ANS PHARMACOLOGY

We will review drugs acting at:
• Axonal membrane
• Cholinergic transmission sites
        – Pre - Synaptic terminals
        – Receptors
                » Nicotinic agonists and antagonists
                        • Autonomic Ganglia
                » Muscarinic agonists and antagonists
                        • Parasympathetic Effectors
        – Acetylcholinesterase Inhibitors
• Adrenergic transmission sites
        – Pre - Synaptic terminals
                » Release and synthesis of catecholamines
        – Receptors
                »  and  Adrenergic agonists and antagonists
        – Inhibitors of catecholamine re-uptake and destruction
• Histaminergic receptors & antagonists
• Selected other stories…..

Presynaptic or axonal agents:
• Tetrodotoxin (TTX) and Saxotoxin*
• Batrachotoxin & scorpion toxin*
• Botulinus  toxin
• Procaine (Novocain) & relatives

• General anesthetics
        – Bind to voltage - gated Na+ channels and prevent them from opening
        – Inhibits axonal transmission of action potential
        – Procaine (Novocain), lidocaine, cocaine, benzocaine
 
 

Muscarinic agonists  (parasympathomimetic)
• ACh*
• Muscarine*
        Amanita muscaria
• Pilocarpine*
       Pilocarpus jaborandi
• Furmethide

Muscarinic antagonists
• Atropine*(belladonna)
  Atropa belladonna, the deadly nightshade
  Datura stramonium, known as Jamestown or jimsonweed, stinkweed,
  thorn-apple, and devil's apple.
• Scopalomine (hyoscine)
  found chiefly in the shrub Hyoscyamus niger (henbane) and
  Scopolia carniolica.

Nicotinic agonists
• ACh*
• Nicotine*
• DMPP
    (1,1-dimethyl-4-phenylpiperazinium)

Nicotinic antagonists
• Hexamethonium (C6)*
        (at ANS ganglia)
        –  Read the Hexamethonium Man on the Web site
• d-Tubocurarine*
        (CURARE)

Anti-Cholinesterases

Reversible & competitive:
            Eserine*
            Prostigmine

Irreversible & non-competitive:
   Organophosphates             (DFPs)
     -Tabun, Sarin, Soman
            -Malathion & Parathion
 

Adrenergic  agonists
• Epinephrine*
• Norepinephrine*
• Phenylephrine*
        – 1 specific
• Psuedoephedrine (Sudafed)
        – 1 specific
• Phenylpropanolamine
 

antagonists
• Phentolamine*
• Phenoxybenzamine?*
• Prazosin
 

agonists
• Epinephrine*
• Isoproterenol*
• Albuterol (Ventolin) 2 only
• Norepinephrine (weak at 2)*
 

antagonists
• Propranolol*
 
 

Synthesis of NE
                  + OH
phenylalanine --------> tyrosine

                   + OH
tyrosine           --------> DOPA

                   - COOH
DOPA             --------> dopamine

                  + OH
dopamine       --------> NE
 
 

EPI & NE Synthesis Inhibitors:
- methyl - p - tyrosine

 ? - methyl – DOPA (ALDOMET) - false neurotransmitter
 

Monoamine Oxidase Inhibitors
• MAO breaks down catecholamines in adrenergic nerve terminals
• It is part of the regulatory mechanisms that insure appropriate [NE] in nerve terminals
 

Inhibitors of NE Re-uptake
• Anti - depressants
        – Amitriptyline
        – Desiprimine
 

Serotonin  -   5 – Hydroxytryptamine (5 HT)
• Receptor is a transmembrane, G - linked protein
• Seven different receptor subtypes
• LSD
        – CNS  5 HT agonist
        – PNS  5 HT antagonist
 

Inhibitors of Serotonin Re-uptake
• Anti-depressants
        – Prozac
        – Zoloft
        – Paxil
 

Other adrenergic agents of interest
• (Meth)amphetamine
• Reserpine
 

Histaminergic agents
 Histamine*
• Receptors
        – H₁
        – H₂
        – H₃
Histamine
• Relaxes vascular smooth muscle  dilates blood vessels,
  drops BP (large systemic response that occurs during anaphylactic
  shock) while usually increasing LOCAL blood flow to site of localized
  response (e.g., insect bite).
• Contracts airway and intestinal smooth muscles
        – Constricts airways - asthma
        – Contracts intestinal muscles - diarrhea
• Increases capillary permeability - edema
 

Histaminergic Antagonists

Antagonists
-  H₁
        – Chlorpheniramine
        – Diphenhydramine
• H₂
        – cimetidine (TAGAMET), famotidine (PEPCID), nizatidine (AXID),
           and ranitidine (ZANTAC)
 

Prostaglandin Synthesis Inhibitors
• Acetyl salicylic acid - Aspirin
• Acetaminophen (Tylenol)
• Ibuprofen (Advil)
• Naproxen (Aleve)
• Indomethacin (Indocin)
 

Other Stuff
• Endogenous Opioids
        – enkephalins, dynorphins, and ?- endorphins
        – Mu, kappa, and delta receptors
• Exogenous Opioids
        – Morphine and heroin
• Naloxone - opiate antagonist
• Ethyl alcohol
        – Depresses neuron function
        – Vasodilation
        – Don’t take a drink from the big dog!