • Voltage-independent blockers—zinc


      • Found in hippocampal pyramidal cells


      • Excitotoxicity theory—Normally the NMDA receptor is blocked by Mg. With enough glutamate binding, the Mg-induced blockade can be overcome and calcium is allowed to enter the cell. This activates intracellular biochemical processes, which can lead to cell destruction.


    • 2-(Aminomethyl)phenylacetic acid (AMPA)



      • Activate mainly sodium channels


      • Major source of CNS fast excitatory postsynaptic potentials (EPSPs)


      • Receptor affinity—AMPA > glutamate > kainate


      • GluR3 receptor implicated in Rasmussen encephalitis


    • Kainate



      • Receptor affinity—kainate > Glutamate > AMPA


    • APCD


    • L-AP4—G-protein coupled formation of AMP


  • Inactivation



    • Reuptake is primary mode of termination.


      Glutamic acid decarboxylase (GAD) is a vitamin-B6-requiring enzyme.

      B6-responsive seizures—decreased B6 can lead to increased glutamate and decreased

      GABA, and in theory, can lead to increased seizures.

      Administration of vitamin B6 helps some children with seizures.


VI. GABA

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Sep 8, 2016 | Posted by in NEUROLOGY | Comments Off on Pharmacology

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