ANS-Parasympathetic Receptors and Cholinergic Stimulating Drugs

Hazel Anne L. Tabo

Neurotransmission2 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

Class II

Amines

Class III

Amino acids

Class IV

Acetylcholine (Ach)

Norepinephrine (NE) Epinephrine (E) Dopamine Serotonin Histamine

-Aminobutyric acid (GABA)GlycineAspartate Glutamate

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.Hypothalamic-releasing hormones

B. Pituitary peptides C. Peptides acting on Gut and Brain

D. From Other Tissues

Thyrotropin RH [TRH] Luteinizing hormone-RH [LHRH] Somatostatin [Growth hormone inhibitory factor]

-Melanocyte-stim. H. [MSH]-EndorphinProlactinLH ThyrotropinGrowth H. [GH]Vasopressin[ADH]OxytocinAdrenocortico-trophic hormone [ACTH]

Leu-enkephalinMet-enkephalinSubstance P GastrinCholecystokininVasoactive intestinal polypep. [VIP]NeurotensinInsulin Glucagon

Angiotensin IIBradykininCarnosineSleep peptidesCalcitonin

HALT (2007) Medical Physiology Lecture

Neural Release of Transmitter

Neuroscience, 2nd edition. 

Cholinergic Transmission – Possible Sites of Drug ActionAction potential in presynaptic nerve fiber –

Ca2+-dependentSynthesis of transmitterStorage – Ach vesiclesMetabolismRelease – synaptic junctionsRe-uptakeDegradationReception of transmitterReceptor - 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 Stimulate Depress

Cholinergic receptors in organs

Cholinergic drugs or Parasympathomimetics

Cholinergic receptor blockers

Antimuscarinic

Nicotinic blockers

Ganglionic receptors Ganglionic stimulants (low doses of nicotine)

Ganglionic blockers (high doses of nicotine)

Neuromuscular junction (in skeletal muscle)

Indirectly-acting cholinergic drugs

Neuromuscular blockers

Mechanism of ActionDirect 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 estersAch – hydrolyzed by Achase

MOA: decrease HR, CO, BP & increase intestinal motility

Methacoline – 3X resistant to AchaseMOA: longer duration of effect

Carbachol & Bethanecol – extremely resistantMOA:Carbachol – profound effect in CVS & GITBethanecol – 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 inhibitors1. Edrophonium (Tensilon)2. Physostigmine3. Neostigmine4. Pyridostigmine5. Carbaryl

B. Irreversible cholinesterase inhibitors (organophosphates)1. Diisopropyl fluorophosphate2. Insecticide (Malathion, Parathion, Fenthion)3. Nerve gases – muscle spasms4. 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 motor-end 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 Ach-receptor sites of the membrane Ach channels blocked (-) depolarization

Drugs stimulating NMJ by inactivating Ach-ase

- Neostigmine, physostigmine, DIFP (diisopropyl-fluorophosphate) combine with Ach-ase for hoursAch 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”SalivationLacrimationUrinary incontinenceDiarrheaGI crampsEmesis

Sources:

Online: Purves, Neuroscience 2nd Ed. Sinauer Associates Inc,2001 In: http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/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 Pareja’s tablesPast Notes and Lectures of Ms. Tabo (patok version)