Lecture 7 - ANS-Parasympathetic Receptors and Cholinergic Stimulating Drugs
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Transcript of Lecture 7 - ANS-Parasympathetic Receptors and Cholinergic Stimulating Drugs
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)