Autonomic Nervous System Pharmacology

By: Tdaele A. (B.pharm., MSc in Pharmacology)

 Objectives

• Reviewing physiology of ANS

• Identify and distinguish different classes of autonomic drugs

• Understand PKs , PDs, clinical indications, adverse effects and

contraindications of common autonomic drugs

Autonomous Nervous System
Visceral Afferent Fibers

• afferent fibers from visceral structures

– are the first link in the reflex arcs of the autonomic system

• two main sensory systems

–cranial nerve (parasympathetic) visceral sensory system

• carries mechanoreceptor & chemosensory information

–spinal (sympathetic) visceral afferent system

• principally convey sensations related to

–temperature & tissue injury of mechanical, chemical, or thermal origin

 Visceral Afferent Fibers….

• Neurotransmitters have not been well characterized unequivocally

–Substance P –Intestinal polypeptides(VIP),

–Calcitonin G related peptide –Cholecytokinin

–Others like somatostatin, –ATP

–Enkephalins –Glutamate and aspartate

Anatomical differences: ANS vs SNS
• neurons b/n CNS and effector cells
– 2 neurons in ANS (pre- & post-ganglionic)

– one neuron in Somatic NS

• synaptic junctions in ANS occur in ganglia

– which lie out side the cerebrospinal axis

– while no such structures occur in somatic NS

• while efferent neurons in somatic NS are myelinated,

– generally postsynaptic autonomic neurons are non myelinated

• sympathetic system is distributed to effectors throughout the body,

• whereas parasympathetic is much more limited

 Central Organization

• central autonomic network:

– cerebral cortex, hypothalamus,

– limbic-amygdala (emotional)

• Peripheral sensors:

– Baro-, chemo-, GI receptors

• Hypothalamus

– is center for integration (boss)

• Efferent: SNS and PNS

Sympathetic vs Parasympathetic
• location of cell body of preganglionic neuron
 parasympathetic:
 from brain stem & sacral segment of the spinal cord (SC)

 Sympathetic:
 from thoracic and lumbar segments of the spinal cord

• location of ganglia
 close to effector cell in parasympathetic
 generally close to vertebral column in sympathetic

• ratio of preganglionic to postganglionic neurons

 almost one to one in parasympathetic
 One to more than 20 in sympathetic
Difference b/n PSNS and SNS….
Parasympathetic NS Sympathetic Nervous System

• is concerned with the conservation • this nervous system is designed

of the body processes
• its main NT is Ach
• Its receptors are muscarinic &
nicotinic
• Craniosacral outflow
• preganglionic neurons is long
– to cope with emergency situations
• the “fright or flight” response
• Its main NTs are Ep & NEP
• Its receptors are α & β receptors
• thoracolumbar outflow
• preganglionic neurons is short
• postganglionic neurons is long

• postganglionic neurons is short

 General functions of ANS:
Sympathetic nervous system
• continually active to some degree
– e.g, in maintaining the tone of vascular beds

• adjusting in response to stress: trauma, fear, hypoglycemia, cold, or exercise

• Sympathetic output is to
– increase HR and BP

– mobilize energy stores of the body,

– and increase bd flow to skeletal muscles and the heart

• while diverting flow from the skin and internal organs
General functions of ANS:
• fight or flight response: triggered by both
• direct stimulation of sympathetic activation of the effector organs

• and stimulation of the adrenal medulla

–to release EPI & lesser amounts of NE

Parasympathetic nervous system

• maintains essential bodily functions,
– such as digestive processes & elimination of wastes
• It usually acts
– to oppose or balance the actions of the sympathetic
– and is generally dominant over the sympathetic system
– in ‘rest and digest’ situations
Function of ANS…
Steps Involved in Neurotransmission
Axonal Conduction

– refers to the passage of an electrical impulse along an axon or muscle fiber

• At rest, the interior of the typical mammalian axon

– is approximately negative 70 mV to the exterior

• In response to depolarization to a threshold level,

• an Action potential (AP) or Nerve Impulse

– is initiated at a local region of the membrane

Axonal Conduction…
• the AP consists of two phases
• The Initial phase

• rapid increase in the permeability of Na+

–Voltage sensitive Na+ channels

• rapid depolarization from the resting potential,

–which continues to a positive overshoot

• The second phase

• rapid inactivation of the Na+ channel

• delayed opening of a K+ channel,

–which permits outward movement of K+
–to terminate depolarization
 Con’t….

• transmembrane adjacent resting channels propagation of the

ionic currents in the axon are
produce activated, & excitation of action potential
• local circuit an adjacent portion of without decrement
currents around the axonal membrane
the axon occurs along the axon

• the region that has undergone depolarization

• remains momentarily in a refractory state

 in myelinated fibers,
permeability changes occur only at the nodes of Ranvier,
thus causing a rapidly progressing type of jumping, or saltatory, conduction
 Con’t….
• with the exception of the local anesthetics,
– few drugs modify axonal conduction in the doses employed therapeutically

• the pufferfish poison tetrodotoxin

• and a close congener found in some shellfish, saxitoxin,

– selectively block axonal conduction by blocking the V. sensitive Na+ channel ….
– preventing the increase in Na+ permeability associated with the rising phase of the AP

• Batrachotoxin:
– extremely potent steroidal alkaloid secreted by South American frog

– increase the permeability of the Na+ channel, a persistent depolarization….cause

paralysis
 Cont’d…
• Scorpion toxins:
–peptides that inhibit the inactivation process

– cause persistent depolarization

• although not important in axonal conduction,

• Ca2+ channels in other tissues (e.g., L-type in heart) contribute to the AP

– by prolonging depolarization by an inward movement of Ca2+

• Ca2+ influx also serves as a stimulus to initiate IC events,

• Ca2+ influx is also important in

• excitation-exocytosis coupling (transmitter release)

Junctional Transmission

• the term transmission refers

– to the passage of an impulse across a synaptic or neuroeffector junction

• arrival of AP at the axonal terminals initiates a series of events

– that trigger transmission of an excitatory or inhibitory

– biochemical message across synapse or neuroeffector junction

• these events are the following:

Synthesis, storage and release of transmitter
• Nonpeptide (small-molecule) NTs, such as biogenic amines,
– are largely synthesized in axonal terminals & stored there in synaptic vesicles

• NT transport into storage vesicles

– is driven by an electrochemical gradient

– generated by the vesicular proton pump (vesicular ATPase)

• Synaptic vesicles cluster in discrete areas

– underlying the presynaptic (PM), active zones

• proteins in the vesicular membrane

– e.g., synapsin, synaptophysin, synaptogyrin

– are involved in development & trafficking of storage vesicle
– to the active zone
• via the assembly & interaction of SNARE proteins,

– vesicles draw near the membrane (docking, priming),

– spatially prepared for the next step

• SNARE proteins are proteins,

– in the memb. of the synaptic vesicle

–embedded in the inner surface of the PM,

–and several cytosolic components

• when Ca2+enters with the AP, fusion & exocytosis occur rapidly
• the processes of fusion and exocytosis involve

– the rapid entry of EC Ca2+ & its binding to synaptotagmins

• after fusion, the chaperone ATPase NSF and its SNAP adapters

– catalyze dissociation of the SNARE complex

• AP causes

– synchronous release of several hundred quanta of NT

• Synaptic vesicles may either fully exocytose with complete fusion

– or form a transient, small pore that closes after NT released,

• In “kiss-and-run” exocytosis,
– the pore closes, & the vesicle is immediately & locally recycled

– for reuse in NT repackaging

• In full-fusion exocytosis,

• the pit formed is clathrin coated & retrieved from the PM

– via endocytosis & transported to an endosome for full recycling

• During the Resting State,

– there is continual slow release of isolated quanta of the transmitter;

–this produces miniature end-plate potentials/MEPPs

– at the post-junctional membrane

– to maintain the physiological responsiveness of the effector organ

• a low level of spontaneous activity within the motor units of sk. muscle

– is particularly important

• b/c skeletal muscle lacks inherent tone

Modulation of Transmitter Release:
Presynaptic modulation
• a number of autocrine and paracrine factors
– may influence the exocytotic process,

– including the released neurotransmitter itself

–adenosine, DA, glutamate, GABA, PGs, & enkephalins

• receptors for these factors exist

–in the membranes of the soma, dendrites, and axons of neurons:

• Soma-dendritic receptors, when activated,

– primarily modify functions of the soma-dendritic region,

– such as protein synthesis and generation of AP

Presynaptic modulation…
• Negative feedback control
– is also found at the presynaptic level
• presynaptic release depends on
– the transmitter themselves
– & chemicals released by other tissues into the synapse
Homotropic inhibition
– is when a transmitter, by binding to a pre-synaptic autoreceptors,

– affects its own release from the nerve terminal

Autoreceptors are located on or close to axon terminals

– via which the neuron’s own transmitter can modify transmitter synthesis & release

– NE may interact with α2 receptors to inhibit neurally released NE

– ACh may interact with M2 & M4 receptors to inhibit neurally released Ach
• Heterotropic inhibition
– is when a neurotransmitter affects the release of another

• Heteroreceptors are presynaptic receptors

– that respond to NTs, neuromodulators, or neurohormones

– released from adjacent neurons or cells

• NE can influence the release of ACh from parasympathetic neurons

– by acting on α2A, α2B, and α2C receptors

• ACh can influence the release of NE from sympathetic neurons

– by acting on M2 and M4 receptors

2. Interaction of the NT with post-junctional receptors

– and production of the post-junctional potential

 the NTs diffuses across the synaptic or junctional cleft

 and combines with specialized receptors on the post-junctional membrane;

 this often results in a localized increase

 in the ionic permeability, or conductance, of the membrane

 with certain exceptions,

 1 of 3 types of permeability change can occur:

• Generalized increase in the permeability to cations

– (notably Na+ but occasionally Ca2+), resulting in

– a localized depolarization of the membrane, i.e., an EPSP

• Selective increase in permeability to anions, usually Cl-

– resulting in stabilization or actual hyperpolarization of the memb,

– which constitutes an IPSP

• Increased permeability to K+ (K+ directed out of the cell)

• hyperpolarization and stabilization of the membrane potential

occur (an IPSP)
3. Initiation of post-junctional activity

• if an EPSP exceeds a certain threshold value,

– it initiates a propagated AP in a postsynaptic neuron

– or a muscle AP in skeletal or cardiac muscle

• by activating voltage-sensitive channels in the immediate vicinity

• In certain smooth muscle types in which propagated impulses are minimal,

– an EPSP may increase the rate of spontaneous depolarization,

• cause Ca2+ release, and enhance muscle tone;

– in gland cells, the EPSP initiates secretion via Ca2+ mobilization

 • an IPSP, which is found in neurons and smooth muscle but not in sk. muscle

– will tend to oppose excitatory potentials

– simultaneously initiated by other neuronal sources

• whether a propagated impulse or other response ensues

– depends on the summation of all the potentials

4. Destruction or dissipation of the transmitter

• at cholinergic synapses involved in rapid neurotransmission,

– high & localized concns. of AChE are available for this purpose
• when AChE activity is inhibited,
– removal of the ACh is accomplished principally by diffusion

• under these circumstances,

– the effects of released ACh are potentiated and prolonged

• rapid termination of NE occurs

– by a combination of simple diffusion and reuptake

– by the axonal terminals of most of the released NE

• termination of the action of amino acid transmitters

– results from their active transport into neurons and surrounding glia

• Peptide NTs
– are hydrolyzed by various peptidases and dissipated by diffusion
5. Non-electrogenic functions

• the activity and turnover of enzymes involved

– in the synthesis and inactivation of NTs,

– the density of presynaptic and postsynaptic receptors,

– and other characteristics of synapses are controlled by:

– trophic actions of NTs

– or other trophic factors released by the neuron or target cells

Cholinergic Transmission
Synthesis and Storage of Ach

Choline Acetyltransferase (ClAtfrase)

 is synthesized within the perikaryon

– and then is transported along the length of the axon to its terminal

 axonal terminals contain a large number of mitochondria,

– where acetyl CoA is synthesized

Choline is taken up from the EC fluid into the axoplasm

– by active transport

the rate-limiting step in ACh biosynthesis

is the uptake of choline
Choline and Choline Transport
• the high-affinity choline transporter CHT1

– present on presynaptic membranes of cholinergic neurons

• choline transport by CHT1 is Na+ and Cl− dependent

• a low-affinity, Na+-independent transporter, CTL1

– supply choline for phospholipid synthesis

– (e.g., phosphatidyl choline, sphigomyelin)

• a lower-affinity, Na+-independent transporter,

– OCT2, found in brain & synaptic vesicles from cholinergic neurons

– Its role in neurons remains to be clarified

Storage of Ach
• ACh is transported into synaptic vesicles by the VAChT

– using the potential energy of a proton electrochemical gradient

– that a vacuolar ATPase establishes,

• such that the transport of protons out of the vesicle

– is coupled to uptake of ACh into the vesicle

– & against a concentration gradient

• there appear to be 2 types of vesicles in cholinergic terminals:

• electron-lucent vesicles and dense-cored vesicles

Cholinergic Transmission..
• the core of the vesicles contains both ACh and ATP,
– which are dissolved in the fluid phase with metal ions (Ca2+ and Mg2+ )
– and a proteoglycan called vesiculin

• Vesi cul i n , negatively charged

– and thought to sequester the Ca2+ or ACh, is bound within the vesicle,
– with the protein moiety anchoring it to the vesicular membrane

• In some cholinergic terminals, there are peptides,

– such as VIP, that act as cotransmitters

• the peptides usually are located in the dense-cored vesicles

Cholinergic Transmission…
Release of ACh

• exocytotic release of ACh and cotransmitters (e.g., ATP, VIP)

– occurs on depolarization of the nerve terminals

• botulinum toxin blocks ACh release

– by interfering with the machinery of transmitter release

• the active fragments of botulinum toxins are endopeptidases;

– the SNARE proteins are their substrates

• tetanus toxins act similarly, but in the CNS

• the active fragments of these toxins cleave synaptobrevin

– and block exocytosis in specific sets of neurons
Life cycle of Acetylcholine
 Cholinergic Transmission Characteristics at Various Sites

• D/cs among various sites of cholinergic transmission with respect to:

–architecture and fine structure

–the distributions of AChE and receptors,

–and the temporal factors involved in normal function

Skeletal Muscle
• Stimulation of a motor nerve results in the release of ACh

• the combination of ACh with NnACh receptors

– induces an immediate, marked increase in cation permeability

– about 50,000 Na+ ions traverse the channel

• the channel-opening process

– is the basis for the localized depolarizing EPP (End Plate Potential )

–which triggers the muscle AP leads to contraction

 Autonomic Effectors
• Stimulation of autonomic effector cells

– occurs on activation of MAch receptors

– the effector is coupled to the receptor by a G-protein

• Smooth muscle and the cardiac conduction system

– [SA node, atrium, AV node, and the His-Purkinje system]

– normally exhibit intrinsic activity,

– both electrical and mechanical,

– that is modulated but not initiated by nerve impulses

 Autonomic Ganglia

• cholinergic transmission in autonomic ganglia

– is similar to that at the NMJ of skeletal muscle

• activation of NnACh receptors Depolarization

• Several 2ndry transmitters enhance or diminish

– the sensitivity of the postganglionic cell to ACh

• Sensitivity appears to be related to

– the membrane potential of the postsynaptic nerve cell body

– or its dendritic branches

Prejunctional Sites
• Nerve terminal varicosities

– contain autoreceptors and heteroreceptors

• Ach acting on M2 and M4 autoreceptors

– represent a physiological negative-feedback control mechanism

• NE acting on α2A- and α2C adrenergic receptors

– inhibit Ach release

• the muscarinic autoreceptors and heteroreceptors

– also represent drug targets for both agonists and antagonists

Prejunctional Sites
• In addition to α2A- & α2C adrenergic receptors,

• other inhibitory heteroreceptors on parasympathetic terminals include:

– Adenosine A1 receptors
– Histamine H3 receptors
– Opioid receptors

• the parasympathetic nerve terminal varicosities

• also may contain additional heteroreceptors

– that could respond by inhibition or enhancement of ACh release

– by locally formed autacoids, hormones, or administered drugs

Extraneuronal Cholinergic Systems
• Ach is present in the vast majority of human cells and organs,
– epithelial cells (airways, alimentary tract, epidermis, glandular tissue)

– mesothelial and endothelial cells

– circulating cells (platelets)

– immune cells (mononuclear cells, macrophages)

• Exact function of non-neuronal ACh is not known precisely

• Proposed roles of ACh

– include the regulation of elementary cell functions:
– mitosis, locomotion, automaticity, ciliary activity, cell-cell contact, barrier
function, respiration and secretion, and regulation of lymphocyte function
Subtypes and characteristics of cholinoceptors
Cholinergic receptors
Muscarine from Amanita muscaria & nicotine from Nicotiana
tabacum
Acetylcholine
• is released at preganglionic fibers of
– both the sympathetic and parasympathetic nervous system

– also released from postganglionic sympathetic neurons

– that innervate the sweat glands

– and from motor neurons that innervate the skeletal muscles

• It is a quaternary ammonium compound

– so cannot penetrate the membrane

• does not have any therapeutic importance,

– because of multiplicity of actions and rapid inactivation by ACHase

Parasympathomimetics agents

Cholinergic drugs or cholinomimetics

• they stimulate parasympathetic NS

– in same manner as does acetylcholine

• they are useful in treating:

 alzheimer’s disease,

 myasthenia gravis, and

 atony of the smooth muscle (GIT, urinary system)

Alzheimer’s disease
– a slowly developing neurodegenerative disease

– that produce a progressive loss of memory & cognitive function, dementia

Myasthenia gravis
– an autoimmune disease in which Abs recognize Nn receptors on sk.muscle

– & decrease the number of functional receptors

– as a result the sensitivity of muscle to Ach decreased

• affect muscles of eye, mouth & throat & -xized by:

–dropping of upper eyelids
– diplopia- double vision

– difficulty of speaking & swallowing

– rapid fatigue of muscle during use

Myasthenia gravis….
• patients having more widespread muscle weakness
– are also treated with immunosuppressant drugs
– (steroids, cyclosporine, and azathioprine)

• In some patients, the thymus gland is removed;

• very severely affected patients

– may benefit from immunoglobulins and plasmapheresis

• IV immunoglobulin (IVIG) consists of immune globulins

– collected from donors
– and acts to destroy & neutralize these Abs in the bloodstream
– and block the production of new Abs
Parasympathomimetics drugs or cholinergic drugs or cholinomimetic

• classified into 2 types :

A. Direct acting: they act by binding directly to cholinoceptors

a. Endogenous choline esters : ACh

b. Synthetic choline esters e.g.: non-selective (carbachol) and M-selective

(e.g., bethanechol, methacholine)

c. Naturally occurring alkaloids eg: nicotine and pilocarpine

B. Indirect acting: act via inhibition of AchE enzyme,

– so increases ACh level in the synapse

– Reversible and Irreversible

Synthetic Direct acting cholinergics
• are lipid insoluble (40 amine)
– so effects are peripheral

• Resistant to metabolism by AchE

• Effects are longer when compared to Ach

Carbachol:
• differs from Ach only in the substitution of a carbamoyl group
• for the terminal CH3 group of Ach

– b/c of its high potency, receptor nonselectivity, and relatively long DOA,
• carbachol is rarely used

• Used in cataract surgery to induce miosis for longer time &

• sometimes effective in Rx open-angle glaucoma

– that are resistant to pilocarpine
What is glaucoma?
• a group of disease characterized by a progressive form of optic nerve damage
– associated with an increased IOP (>21 mmhg)

• Sometimes referred as ocular hypertension,

• Open-angle glaucoma (a chronic condition )

• in which the porosity of the trabecular meshwork
• is insufficient to permit the mov’t of fluid into the cannal of schlemm

• can effectively be controlled by using drugs

• Acute-angle (angle-closure) (an emergency condition

– in which an abnormal position of peripheral iris
– blocks the access of fluid to the trabecular meshwork
– drugs reduce symptoms
Rx targets two options
1. Reducing the secretion of aqueous humour
– which can be achieved by using topical drugs

– E.g., BBs (Timolol/Betaxolol eye drop) & acetazolamide

2. by promoting the drainage of the aqueous humour achieved

– by using cholinergic drugs like pilocarpine/neostigmine eye drop

• b/c parasympathetic pulls on the iris to open the trabecular meshwork

– & facilitate outflow of aqueous into the canal of schlemm & drain the fluid

 Paralytic ileus: functional obstruction of the ileum

– due to loss of intestinal movement,

– which may be caused by abdominal surgery, spinal injury or hypokalemia

 Xerostomia: dry mouth & lips due to inadequate salivary secretion

Bethanechol
• It is not hydrolysed by acetylcholinesterase

• It has strong muscarinic action, but no nicotinic action

Therapeutic uses

• Paralytic ileus since it directly stimulates M3 receptors

– causing increased intestinal motility and tone

• Urinary retentions (M3-R)

– postpartum or postoperative, diabetic autonomic neuropathy,

– and certain cases of chronic hypotonic, myogenic, or neurogenic bladder;

• when nonobstructive urinary retention

Methacoline:

• Is structurally β-methylated Ach

• renders the drug more selective

– to muscarinic receptors

– and resistant to cholinesterase activity

• Increased potency & DoA relative to Ach

• is used to identify bronchial hyper-reactivity

– in patients without clinically apparent asthma

Naturally occuring alkaloiods

• Pilocarpine, muscarine, nicotine, lobeline

– Pilocarpine, nicotine, lobeline

– are tertiary amines and can readily cross membranes,

• while muscarine, a 4nry ammonium cpd

– does not cross membranes

• excreted mainly by the kidney

• acidification of the urine accelerates clearance of the 3ry amines

Pilocarpus jaborandi
Pilocarpine:
• An alkaloid, lipid soluble and stable to hydrolysis by cholinsterases
– It has muscarinic activity only

• less potent but is uncharged and can penetrate the CNS

– at any therapeutic doses

• when applied locally to cornea produces rapid miosis (M3)

– contraction of ciliary muscle produces of spasm of accommodation

– and vision is fixed at particular distance

– and it impossible to focus for far situated objects

• Used in glaucoma (outflow obstruction of aqueous humour)

– since it facilitate the drainage

• Rx of Xerostomia that follows head & neck radiation Rx

– or that is associated with Sjögren syndrome
Cont’d…
• Sjögren syndrome, an autoimmune disorder occurring primarily in women

– in whom secretions, particularly salivary and lacrimal, are compromised

Cevimeline:
• is a muscarinic agonist that seems

– to preferentially activate M1 and M3 receptors

– on lacrimal and salivary gland epithelia

• the drug has a long-lasting sialogogic action

– and may have fewer SEs and better patient compliance than pilocarpine

– the usual dose is 30 mg TID

Adverse Effects of Direct-acting drugs

• nausea, abdominal cramps, diarrhea, salivation,

• hypotension with reflex tachycardia,

• cutaneous vasodilation, sweating,

• bronchoconstriction

• Pilocarpine can cross BBB & affect cognitive function

• Bethanechol IM or IV

– produce circulatory collapse and cardiac arrest

Toxicology

- Poisoning from the ingestion of plants containing

- pilocarpine, muscarine, or arecoline alkaloids

- is characterized chiefly by exaggeration of their various cholinergic effects

- Rx consists of the parenteral administration of atropine

- in doses sufficient to cross the BBB

- & measures to support the respiratory and CV systems

- and to counteract pulmonary edema

Indirect acting cholinergic agonists
Reversible AchE inhibitors Irreversible AchE inhibitors

– Carbamate Inhibitors: Organophosphates

– Isofluorophate
• Physostigmine, Neostigmine, Pyridostigmine
(Neostigmine congner), Ambenonium, – Diisopropyl
fluorophosphate
Rivastigmine
– Ecothiophate
– Carbamate insecticides:
– Malathion
• carbaryl, propoxur, & aldicarb – Parathion
– Edrophonium – DEP, Sarin, Soman,
tabun
– Tacrine, Danopezil, Galantamine

– propidium & snake peptidic toxin fasciculin

 Mechanism of action

• they act via inhibition of

acetylcholinesterase (AchE)

enzyme,

– so they increases Ach level in the

synapse
 Edrophonium
• Edrophonium is the prototype short-acting AChE inhibitor

• it binds reversibly to the active center of AChE, preventing hydrolysis of ACh

• It has a short DOA of 10 to 20 minutes due to rapid renal elimination

• it is a quaternary amine, and its actions are limited to the periphery

• It is used in the Dx of myasthenia gravis,

– IV injection of edrophonium leads to a rapid increase in muscle strength in

patients with myasthenia gravis

 Edrophonium cont….
• Excess drug may provoke a cholinergic crisis

–atropine is the antidote

• It may also be used to assess cholinesterase inhibitor

therapy,

–for differentiating cholinergic and myasthenic crises,

–and for reversing the effects of (NDNMBs) after surgery

• Due to the availability of other agents,

–edrophonium use has become limited
Physostigmine
• It is a tertiary amine , hence completely absorbed from the GIT

• Highly distributed throughout the body including BBB

• It has intrinsic activity on muscarnic receptors

• It is intermediate-acting (30-1hr DoA)

• Indications:

glaucoma (Open-angle) but it can cause cataracts

 overdoses of anticholinergic drugs such as atropine

 Treatment of Friedreich or other inherited ataxias

• Muscarinic stimulation can cause
– contraction of GI smooth muscles, miosis, bradycardia, and hypotension

• Nicotinic stimulation can cause

– skeletal muscle twitches, fasciculations, and skeletal muscle paralysis (at higher doses)

• It is used in the Rx of overdoses of drugs with anticholinergic actions,

atropine and to reverse the effects of NMBs

• Indicated for glaucoma(closed), atony (intestinal and bladder)

– high doses of physostigmine may lead to convulsions & bradycardia and a fall in CO

• Inhibition of AChE at the NMJ causes the accumulation of ACh

– and, ultimately via continuous depolarization, results in paralysis of skeletal muscle

• However, these effects are rarely seen with therapeutic doses

Neostigmine (Quaternary ammonium)
• Like pyridostigmine (40-amine) & ambenonium (4o-amine alcohol),
– it has additionally a direct nicotinic action on sk. muscle

• Has a intermediate duration of action, usually 2.5 to 4 Hrs.

• Poorly distributed throughout the body (cannot pass the BBB).

• poorly absorbed after PO administration

• Nevertheless, is PO active if larger doses are employed

• Its effect on skeletal muscle is greater than physostigmine,

• and it can stimulate contractility before it paralyzes

• Adverse effects:

– salivation, flushing, decreased BP, nausea, abdominal pain, diarrhea, and

bronchospasm
Neostigmine……

• Indications

–Intestinal and bladder atony

• (paralytic ileus & post operative urine retention)

–Like pyridostigmine & edrophonium,

• reversal of effect of non-depolarizing muscle relaxants, e.g. tubocurarine.

–Like pyridostigmine, for myasthenia gravis: muscle weakness

• A young man broke his leg in a skiing accident, causing severe
muscular spasm that necessitated relaxation of the muscle with a
competitive nicotinic receptor antagonist before the fracture could be
set.
• At the end of the orthopaedic procedure, the doctor restored
neuromuscular transmission by administering:
(A) Succinylcholine
(B) Carbachol
(C) Physostigmine
(D) Neostigmine