Pharmacology and

Therapeutics-ANS
By
Dr. Rita Gabriel Tulba
Pharmacy Specialist
D pharm. FPHS .SMSB
 Introduction to the Nervous System
• The nervous system is divided into two anatomical divisions:
• 1. The central nervous system (CNS), which is composed of the brain and
spinal cord, and
• 2. The peripheral nervous system, which includes neurons located outside
the brain and spinal cord that is, any nerves that enter or leave the CNS .
• The peripheral nervous system is subdivided into the
• 1. The efferent division, the neurons of which carry signals away from the
brain and spinal cord to the peripheral tissues, and
• [Link] afferent division, the neurons of which bring information from the
periphery to the CNS.
• Afferent neurons provide sensory input to modulate the function of the
efferent division through reflex arcs, that is, neural pathways that mediate a
reflex action.
• The efferent portion of the peripheral nervous system is further divided into two
major functional subdivisions, the somatic and the autonomic systems.
• [Link] somatic efferent neurons are involved in the voluntary control of functions
such as contraction of the skeletal muscles essential for locomotion.
• [Link] autonomic system regulates the everyday requirements of vital bodily
functions without the conscious participation of the mind. It is composed of
efferent neurons that innervate smooth muscle of the viscera cardiac muscle,
vasculature, and the exocrine glands, thereby controlling digestion, cardiac output,
blood flow, and glandular secretions
Organization of the nervous system
 Autonomic Nervous System
(ANS)
• The autonomic nervous system, along with the endocrine system,
coordinates the regulation and integration of bodily functions.
• The endocrine system sends signals to target tissues by varying the levels of
blood-borne hormones.
• In contrast, the nervous system exerts its influence by the rapid
transmission of electrical impulses over nerve fibers that terminate at
effector cells, which specifically respond to the release of neuromediator
substances.
Anatomy of the Autonomic Nervous system
Efferent neurons:
• The autonomic nervous system carries nerve impulses from the CNS to the effector organs
by way of two types of efferent neurons:
• The first nerve cell is called a preganglionic neuron, and its cell body is located within the
CNS. Preganglionic neurons emerge from the brainstem or spinal cord and make a synaptic
connection in ganglia (an aggregation of nerve cell bodies located in the peripheral nervous
system). These ganglia function as relay stations between a preganglionic neuron and a
second nerve cell.
• The second nerve postganglionic neuron. The latter neuron has a cell body originating in
the ganglion. It is generally nonmyelinated and terminates on effector organs, such as
smooth muscles of the viscera, cardiac muscle, and the exocrine glands.
Afferent neurons:
• The afferent neurons (fibers) of the autonomic nervous system are
important in the reflex regulation of this system (for example, by sensing
pressure in the carotid sinus and aortic arch) and signaling the CNS to
influence the efferent branch of the system to respond.
The efferent autonomic nervous system is divided into:
• The sympathetic.
• The parasympathetic nervous systems.
• The enteric nervous system .
Anatomically, they originate in the CNS and emerge from two different spinal
cord regions.
Sympathetic neurons:
• The preganglionic neurons of the sympathetic system come from thoracic
and lumbar regions of the spinal cord, and they synapse in two cord-like
chains of ganglia that run in parallel on each side of the spinal cord.
• The preganglionic neurons are short in comparison to the postganglionic
ones. Axons of the postganglionic neuron extend from these ganglia to the
tissues that they innervate and regulate.
Parasympathetic neurons:
• The parasympathetic preganglionic fibers arise from the cranium (from cranial
nerves III, VII, IX, and X) and from the sacral region of the spinal cord and
synapse in ganglia near or on the effector organs.
• In contrast to the sympathetic system, the preganglionic fibers are long, and the
postganglionic ones are short, with the ganglia close to or within the organ
innervated.
• In most instances there is a one-to-one connection between the preganglionic and
postganglionic neurons, enabling the discrete response of this division
Enteric neurons:
• The enteric nervous system is the third division of the autonomic nervous system.
• It is a collection of nerve fibers that innervate the gastrointestinal tract, pancreas,
and gallbladder, and it constitutes the brain of the gut.
• This system functions independently of the CNS and controls the motility, exocrine
and endocrine secretions, and microcirculation of the gastrointestinal tract.
• It is modulated by both the sympathetic and parasympathetic nervous systems.
Functions of the Sympathetic nervous system

• The sympathetic division has the property of adjusting in response to stressful

situations, such as trauma, fear, hypoglycemia, cold, or exercise.
Effects of stimulation of the sympathetic division:
1. Increase heart rate and blood pressure.
2. Mobilize energy stores of the body, and to increase blood flow to skeletal muscles
and the heart while diverting flow from the skin and internal organs.
3. Dilation of the pupils and the bronchioles.
4. Affects gastrointestinal motility and the function of the bladder and sexual organs.
Fight or flight response: The changes experienced by the body during emergencies have been
referred to as the fight or flight response .
• These reactions are triggered both by direct sympathetic activation of the effector organs and by:
• stimulation of the adrenal medulla to release epinephrine and lesser amounts of norepinephrine.
• These hormones enter the bloodstream and promote responses in effector organs that contain
adrenergic receptors .
• The sympathetic nervous system tends to function as a unit, and it often discharges as a complete
system for example, during severe exercise or in reactions to fear . This system, is involved in a
wide array of physiologic activities, but it is not essential for life.
 Functions of the Parasympathetic nervous
system
The parasympathetic division maintains essential bodily functions, such as:
• Digestive processes and elimination of wastes, and is required for life.
• It usually acts to oppose or balance the actions of the sympathetic division and is
generally dominant over the sympathetic system in rest and digest situations.
• The parasympathetic system is not a functional entity as such, and it never
discharges as a complete system.
• If it did, it would produce massive, undesirable, and unpleasant symptoms.
• Instead, discrete parasympathetic fibers are activated separately, and the system
functions to affect specific organs, such as the stomach or eye
Action of sympathetic and parasympathetic nervous
systems on effector organs
 Role of the CNS in autonomic control
functions
• Although the autonomic nervous system is a motor system, it does require sensory
input from peripheral structures to provide information on the state of affairs in the
body.
• This feedback is provided by streams of afferent impulses, originating in the
viscera and other autonomically innervated structures, that travel to integrating
centers in the CNS.
• That is, the hypothalamus, medulla oblongata, and spinal cord.
• These centers respond to the stimuli by sending out efferent reflex impulses
via the autonomic nervous system
1. Reflex arcs:
• Most of the afferent impulses are translated into reflex responses without involving
consciousness.
• For example, a fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the
heart, vena cava, aortic arch, and carotid sinuses) to send fewer impulses to cardiovascular centers
in the brain.
• This prompts a reflex response of increased sympathetic output to the heart and vasculature and
decreased parasympathetic output to the heart, which results in a compensatory rise in blood
pressure and tachycardia
2. Emotions and the autonomic nervous system: Stimuli that evoke feelings of strong emotion,
such as rage, fear, or pleasure, can modify the activity of the autonomic nervous system.
Baroreceptor reflex arc responds to a decrease
in blood pressure
 Innervation by the autonomic nervous system
1. Dual innervation:
• Most organs in the body are innervated by both divisions of the autonomic nervous system.
• Thus, vagal parasympathetic innervation slows the heart rate, and sympathetic innervation
increases the heart rate.
• Despite this dual innervation, one system usually predominates in controlling the activity of
a given organ.
• For example in the heart, the vagus nerve is the predominant factor for controlling rate.
This type of antagonism is considered to be dynamic and is fine-tuned at any given time to
control homeostatic organ functions.
2. Organs receiving only sympathetic innervation:
• Although most tissues receive dual innervation, some effector organs, such
as the adrenal medulla, kidney, pilomotor muscles, and sweat glands, receive
innervation only from the sympathetic system.
• The control of blood pressure is also mainly a sympathetic activity, with
essentially no participation by the parasympathetic system.
 Somatic nervous system
• The efferent somatic nervous system differs from the autonomic system in
that a single myelinated( myelin sheath allow the quick transmit of impulses
along the verve cell) motor neuron, originating in the CNS, travels directly to
skeletal muscle without the mediation of ganglia.
• As noted earlier, the somatic nervous system is under voluntary control,
whereas the autonomic is an involuntary system.
 Chemical Signaling Between Cells
• Neurotransmission in the autonomic nervous system is an example of the
more general process of chemical signaling between cells.
• In addition to neurotransmission, other types of chemical signaling are the
release of local mediators and the secretion of hormones
1. Local mediators:
• Most cells in the body secrete chemicals that act locally that is, on cells in
their immediate environment.
• These chemical signals are rapidly destroyed or removed; therefore, they do
not enter the blood and are not distributed throughout the body.
• Histamine and the prostaglandins are examples of local mediators
[Link] :
• Specialized endocrine cells secrete hormones into the bloodstream, where
they travel throughout the body exerting effects on broadly distributed target
cells in the body.
 [Link]
• Communication between nerve cells and between nerve cells and effector organs
occurs through the release of specific chemical signals, called neurotransmitters,
from the nerve terminals.
• This release is triggered by the arrival of the action potential at the nerve ending,
leading to depolarization.
• Uptake of Ca2+ initiates fusion of the synaptic vesicles with the presynaptic
membrane and release of their contents.
• The neurotransmitters rapidly diffuse across the synaptic cleft or space (synapse)
between neurons and combine with specific receptors on the postsynaptic (target)
cell
 Types of neurotransmitters:
• Although over fifty signal molecules in the nervous system have tentatively been
identified
• six signal compounds norepinephrine ,acetylcholine, dopamine, serotonin,
histamine, and γ-aminobutyric acid are most commonly involved in the actions of
therapeutically useful drugs.
• Each of these chemical signals binds to a specific family of receptors.
Acetylcholine and norepinephrine are the primary chemical signals in the autonomic
nervous system, whereas a wide variety of neurotransmitters function in the CNS.
• Not only are these neurotransmitters released on nerve stimulation, cotransmitters,
such as adenosine, often accompany them and modulate the transmission process
Acetylcholine:
• The autonomic nerve fibers can be divided into two groups based on the chemical
nature of the neurotransmitter released.
• If transmission is mediated by acetylcholine, the neuron is termed cholinergic .
• Acetylcholine mediates the transmission of nerve impulses across autonomic
ganglia in both the sympathetic and parasympathetic nervous systems.
• In the somatic nervous system, transmission at the neuromuscular junction (that is,
between nerve fibers and voluntary muscles) is also cholinergic
Norepinephrine and epinephrine:
• When norepinephrine or epinephrine is the transmitter, the fiber is termed
adrenergic (adrenaline being another name for epinephrine).
• In the sympathetic system, norepinephrine mediates the transmission of
nerve impulses from autonomic postganglionic nerves to effector organs.
 Second Messenger Systems in Intracellular
Response
• The binding of chemical signals to receptors activates enzymatic processes within
the cell membrane that ultimately result in a cellular response, such as the
phosphorylation of intracellular proteins or changes in the conductivity of ion
channels.
• A neurotransmitter can be thought of as a signal and a receptor as a signal detector
and transducer.
• Second-messenger molecules, produced in response to neurotransmitter binding to
a receptor, translate the extracellular signal into a response that may be further
propagated or amplified within the cell
• Second-messenger molecules so named because they intervene between the
original message (the neurotransmitter or hormone) and the ultimate effect
on the cell .
• Are part of the cascade of events that translates neurotransmitter binding
into a cellular response, usually through the intervention of a G protein.
• The two most widely recognized second messengers are the adenylyl cyclase
system and the calcium/phosphatidylinositol system
 Autonomic Nervus system Drugs
• Are Drugs that produce their primary therapeutic effect by mimicking or
altering the functions of the autonomic nervous system.
• These autonomic agents act either by stimulating portions of the autonomic
nervous system or by blocking the action of the autonomic nerves.
• Drugs affecting the autonomic nervous system are divided into two groups
according to the type of neuron involved in their mechanism of action. The
cholinergic drugs and adrenergic drugs
 Cholinergic Agonists
Direct-Acting Cholinergic Agonists Cholinergic agonists:
• Also known as parasympathomimetics mimic the effects of acetylcholine by binding
directly to cholinoceptors.
• These agents may be broadly classified into two groups:
• Choline esters, which include acetylcholine.
• Synthetic esters of choline, such as carbachol and bethanechol.
• All of the direct-acting cholinergic drugs have longer durations of action than acetylcholine.
• Some of the more therapeutically useful drugs pilocarpine and bethanechol
 [Link] Acetylcholine:
• Is a quaternary ammonium compound that cannot penetrate membranes
• It is therapeutically of no importance because of its multiplicity of actions and its
rapid inactivation by the cholinesterases.
• Its actions include:
1. Decrease in heart rate and cardiac output: The actions of acetylcholine on the heart
mimic the effects of vagal stimulation negative chronotropy
[Link] in blood pressure: Injection of acetylcholine causes vasodilation and
lowering of blood pressure by an indirect mechanism of action.
• Other actions:
• In the gastrointestinal tract, acetylcholine increases salivary secretion and
stimulates intestinal secretions and motility.
• Bronchiolar secretions are also enhanced.
• In the genitourinary tract, the tone muscle is increased, causing expulsion of
urine.
• In the eye, causing miosis
[Link] :
• Is structurally related to acetylcholine
• It is not hydrolyzed by acetylcholinesterase (due to the addition of carbonic
acid),
• Its major actions are on the smooth musculature of the bladder and
gastrointestinal tract.
• It has a duration of action of about 1 hour.
Actions:
• Bethanechol directly stimulates muscarinic receptors, causing increased intestinal motility and tone.
• It also stimulates the detrusor muscles of the bladder whereas the trigone and sphincter are relaxed, causing
expulsion of urine.
Therapeutic applications:
• In urologic treatment, particularly in postpartum or postoperative, nonobstructive urinary retention.
Adverse effects:
• These include sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and
bronchospasm.
[Link] :
• has both muscarinic as well as nicotinic actions
Actions:
• Carbachol has profound effects on both the cardiovascular system and the gastrointestinal system because of
its ganglion-stimulating activity, and it may first stimulate and then depress these systems.
Therapeutic uses:
• In the eye as a miotic agent to treat glaucoma by causing pupillary contraction and a decrease in intraocular
pressure.
Adverse effects: At doses used ophthalmologically, little or no side effects occur due to lack of systemic
penetration (quaternary amine)
[Link]
• Exhibits muscarinic activity and is used primarily in ophthalmology.
Actions: Applied topically to the cornea, pilocarpine produces a rapid miosis and contraction of the ciliary muscle.
Therapeutic use in glaucoma: Pilocarpine is the drug of choice in the emergency lowering of intraocular pressure of both
narrow-angle (also called closed-angle) and wide-angle (also called open-angle) glaucoma. causing an immediate drop in
intraocular pressure as a result of the increased drainage of aqueous humor. This action lasts up to 8 hours and can be repeated
• Note: Carbonic anhydrase inhibitors, such as acetazolamide, as well as the beta adrenergic blocker timolol, are effective in
treating glaucoma chronically but are not used for emergency lowering of intraocular pressure.
Adverse effects:
• Pilocarpine can enter the brain and cause CNS disturbances.
• It stimulates profuse sweating and salivation.
Indirect-Acting Cholinergic Agonsists: Anticholinesterases (Reversible)
• Acetylcholinesterase is an enzyme that specifically cleaves acetylcholine to acetate and choline
and, thus, terminates its actions.
• It is located both pre- and postsynaptically in the nerve terminal, where it is membrane bound.
• Inhibitors of acetylcholinesterase indirectly provide a cholinergic action by prolonging the
lifetime of acetylcholine produced endogenously at the cholinergic nerve endings.
• This results in the accumulation of acetylcholine in the synaptic space .
• These drugs can thus provoke a response at all cholinoceptors in the body, including both
muscarinic and nicotinic receptors of the autonomic nervous system, as well as at neuromuscular
junctions and in the brain.
Mechanisms of action of indirect (reversible)
cholinergic agonists
[Link]
Actions: Physostigmine has a wide range of effects as a result of its action
• Its duration of action is about 2 to 4 hours, and it is considered to be an intermediate-acting
agent.
Therapeutic uses: The drug increases intestinal and bladder motility.
• Placed topically in the eye to treat glaucoma, but pilocarpine is more effective.
• Physostigmine is also used in the treatment of overdoses of drugs with anticholinergic actions,
such as atropine, phenothiazines, and tricyclic antidepressants.
Adverse effects: The effects of physostigmine on the CNS may lead to convulsions when high
doses are used. Bradycardia and a fall in cardiac output may also occur
[Link]
• Is a synthetic compound that is it reversibly inhibits acetylcholinesterase in a manner similar to that of physostigmine.
• Is more polar and does not enter the CNS.
• Neostigmine has a moderate duration of action, usually 30 minutes to 2 hours.
• It is used to stimulate the bladder and GI tract, and
• it is also used as an antidote for tubocurarine and other competitive neuromuscular blocking agents
• Neostigmine has found use in symptomatic treatment of myasthenia gravis, an autoimmune disease caused by antibodies to
the nicotinic receptor at neuromuscular junctions. This causes their degradation and, thus, makes fewer receptors available
for interaction with the neurotransmitter.
Adverse effects: of neostigmine include those of generalized cholinergic stimulation, such as salivation, flushing, decreased
blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm.
• Neostigmine does not cause CNS side effects
[Link] and ambenomium:
• Other cholinesterase inhibitors that are used in the chronic management of
myasthenia gravis.
• Their durations of action are intermediate (3 to 6 hours and 4 to 8 hours,
respectively), but longer than that of neostigmine.
• Adverse effects of these agents are similar to those of neostigmine.
[Link]: used to treat chronic open-angle glaucoma.
[Link], donepezil, rivastigmine, and galantamine :
• Patients with Alzheimer's disease have a deficiency of cholinergic neurons in the CNS.
• This observation led to the development of anticholinesterases as possible remedies for the
loss of cognitive function.
• Tacrine was the first to become available, but it has been replaced by the others because of
its hepatotoxicity.
• Donepezil , Rivastigmine and Galantamine can delay the progression of the disease.
Adverse effect :Gastrointestinal distress is their primary.
Indirect-Acting Cholinergic Agonsists: Anticholinesterases (Irreversible)
• A number of synthetic organophosphate compounds have the capacity to bind
covalently to acetylcholinesterase.
• The result is a long-lasting increase in acetylcholine at all sites where it is released.
• Many of these drugs are extremely toxic and were developed by the military as
nerve agents.
• Related compounds, such as parathion, are employed as insecticides.
[Link] :
• Mechanism of action: Echothiophate is an organophosphate that covalently binds acetylcholinesterase .
• Once this occurs, the enzyme is permanently inactivated.
• Actions: Actions include paralysis of motor function (causing breathing difficulties), and convulsions. Echothiophate
produces intense miosis and, thus, has found therapeutic use.
• Atropine in high dosage can reverse many of the muscarinic and some of the central effects of echothiophate.
• Therapeutic uses: An ophthalmic solution of the drug is used directly in the eye for the chronic treatment of open-angle
glaucoma. The effects may last for up to one week after a single administration. Echothiophate is not a first-line agent in
the treatment of glaucoma.
• Reactivation of acetylcholinesterase: Pralidoxime can reactivate inhibited acetylcholinesterase. However, it is unable to
penetrate into the CNS.
Summary of actions of some cholinergic
agonists
 Cholinergic Antagonists
• The cholinergic antagonists also called cholinergic blockers, parasympatholytics or anticholinergic
drugs.
• bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects.
• The most useful of these agents selectively block muscarinic synapses of the parasympathetic
nerves. The effects of parasympathetic innervation are thus interrupted, and the actions of
sympathetic stimulation are left unopposed.
• A second group of drugs, the ganglionic blockers, show a preference for the nicotinic receptors
of the sympathetic and parasympathetic ganglia.
• A third family of compounds, the neuromuscular blocking agents, interfere with transmission of
efferent impulses to skeletal muscles. These agent are used as adjuvants in anesthesia during
surgery.
 [Link] Agents
• Commonly known as antimuscarinics, these agents (for example, atropine
and scopolamine)
• Block muscarinic receptors causing inhibition of all muscarinic functions.
• In addition, these drugs block the few exceptional sympathetic neurons that
are cholinergic, such as those innervating salivary and sweat glands.
Sites of actions of cholinergic antagonists
[Link]:
• Has a high affinity for muscarinic receptors, where it binds competitively, preventing
acetylcholine from binding to those sites .
• Atropine acts both centrally and peripherally.
• Its general actions last about 4 hours except when placed topically in the eye, where the
action may last for days.
• Actions: Eye: Atropine blocks all cholinergic activity on the eye, resulting in persistent
mydriasis (dilation of the pupil, unresponsiveness to light), and cycloplegia (inability to focus
for near vision).
• In patients with narrow-angle glaucoma, intraocular pressure may rise dangerously.
• Gastrointestinal (GI): Atropine can be used as an antispasmodic to reduce
activity of the GI tract. Atropine and scopolamine
• Urinary system: Atropine is also employed to reduce hypermotility states of
the urinary bladder.
• Cardiovascular: Atropine produces divergent effects on the cardiovascular system,
depending on the dose:
• At low doses, the predominant effect is a decreased cardiac rate (bradycardia). Originally
thought to be due to central activation of vagal efferent outflow, the effect is now known to
result from blockade of the M1 receptors on the inhibitory (or presynaptic) neurons, thus
permitting increased acetylcholine release.
• With higher doses of atropine, the M2 receptors on the sinoatrial node are blocked, and the
cardiac rate increases modestly.
• Secretions: Atropine blocks the salivary glands, producing a drying effect on the oral
mucous membranes (xerostomia). Sweat and lacrimal glands are also affected. [Note:
Inhibition of secretions by sweat glands can cause elevated body temperature.]
Therapeutic uses:
[Link]: in the eye topical atropine exerts both mydriatic and cycloplegic effects, and it permits the
measurement of refractive errors without interference by the accommodative capacity of the eye.
[Link]: Atropine is used as an antispasmodic agent to relax the GI tract and bladder.
[Link] for cholinergic agonists: Atropine is used for the treatment of overdoses of cholinesterase inhibitor
insecticides and some types of mushroom poisoning (certain mushrooms contain cholinergic substances that
block cholinesterases). Massive doses of the antagonist may be required over a long period of time to counteract
the poisons. The ability of atropine to enter the central nervous system (CNS) is of particular importance.
[Link]: The drug is sometimes used as an antisecretory agent to block secretions in the upper and lower
respiratory tracts prior to surgery.
• Pharmacokinetics:
[Link] is readily absorbed, partially metabolized by the liver, and eliminated
primarily in the urine.
[Link] has a half-life of about 4 hours.
• Adverse effects: Depending on the dose, atropine may cause
[Link] mouth,
[Link] vision,
[Link], and constipation.
• Effects on the CNS include:
• Restlessness, confusion, hallucinations, and delirium, which may progress to
depression, collapse of the circulatory and respiratory systems, and death.
• Low doses of cholinesterase inhibitors such as physostigmine may be used to
overcome atropine toxicity.
• In older individuals, the use of atropine may exacerbate an attack of glaucoma in
someone with a latent condition. In other older individuals, atropine may induce
urinary retention. Children are sensitive to effects of atropine in particular, the rapid
increases in body temperature that it may elicit. This may be dangerous in children
2. Scopolamine:
• produces peripheral effects similar to those of atropine. However, scopolamine has greater action
on the CNS (unlike with atropine, CNS effects are observed at therapeutic doses) and a longer
duration of action in comparison to those of atropine
Actions:
• anti motion sickness
• sedation, but at higher doses it can produce euphoria and is subject to abuse.
• Therapeutic uses:
• prevention of motion sickness and to blocking short-term memory (amnesic action ) of
scopolamine makes it an important adjunct drug in anesthetic procedures
[Link]
• Inhaled ipratropium a quaternary derivative of atropine.
• Is useful in treating asthma in patients who are unable to take adrenergic agonists.
• Ipratropium is also beneficial in the management of chronic obstructive pulmonary disease.
• Because of its positive charge, it does not enter the systemic circulation or the CNS.
[Link] and cyclopentolate: These agents are used as ophthalmic solutions for similar
conditions as atropine (mydriasis and cyclopegia). Their duration of action is shorter than that
of atropine; tropicamide produces mydriasis for 6 hours and cyclopentolate for 24 hours.
Competition of atropine and scopolamine with
acetylcholine for the muscarinic receptor
 [Link] Blockers
• Ganglionic blockers specifically act on the nicotinic receptors of both
parasympathetic and sympathetic autonomic ganglia.
• Some also block the ion channels of the autonomic ganglia.
• Are not effective as neuromuscular antagonists.
• The responses observed are complex and unpredictable, making it impossible to
achieve selective actions.
• Therefore, ganglionic blockade is rarely used therapeutically. However, ganglionic
blockers often serve as tools in experimental pharmacology.
[Link]
• A component of cigarette smoke, nicotine is a poison with many undesirable actions.
• It is without therapeutic benefit and is deleterious to health.
• The drug is absorbed and is effective in reducing the craving for nicotine in people who wish to stop
smoking.
• Depending on the dose, nicotine depolarizes autonomic ganglia, resulting first in stimulation and then in
paralysis of all ganglia.
• The stimulatory effects are complex due to effects on both sympathetic and parasympathetic ganglia.
• The effects include increased blood pressure and cardiac rate and increased peristalsis and secretions.
• At higher doses, the blood pressure falls because of ganglionic blockade, and activity both in the GI tract
and bladder musculature ceases
[Link]:
• Produces a competitive nicotinic blockade of the ganglia.
• The duration of action is about 10 hours after a single administration.
• The uptake of the drug via oral absorption is good.
• Used in treatment of moderate to sever hypertension.
 [Link] Blocking Drugs
• These drugs block cholinergic transmission between motor nerve endings and the
nicotinic receptors on the neuromuscular end plate of skeletal muscle.
• These neuromuscular blockers are structural analogs of acetylcholine, and they act
either as antagonists (nondepolarizing type) or agonists (depolarizing type) at
the receptors on the end plate of the neuromuscular junction.
• Neuromuscular blockers are clinically useful during surgery for producing complete
muscle relaxation, without having to employ higher anesthetic doses to achieve
comparable muscular relaxation.
• Agents are also useful in facilitating intubation as well.
Nondepolarizing (competitive) blockers:
These agents compete with acetylcholine at the receptor without stimulating the receptor.
• The first drug that was found to be capable of blocking the skeletal neuromuscular junction was curare,
which the native hunters of the Amazon in South America used to paralyze game.
1. Tubocurarine :
• Considered to be the prototype agent in this class.
• The neuromuscular blocking agents have significantly increased the safety of anesthesia, because less
anesthetic is required to produce muscle relaxation, allowing patients to recover quickly and completely
after surgery.
• Note: Higher doses of anesthesia may produce respiratory paralysis and cardiac depression, increasing
recovery time after surgery.
Mechanism of action:
• At low doses: Nondepolarizing neuromuscular blocking drugs interact with the nicotinic receptors to
prevent the binding of acetylcholine. These drugs thus prevent depolarization of the muscle cell membrane
and inhibit muscular contraction.
• Their action can be overcome by increasing the concentration of acetylcholine in the synaptic gap for
example, by administration of cholinesterase inhibitors, such as neostigmine, pyridostigmine, or
edrophonium.
• Anesthesiologists often employ this strategy to shorten the duration of the neuromuscular blockade.
• At high doses: Nondepolarizing blockers can block the ion channels of the end plate. This leads to further
weakening of neuromuscular transmission, and it reduces the ability of acetylcholinesterase inhibitors to
reverse the actions of nondepolarizing muscle relaxants.
Actions:
• Contraction of Small, rapidly contracting muscles of the face and eye are most susceptible
and are paralyzed first, followed by the fingers. Thereafter, the limbs, neck, and trunk
muscles are paralyzed. Then the intercostal muscles are affected, and lastly, the diaphragm
muscles are paralyzed.
• Those agents which release histamine, can produce a fall in blood pressure, flushing, and
bronchoconstriction.
Therapeutic uses: Tubocurarine, Mivacurium, and Atracurium : These blockers are used
therapeutically as adjuvant drugs in anesthesia during surgery to relax skeletal muscle. These
agents are also used to facilitate intubation as well as during orthopedic surgery.
Pharmacokinetics:
• All agents are injected intravenously.
• They penetrate membranes very poorly and do not enter cells or cross the blood-brain barrier.
• Many of the drugs are not metabolized; their actions are terminated by redistribution .
• For example, tubocurarine, pancuronium, mivacurium, metocurine, and doxacurium are excreted in
the urine unchanged.
• Atracurium is degraded spontaneously in the plasma and by ester hydrolysis.
• Vecuronium and rocuronium are deacetylated in the liver,.
• The choice of an agent will depend on how quickly muscle relaxation is needed and on the duration of the
muscle relaxation.
• Adverse effects: In general, agents are safe with minimal side effects
• Drug interactions:
• Cholinesterase inhibitors: Drugs such as neostigmine, physostigmine, pyridostigmine, and edrophonium can
overcome the action of nondepolarizing neuromuscular blockers.
• Halogenated hydrocarbon anesthetics: Drugs such as halothane act to enhance neuromuscular blockade by
exerting a stabilizing action at the neuromuscular junction
• Aminoglycoside antibiotics: Drugs such as gentamicin or tobramycin inhibit acetylcholine release from
cholinergic nerves by competing with calcium ions. They synergize with tubocurarine and other competitive
blockers, enhancing the blockade.
• Calcium-channel blockers: These agents may increase the neuromuscular block of tubocurarine and other
competitive blockers as well as depolarizing blockers.
Depolarizing agents:
[Link]
• Mechanism of action: The depolarizing neuromuscular blocking drug attaches to
the nicotinic receptor and acts like acetylcholine to depolarize the junction .
• Unlike acetylcholine, which is instantly destroyed by acetylcholinesterase, the
depolarizing agent persists at high concentrations in the synaptic cleft, remaining
attached to the receptor for a relatively longer time and providing a constant
stimulation of the receptor.
• Actions: The sequence of paralysis may be slightly different, but as with the competitive
blockers, the respiratory muscles are paralyzed last
• Therapeutic uses: succinylcholine is useful when rapid endotracheal intubation is required
during the induction of anesthesia
• A rapid action is essential if aspiration of gastric contents is to be avoided during intubation.
• It is also employed during electroconvulsive shock treatment.
• Pharmacokinetics: Succinylcholine is injected intravenously.
• Its brief duration of action (several minutes) results from redistribution and rapid hydrolysis by
plasma cholinesterase.
• It therefore is usually given by continuous infusion.
Adverse effects:
• Hyperthermia
• Apnea: Administration of succinylcholine to a patient who is genetically
deficient in plasma cholinesterase or has an atypical form of the enzyme can
lead to prolonged apnea due to paralysis of the diaphragm.
• Hyperkalemia: Succinylcholine increases potassium release from intracellular
stores.
Mechanism of action of competitive
neuromuscular blocking drugs
Summary of cholinergic antagonists
THANK YOU
DR. RITA GABRIEL TULBA
Email: rita.tulba1969@[Link]
Tel:+211912838737