ANS-Parasympathetic Receptors and Cholinergic Stimulating Drugs

Hazel Anne L. Tabo

Neurotransmission
2 Broad Categories: 1. Peptides & enzyme transmitters - enkephalin, substance P, neuropeptide Y, VIP, and somatostatin; Purines (purinergic transmitters) - ATP and adenosine 2. Small molecules NO (nitric oxide),  These substances can depolarize or hyperpolarize nerve terminals or postsynaptic cells.  Histochemical, immunocytochemical, and autoradiographic studies have demonstrated that one or more of these substances is present in the same neurons that contain one of the classical biogenic amine neurotransmitters (Bartfai et al., 1988; Lundberg et al., 1996). These observations suggest that synaptic transmission in many instances may be mediated by the release of more than one neurotransmitter. Ex: Enkephalins - in postganglionic sympathetic neurons and adrenal medullary chromaffin cells. VIP - localized selectively in peripheral cholinergic neurons that innervate exocrine glands, and Neuropeptide Y - in sympathetic nerve endings

I. Small molecules, Rapidly-acting neurotransmitters Brief in duration <1millisecond, involved in ion channel-opening or closure. They are rapidly inactivated after they bind to their receptors.

Class I Cholinergic Acetylcholine (Ach)

Class II Amines Norepinephrine (NE) Epinephrine (E) Dopamine Serotonin Histamine

Class III Amino acids K-Aminobutyric acid (GABA) Glycine Aspartate Glutamate

Class IV

Nitric oxide (NO)

HALT (2007) Medical Physiology Lecture

II. Neuroactive peptides or Neuropeptides Slow-acting neurotrans. or prolonged duration (sustained in mins., hrs., /days); synthesized in the soma as integral components of large CHONS; vesicles are brought to axon terminals & released into the synaptic cleft A.Hypothalamicreleasing hormones Thyrotropin RH [TRH] Luteinizing hormone-RH [LHRH] Somatostatin [Growth hormone inhibitory factor] B. Pituitary peptides C. Peptides acting on Gut and Brain Leu-enkephalin Met-enkephalin Substance P Gastrin Cholecystokinin Vasoactive intestinal polypep. [VIP] Neurotensin Insulin Glucagon D. From Other Tissues Angiotensin II Bradykinin Carnosine Sleep peptides Calcitonin

E-Melanocyte-stim. H. [MSH] F-Endorphin Prolactin LH Thyrotropin Growth H. [GH] Vasopressin[ADH] Oxytocin Adrenocortico-trophic hormone [ACTH]

HALT (2007) Medical Physiology Lecture

Neural Release of Transmitter

Neuroscience, 2nd edition.

Cholinergic Transmission Possible Sites of Drug Action

 Action potential in presynaptic nerve fiber Ca2+-dependent  Synthesis of transmitter  Storage Ach vesicles  Metabolism  Release synaptic junctions  Re-uptake  Degradation  Reception of transmitter  Receptor - induced increase or decrease in ionic conductance

The synthesis, packaging, secretion and removal of neurotransmitters

The synthesis, packaging, secretion and removal of neurotransmitters

 A) Small molecule neurotransmitters are synthesized at nerve terminals. The enzymes necessary for neurotransmitter synthesis are made in the cell body of the presynaptic cell. (1) Transported down the axons by slow transport (2). Precursors are taken into the terminal by specific transporters and neurotransmitters synthesis and packaging take place within the nerve endings (3). After vesicles fusion and release (4) the neurotransmitters may be enzymatically degraded. The reuptake of the neurotransmitters starts another cycle of synthesis, packaging, release, and removal.  B) Peptide transmitters and enzymes are synthesized in the cell body (1). Enzymes and propeptides are packaged into the Golgi apparatus. During fast axonal transport of these vesicles to the nerve terminal (2), the enzymes modify the propeptides to produce one or more neurotransmitter peptides(3). After vesicle fusion and exocytosis, the peptides diffuse away and are degraded by proteolytic enzymes.

Excitatory Neurotransmitter: synthesis, release & reuptake

Inhibitory Neurotransmitters: GABA & Glycine

 GABA is synthesized from glutamate by the enzymes glutamic acid decarboxylase, which requires pyridoxal phosphate.  Glycine can be synthesized by a number of metabolic path ways in the brain, the major precursor is serine. High affinity transporters terminate the actions of these transmitters and return GABA or glycine to the synaptic terminals for reuse.

Cholinergic (Parasympathetic) Receptors

 Muscarinic receptor - found in effector (target) organs such as heart, smooth muscles and exocrine glands (sweat glands) - subtypes: M1-M5 - *muscarine (alkaloid) CN X stimulation (Dixon 1907); Ach & choline esters (Reid Hunt)  Nicotinic receptor - found in autonomic ganglia, neuromuscular junction, skeletal muscle and adrenal medulla -subtypes: muscle type (NM) nicotinic I neuronal type (NN) nicotinic II

Nicotinic receptors

Muscarinic receptors

Cholinergic Drugs
Receptors Cholinergic receptors in organs Stimulate Depress Cholinergic drugs or Cholinergic receptor Parasympathomimetics blockers Antimuscarinic Nicotinic blockers Ganglionic blockers (high doses of nicotine) Neuromuscular blockers

Ganglionic receptors Ganglionic stimulants (low doses of nicotine) Neuromuscular junction (in skeletal muscle) Indirectly-acting cholinergic drugs

Mechanism of Action
 Direct acting binds directly to and activate NM and NN receptors  Indirect acting inhibits acetylcholinesterase (Achase) and thus increase endogenous Ach neurotransmitter
Reversible - Bind to cholinesterase for a period of minutes to hours (reversible cholinergic inhibitors) Irreversible - Bind to cholinesterase and form a permanent covalent bond (The body must make new cholinesterase to break these bonds). (irreversible cholinergic inhibitors)

Parasympathomimetic Drugs

Mode of Actions (MOA)

 Reversible competes with receptors increased enzyme: low substrate concentration (Ach) Reversible drugs substrate analogs of Ach that binds to Achase enzyme promotes cholinergic effect (ex: muscle contraction)  Irreversible binds to other receptor site (non-competitive inhibition) Irreversible drugs inhibits enzyme activity promotes cholinergic effect

I. Direct-acting cholinoceptor stimulants

Absorption of Choline esters

 Ach hydrolyzed by Achase MOA: decrease HR, CO, BP & increase intestinal motility  Methacoline 3X resistant to Achase MOA: longer duration of effect  Carbachol & Bethanecol extremely resistant MOA: Carbachol profound effect in CVS & GIT Bethanecol increase intestinal motility, stimulate detrussor muscles (urinary bladder) promoting urination

Cholinomimetic Alkaloids
*Pilocarpine rapid miosis (eyes) or pupilloconstriction ideal for tx. of glaucoma *Nicotine *Lobeline *well-absorbed by the body Muscarine less absorbed by the body but highly toxic (Narrow TI)

Effects on Organs: Choline esters & Cholinomimetic alkaloids

II. Indirectly-acting Parasympathomimetic drugs: promote choline effect

 A. Reversible cholinesterase inhibitors 1. Edrophonium (Tensilon) 2. Physostigmine 3. Neostigmine 4. Pyridostigmine 5. Carbaryl  B. Irreversible cholinesterase inhibitors (organophosphates) 1. Diisopropyl fluorophosphate 2. Insecticide (Malathion, Parathion, Fenthion) 3. Nerve gases muscle spasms 4. Echothiophate iodide III. Others: Metoclopramide (Plasyl); Amine derivatives (Tacrine, Velnacrine)

Drugs that affect transmission at the NMJ

 Drugs stimulating the muscle fiber by acetylcholine-like action - Ex: metacholine, carbachol, nicotine same effect like Ach but have prolonged action due to non-degradation of the acetylcholinesterase. Spasm: Localized depolarization at motorend plate causing new AP, complete repolarization is not achieved by the entire muscle due to continuous depolarization.  Drugs blocking transmission at NMJ - Curariform (curare), D-tubocurarine prevents impulse transmission from end-plate into the muscle by binding to Achreceptor sites of the membrane Ach channels blocked (-) depolarization  Drugs stimulating NMJ by inactivating Ach-ase - Neostigmine, physostigmine, DIFP (diisopropylfluorophosphate) combine with Ach-ase for hours Ach accumulation repetitive muscular stimulation causing spasm. - DIFP potential nerve gas inactivating Ach-ase for weeks

Therapeutic Uses of Cholinergic Stimulants

 Ophthalmologic glaucoma of the eyes cause headache (intracranial pressure); promote ciliary muscle activity to release the fluid pressure in the eyes (aqueous humor).  Neuromuscular junction (NMJ) Myasthenia gravis Curare or curare-like overdosage Adjunct to surgical anesthesia  GIT Paralytic ileus Congenital megacolon Reflux esophagitis (heartburn) esophageal valve defaults  GUT Atony of urinary bladder (non-contraction)  Antimuscarinic drug intoxication Atropine cause muscle paralysis

Pharmacokinetics

Adverse Reactions
Sludge effect Salivation Lacrimation Urinary incontinence Diarrhea GI cramps Emesis

Sources:
 Online: Purves, Neuroscience 2nd Ed. Sinauer Associates Inc,2001 In: http://www.cs.stedwards.edu/chem/Chemistry/C HEM43/CHEM43/NeuroT/raja.html  Brunton L, JS Lazo & KL Parker (Eds.) Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition. McGrawHill  Dela Cruz MLD et al. (1999). Didactic Study Guide in Pharmacology: Dept. of Pharmacology College of Medicine DLSUHSC  MC Parejas tables  Past Notes and Lectures of Ms. Tabo (patok version)