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Dr.

Sukanta Sen
Professor
Dept. of Pharmacology
IIMSAR, Haldia
Nervous
Nervous System
System

CNS
CNS PNS
PNS

Autonomic
Autonomic Somatic
Somatic

Sympathetic
Sympathetic Parasympathetic
Parasympathetic
 The autonomic nervous system (ANS) is the primary moment-
to-moment regulator of the internal environment of the organism,
regulating specific functions that occur without conscious
control, for example,

 respiration,

 circulation,

 digestion,

 body temperature,

 metabolism,

 sweating, and the secretions of certain endocrine glands.


 In the periphery, the ANS consists of nerves, ganglia, and
plexuses that innervate the heart, blood vessels, glands, other
visceral organs, and smooth muscle in various tissues.

 Based on considerations of anatomy and neurotransmitters, we


divide the ANS into sympathetic and parasympathetic
branches.
DIFFERENCES BETWEEN AUTONOMIC &
SOMATIC NERVES
 The efferent nerves of the ANS supply all innervated
structures of the body except skeletal muscle, which is served
by somatic nerves.

 The most distal synaptic junctions in the autonomic reflex arc


occur in ganglia that are entirely outside the cerebrospinal axis.

 Somatic nerves contain no peripheral ganglia, and the synapses


are located entirely within the cerebrospinal axis.
 Many autonomic nerves form extensive peripheral plexuses;
such networks are absent from the somatic system.

 Postganglionic autonomic nerves generally are


nonmyelinated; motor nerves to skeletal muscles are
myelinated.

 When the spinal efferent nerves are interrupted, smooth


muscles and glands generally retain some level of spontaneous
activity, whereas the denervated skeletal muscles are
paralyzed.
ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM
❑The sympathetic (thoracolumbar) division

and the parasympathetic (craniosacral) division.

❑ Both divisions originate in nuclei within the central


nervous system and give rise to preganglionic efferent
fibers that exit from the brain stem or spinal cord and
terminate in motor ganglia.
 The sympathetic preganglionic fibers leave the central
nervous system through the thoracic and lumbar spinal
nerves.

 The parasympathetic preganglionic fibers leave the central


nervous system through the cranial nerves (especially the
third, seventh, ninth, and tenth) and the third and fourth
sacral spinal roots.
 Most of the sympathetic preganglionic fibers
terminate in ganglia located in the
paravertebral chains that lie on either side of
the spinal column.
 The majority of parasympathetic
preganglionic fibers terminate on ganglion
cells distributed diffusely or in networks in the
walls of the innervated organs.
 The enteric nervous system (ENS) is a large and highly
organized collection of neurons located in the walls of the
gastrointestinal system .
 It is sometimes considered a third division of the ANS.
 The ENS includes the myenteric plexus (the plexus of Auerbach)
and the submucous plexus (the plexus of Meissner).
 The muscle layers of the GI tract are dually innervated by
excitatory and inhibitory motor neurons with cell bodies
primarily in the myenteric ganglia.
 ACh is a primary excitatory motor neurotransmitter released from
postganglionic neurons.
 ACh activates M2 and M3 receptors in postjunctional cells to
elicit motor responses.
 The parasympathetic system, organized mainly for
discrete and localized discharge,

➢ slows the heart rate,

➢ lowers the blood pressure,

➢ stimulates GI movements and secretions,

➢ aids absorption of nutrients,

➢ protects the retina from excessive light, and

➢ empties the urinary bladder and rectum.


Neurotransmitters
 The neurotransmitter of all preganglionic autonomic fibers, all
postganglionic parasympathetic fibers, and a few postganglionic
sympathetic fibers is acetylcholine (ACh).
 Some postganglionic parasympathetic nerves use nitric oxide (NO)
and are referred to as nitrergic.
• Adrenergic fibers comprise the majority of the postganglionic
sympathetic fibers; here, the transmitter is norepinephrine (NE,
noradrenaline).
• Substance P and glutamate may also mediate many afferent
impulses.
COMPARISON OF SYMPATHETIC, PARASYMPATHETIC,
& MOTOR NERVES
 The sympathetic system is distributed to effectors throughout the
body, whereas parasympathetic distribution is much more
limited.
 A preganglionic sympathetic fiber may traverse a considerable
distance of the sympathetic chain and pass through several
ganglia before it finally synapses with a postganglionic neuron;
also, its terminals make contact with a large number of
postganglionic neurons.
 The parasympathetic system has terminal ganglia very near or
within the organs innervated and is generally more
circumscribed in its influences.
Somatic
Motor Fiber Skeletal
Ach Muscle
Sympathetic Ganglion Smooth Muscle
Postganglionic Fiber;
Adrenergic Cardiac Cells
Ac NGland Cells
h E
Sympathetic Ganglion
Sweat
Ac Ach
Glands
h
Sympathetic
EPI/NE
Ac
Smooth Muscle
Para-
h Adrenal Gland
Cardiac Cells
sympathetic Ganglio Gland Cells
n Ac Ach
h
Parasympathetic Nervous System (Craniosacral Outflow)
SA & AV Node Bronchi/Bronchial
Sphincter Muscle of Iris Glands
Ciliary Muscle Stomach

Small Intestines
Lacrimal Gland
Bile Ducts
Gallbladder

Submaxillary & Kidney


Sublingual
Glands Large Intestines

Bladder
Parotid Gland
Genitalia
NEUROTRANSMISSION
•Nerve impulses elicit responses in smooth, cardiac, and skeletal
muscles, exocrine glands, and postsynaptic neurons by liberating
specific chemical neurotransmitters.
•Neurohumoral transmission relates to the transmission of
impulses from postganglionic autonomic fibers to effector
cells.
STEPS INVOLVED IN NEUROTRANSMISSION
The sequence of events involved in neurotransmission is of particular importance
because pharmacologically active agents modulate the individual steps.
AXONAL CONDUCTION: At rest, the interior of the typical mammalian axon
is ~70 mV negative to the exterior.
In response to depolarization to a threshold level, an action potential is initiated at
a local region of the membrane.
The action potential consists of 2 phases. Following depolarization that induces
an open conformation of the channel, the initial phase is caused by a rapid
increase in the permeability and inward movement of Na+ through voltage-
sensitive Na+ channels, and a rapid depolarization from the resting potential
continues to a positive overshoot.
The second phase results from the rapid inactivation of the Na+ channel and the
delayed opening of a K+ channel, which permits outward movement of K+ to
terminate the depolarization.
JUNCTIONAL TRANSMISSION:
The arrival of the action potential at the axonal terminals initiates
events that trigger transmission of an excitatory or inhibitory
impulse across the synapse or neuroeffector junction.
Acetylcholine:
•Chemically, Ach is the acetic acid ester of choline.
•Ach is synthesized in the axonal terminal from choline and
acetylcoenzyme(Acetyl-CoA) by the cytosolic enzyme choline
acetyltransferase( ChAT).
•Acetyl CoA is synthesized from pyruvate in mitochondria.
•Choline is transported from ECF by a high affinity Na+-dependent
–choline transport protein-is the rate limiting steps.
• Ach storage at in vesicles.
•Release: in the presence of AP at the nerve terminal causes influx of
Ca++ ions, which trigger the release of Ach by exocytosis.
SUMMARY OF CHOLINERGIC NEUROTRANSMISSSION

Neuroeffector Junction

Parasympathetic/Sympathetic Parasympathetic or
Preganglionic Fiber or Sympathetic
Parasympathetic Postganglionic Postganglionic Fiber
Fiber or Effector Cell
Metabolism (termination of action):
•Ach is hydrolysed by an enzyme called acetylcholinesterase (AChE)to
choline and acetic acid.
•Choline is then recycled in Ach biosynthesis.
•Cholinergic synapse is very rich of AChE, therefore plasma t1/2 of ACh is
very short (few seconds).
•Two types of AChEs-
➢true acetylcholine esterase and
➢plasma choline esterase(pseudo cholinesterase or butyryl cholinesterase)
➢All the pharmacological actions of anti-AChE drug are due to
inhibition of true AChE.
Q. Why acetylcholine is not used clinically?
-Ach is rapidly metabolized by AChE
-Its actions are of very short duration
-Poor penetration through cornea
-Rapidly broken down by AChE before it reaches its site of
action.
Properties and Subtypes of Cholinergic Receptors:
❖Nicotinic receptors are ligand-gated ion channels whose
activation always causes a rapid (millisecond) increase in cellular
permeability to Na+ and Ca2+, depolarization, and excitation.
❖ By contrast, muscarinic receptors are G protein-coupled
receptors (GPCRs).
Receptor Location Transducer Functions Agonists Antagonists
Type mechanism
CNS; Most Activation of Increased Acetylcholine, Atropine,
M1
abundant in PLC; ↑ IP3 and cognitive Carbachol, Dicycloverine,
cerebral ↑DAG → ↑Ca2+ function Oxotremorine, Tolterodine,
cortex, and PKC; (learning McNA343, Oxybutynin,
hippocampus depolarization and Talsaclidine Ipratropium,
and striatum; and excitation memory); Pirenzepine,
autonomic increase in Telenzepine,
ganglia; Gastric & Mamba toxin
glands (gastric other
and salivary) secretions;
and enteric
nerves
M2 Widely Inhibition of Heart: Methach Atropine,
expressed in adenylyl SA node: slowed oline & Methoctramin
CNS, heart, cyclase, spontaneous same as e,
smooth ↓cAMP, ↓K+ depolarization; M1 Tripitramine, ,
muscle, conductance, hyperpolarization, Dicycloverine,
autonomic ↓Ca2+ ↓HR; Tolterodine,
Oxybutynin,
nerve terminals conductance AV node: decrease in
Ipratropium,
conduction velocity;
Gallamine
Atrium: ↑ refractory
period, ↓ contraction;
Smooth muscle: ↑
Contraction; Neural
inhibition; ↓
Ganglionic
transmission; Central
muscarinic effects (e.g.
tremor, hypothermia)
M3 Exocrine glands: Activation of Gastric, Same as Atropine,
gastric, salivary, PLC; ↑ IP3 salivary M1 Dicycloverine
etc. and ↑DAG → secretion, ,
Smooth muscle: ↑Ca2+ and Gastrointest Tolterodine,
gastrointestinal PKC; inal smooth Oxybutynin,
tract, eye, airways, depolarizatio muscle Ipratropium,
bladder n and contraction, Darifenacin
Blood vessels: excitation Ocular
endothelium CNS accommoda
tion,
Vasodilatati
on
M4 Preferentially Inhibition of Enhanced Same as Atropine,
expressed in adenylyl locomotion; M1 Dicycloverine,
CNS cyclase, ↓cAMP analgesia; Tolterodine,
facilitation Oxybutynin,
of Ipratropium,
dopamine Mamba toxin,
release MT3
M5 CNS: very Activation of PLC; Facilitates Same as Atropine,
↑ IP3 and ↑DAG dopamine M1 Dicycloverine,
localised
→ ↑Ca2+ and release; Tolterodine,
expression in PKC; augmentation Oxybutynin
substantia depolarization and of drug
nigra, excitation seeking
behavior and
Salivary
reward (e.g.,
glands , opiates,
Iris/ciliary cocaine)
muscle
Skeletal Skeletal Excitatory, skeletal Acetylcholine, Tubocurarine
muscle neuromuscul Increased cation muscle Carbachol, ,
ar junction permeability contracti Nicotine, Pancuronium,
(NM) + +
(postjunctio (mainly Na , K ) on Succinylcholin Atracurium,
nal) e, Vecuronium,
PTMA(phenylt α-
rimethyl Bungarotoxin
ammonium) ,
α-Conotoxin
Peripher Autonomic Excitatory Excitatory; Acetylcholi Mecamylamin
ganglia; Increased cation depolarizatio ne, e ,
al
adrenal permeability n; firing of Carbachol, Trimetaphan ,
neuronal
medulla (mainly Na+, K+) postganglion Nicotine, Hexamethoni
(NN) neuron; Epibatidine um ,
depolarizatio , α-Conotoxin
n and DMPP(Dim
secretion of ethylphenyl
catecholami -
nes piperaziniu
m)
Summary of Adrenergic and Cholinergic Responses
Summary of Adrenergic and Cholinergic Responses
Summary of Adrenergic and Cholinergic Responses
Classification of cholinergic drugs/parasympathomimetic drugs

Directly acting Indirectly acting(anticholinesterases)


1. Acetylcholine (prototype) REVERSIBLE IRREVERSIBLE
2. Synthetic Choline esters 1.Natural Alkaloids 1.Organophosphorus
i) Methacholine Physostigmine i) Ecothiophate
ii) Carbachol 2.Quaternary compounds ii)Isoflurophate
iii) Bethanechol i) Edrophonium iii)Paraoxon
1. Natural Alkaloids ii) Neostigmine iv)Parathion
i)Arecoline iii)Pyridostigmine v)Malathion
ii)Nicotine iv)Ambenonium vi)Diazinon
iii)Muscarine v)Demecarium 2.Carbamates
iv)Pilocarpine vi)Rivastigmine Propoxur
Q. What are the pharmacological actions of Ach in human heart?
Ans-The primary cardiovascular effects of muscarinic agonists are
reduction in peripheral vascular resistance and changes in heart rate.
Intravenous infusions of minimally effective doses of acetylcholine in
humans (eg, 20–50 mcg/min) cause vasodilation, resulting in a reduction
in blood pressure, often accompanied by a reflex increase tachycardia.

Larger doses of acetylcholine produce bradycardia and decrease


atrioventricular node conduction velocity in addition to hypotension.
The direct cardiac actions of muscarinic stimulants include the
following: (1) an increase in a potassium current (IK(ACh)) in atrial
muscle cells and in the cells of the sinoatrial and atrioventricular
nodes as well; (2) a decrease in the slow inward calcium current
(ICa) in heart cells; and (3) a reduction in the hyperpolarization-
activated current (If) that underlies diastolic depolarization.
All of these actions are mediated by M2 receptors and contribute
to slowing the pacemaker rate.
Effects (1) and (2) cause hyperpolarization and decrease the
contractility of atrial cells.
Pharmacological Properties
1) Gastrointestinal Tract- All muscarinic agonists
increase tone and motility; large doses will cause spasm
and tenesmus.
2) Urinary Tract- The choline esters and pilocarpine
contract the detrusor muscle of the bladder, increase
voiding pressure, decrease bladder capacity, and increase
ureteral peristalsis. In addition, the trigone and external
sphincter muscles relax.
3)Exocrine Glands- The choline esters and muscarinic alkaloids
stimulate secretion of the lacrimal, salivary, digestive,
tracheobronchial, and sweat glands.
Salivation also is increased markedly by Pilocarpine.

4)Respiratory System- In addition to tracheobronchial secretions,


bronchial smooth muscle is stimulated by the muscarinic agonist-
cause bronchoconstriction.

5)Cardiovascular System-elicits hypotension and bradycardia.


Q. If pilocarpine is injected through i.v. route what will happen?
•Ans-The cardiovascular effects of most of the cholinomimetic natural
alkaloids and the synthetic analogs are generally similar to those of
acetylcholine.
•Pilocarpine is an interesting exception to the above statement. If given
intravenously (an experimental exercise), it may produce hypertension
after a brief initial hypotensive response.
•The longer-lasting hypertensive effect can be traced to sympathetic
ganglionic discharge caused by activation of postganglionic cell
membrane M1 receptors, which close K+ channels and elicit slow
excitatory (depolarizing) postsynaptic potentials.
Q. What are pharmacological effects of cholinomimetic drugs on
G.I.T?
Ans:
➢Peristaltic activity is increased throughout the gut, and most
sphincters are relaxed.
➢Stimulation of contraction in this organ system involves
depolarization of the smooth muscle cell membrane and
increased calcium influx.
➢The M3 receptor is required for direct activation of smooth
muscle contraction while the M2 receptor reduces cAMP
formation and relaxation caused by sympathomimetic drugs.
Therapeutic uses:
1)Acetylcholine is available as an ophthalmic surgical aid for the
rapid production of miosis.
2) Pilocarpine hydrochloride is available as 5- or 7.5-mg oral
doses for treatment of xerostomia or as ophthalmic solutions.
3) Methacholine chloride may be administered for diagnosis of
bronchial hyperreactivity.
4) Cevimeline is a newer muscarinic agonist with activity at M3
muscarinic receptors available orally for use in treatment of
xerostomia.
5)Bethanechol can be useful in certain cases of postoperative
abdominal distention and in gastric atony or gastroparesis.

5)Bethanechol may be useful in treating urinary retention and


inadequate emptying of the bladder when organic obstruction is
absent, as in postoperative and postpartum urinary retention and in
certain cases of chronic hypotonic, myogenic, or neurogenic
bladder.
5)Pilocarpine also is used in the treatment of acute congestive

glaucoma.

6) Agonists for M1 and M2 receptors have been targets for drug

development for use in treating the cognitive impairment

associated with Alzheimer's disease.


Treatment/management of mushroom poisoning/mycetism
❑The most dangerous species of mushroom are Amanita phalloides,
Amanita verna, Amanita virosa, Gyromitra esculenta, and the Galerina
species, all of which contain amatoxin, a potent cytotoxin.
❑ Ingestion of even a portion of one mushroom of a dangerous species
may be sufficient to cause death.
❑The principal toxins are the amatoxins (α- and β-amanitin), a group
of cyclic octapeptides that inhibit RNA polymerase II and hence block
mRNA synthesis.
❑This causes cell death, manifested particularly in the gastrointestinal
mucosa, liver, and kidneys.
Clinical findings and treatment:
Types Genus Symptoms and Signs Treatment
Amatoxin- A After a latent interval A variety of antidotes (eg,
type phalloides, of 8–12 hours, severe thioctic acid, penicillin,
cyclopeptides A verna, A abdominal cramps corticosteroids);
virosa, and and vomiting begin aggressive fluid
Galerina and progress to profuse replacement; intensive
species diarrhea, followed in supportive care; Silymarin
1–2 days by hepatic (a derivative of milk thistle)
necrosis, hepatic is commonly used in
encephalopathy, and Europe (20 mg/kg over 24
frequently renal failure. hours given in four 2-hour
The fatality rate is infusions).
about 20%.

Cooking the mushroom


does not prevent
poisoning.
Muscarinic Inocybe • Vomiting, For mushrooms
type and diarrhea, producing
Clitocybe bradycardia, predominantly
species hypotension, muscarinic-cholinergic
salivation, symptoms, give
miosis, atropine, 0.005–0.01
bronchospasm, mg/kg intravenously,
and lacrimation and repeat as needed.
occur shortly
after ingestion.
• Cardiac
arrhythmias
may occur.
• Fatalities are
rare.
Anticholiner Amanita • This type causes a • For
gic type muscaria, variety of anticholinesteras,
Amanita symptoms that may physostigmine,
pantherin be atropine-like, 0.5–1 mg i.v..
a including • Alternately, use a
excitement, benzodiazepine
delirium, flushed such as
skin, dilated lorazepam, 1–2
pupils, and mg i.v..
muscular jerking
tremors, beginning
1–2 hours after
ingestion.
• Fatalities are rare.
Gastrointes Boletus, • Nausea, Treat with anti-
tinal Cantharel vomiting, and emetics and
irritant lus diarrhea occur intravenous or oral
type shortly after fluids.
ingestion.
• Fatalities are
rare.
Hallucinoge Psilocybe • Mydriasis, • Provide a quiet,
nic and nausea and supportive
Panaeolus vomiting, and atmosphere.
species intense visual • Diazepam or
hallucinations haloperidol may be
occur 1–2 hours used for sedation.
after ingestion.
• Fatalities are
rare.
Q. Why atropine should not be prescribed in Anti-cholinergic type of
mushroom poisoning?
❑Intoxication produced by A. muscaria and related Amanita species
arises from the neurologic and hallucinogenic properties of muscimol,
ibotenic acid, and other isoxazole derivatives.
❑These agents stimulate excitatory and inhibitory amino acid
receptors.
❑Symptoms range from irritability, restlessness, ataxia, hallucinations,
and delirium to drowsiness and sedation.
❑Treatment is mainly supportive; benzodiazepines are indicated when
excitation predominates, whereas atropine often exacerbates the
delirium.
Anti-cholinesterase agents:
❖The function of acetylcholinesterase (AChE) in terminating the
action of acetylcholine (ACh) at the junctions of the various
cholinergic nerve endings with their effector organs or post-synaptic
sites.
❖Drugs that inhibit AChE are called anticholinesterase (anti-ChE)
agents.
❖There are two subtypes of anti-ChE agents i.e. Reversible
(Competitive) and irreversible inhibitors.
➢Mechanism of Action of AChE Inhibitors-

Three distinct domains on AChE constitute binding sites for


inhibitory ligands and form the basis for specificity differences
between AChE and butyrylcholinesterase: the acyl pocket of the
active center, the choline subsite of the active center, and the
peripheral anionic site.
➢The active site of AChE comprises two distinct regions: an
anionic site (glutamate residue), which binds the basic (choline)
moiety of ACh; and an esteratic site (histidine + serine).
➢In the initial catalytic step, acetylcholine binds to the
enzyme's active site and is hydrolyzed, yielding free choline
and the acetylated enzyme.
➢ In the second step, the covalent acetylenzyme bond is split,
with the addition of water (hydration).
➢The competitive inhibitors reversibly bind electrostatically
and by hydrogen bonds to the active site, thus preventing
access of acetylcholine.
• What is acetyl choline esterase?
It is an enzyme which catalyzes the hydrolysis of acetylcholine
to acetate and choline.
The active region of acetylcholine esterase contains an aromatic
anionic site [near tryptophan 86] and an esteratic site formed
by serine 203, glutamate 334 and histidine 447.
Hydrolysis of acetylcholine involves electrostatic attraction between the
positive N+ of acetylcholine to the aromatic pocket and nucleophilic attack
of serine-OH leading to acetylation of serine.
•How do Organophoshates react with acetyl choline esterase?
Organophosphates attach to the esteratic site
The anionic site is free
If the organophosphate molecule loses it's alkyl group, it becomes resistant to
hydrolysis. This process is called aging.
So if you have to rescue your acetylcholine enzyme from the evil force of
Organophosphorous compounds, you'll have to do it before aging (6-8 hours).
How do you do it? Use cholinesterase reactivators!
Pralidoxime has a quarternary nitrogen which attaches to the anionic site.
It's oxime end reacts with the phosphorous atom attached to the esteratic site
The oximephosphonate so formed diffuses away leaving the reactivated
cholinesetrase.
General features of reversible anticholinesterases
(CARBAMATES)
1. They are usually esters of carbamic acid and have structural
similarity with Ach.
2. They may combine with both anionic and esteric sites (e.g.
physostigmine) or with one of these sites of enzyme
cholinesterase ( e.g. edrophonium)
3. They form complexes which are hydrolysed at a rate slower
than the acetylated enzymes leading to temporary inhibition of
enzyme and resulting accumulation of Ach at cholinergic sites.
4. They inhibit AChE and BuChE almost EQUALLY.

5. Lipid soluble agents e.g. physostigmine have more

muscarinic, ganglionic stimulant & CNS effects as they cross BBB

and less effect on NMJ.

6. Lipid insoluble agents (e.g. neostigmine, edrophonium) have

more marked effects on skeletal muscle and ganglia.


Therapeutic uses:
1) Physostigmine- as a miotic, ocular hypotensive in glaucoma,
and in atropine and tricyclic antidepressants (TCA)
poisoning to antagonize the central and peripheral actions of
atropine and atropine like effects.
2) Neostigmine- poor oral absorption, does not cross BBB and
conjunctiva. Used for t/t of myasthenia gravis, poisoning of d-
tubocurarine.
3) Edrophonium- action is brief. Used for diagnosis of
Myasthenis gravis, reversal of curare.
4) Pyridostigmine- used in Myasthenia gravis.
5) Ambenonium- for myasthenia gravis.
6) Demecarium- glaucoma.
Drugs for Alzheimer’s disease
1) Tacrine: structurally lipophilic acridine compound. MOA- Acts
by elevating Ach conc. in the cerebral cortex by slowing the
degradation. It is indicated for the t/t of mild to moderate
dementia of Alzheimer's disease.
2) Donepezil- reversible inhibitor of enzyme AChE. It improves
cognitive function .
3) Rivastigmine- long acting reversible non-competitive carbamate
AChE inhibitor. Used for mild to moderately severe AD.
4) Galantamine – oral BA= 90%. Used for symptomatic t/t of AD.
5) Memantine
Choline Ester Susceptibility to Muscarinic Nicotinic
Cholinesterase Action Action

Acetylcholine ++++ +++ +++

Methacholine + ++++ None

Carbachol Negligible ++ +++

Bethanechol Negligible ++ None


Treatment of Organophosphorus poisoning:
❖Organophosphorus and carbamate insecticides
(organophosphates: parathion, malathion, etc; carbamates:
carbaryl, aldicarb, etc) are widely used in commercial
agriculture and home gardening.
❖Most chemical warfare "nerve agents" (tabun, sabin,
soman etc) are organophosphates.
❖They inhibit the enzyme acetylcholinesterase—cause an
increase in acetylcholine activity at nicotinic and muscarinic
receptors and in the central nervous system.
Clinical Findings
❖Inhibition of cholinesterase results in abdominal cramps, diarrhea,

vomiting, excessive salivation, sweating, lacrimation, miosis

(constricted pupils), wheezing and bronchorrhea, seizures, and skeletal

muscle weakness.

❖Initial tachycardia is usually followed by bradycardia.

❖Profound skeletal muscle weakness, aggravated by excessive

bronchial secretions and wheezing, may result in respiratory arrest and

death.
The mnemonic DUMBELS
• (diarrhea, urination, miosis and muscle weakness,
bronchospasm, excitation, lacrimation, and seizures,
sweating, and salivation) helps recall the common
findings.
• Mnemonic devices used to remember the muscarinic
effects of organophosphates are SLUDGE (salivation,
lacrimation, urination, diarrhea, GI upset, emesis)
➢The diagnosis should be suspected in patients who

present with miosis, sweating, and hyperperistalsis.

➢Serum and red blood cell cholinesterase activity is

usually depressed at least 50% below baseline.


Treatment
Organophosphorus is treated by decontamination, respiratory support,
and three antidotes—an anticholinergic, an oxime, and an
anticonvulsant.
•Emergency and Supportive Measures- Removal of clothing, empty the
stomach by gastric lavage and administer activated charcoal.
•Providers must take care to avoid skin exposure by wearing gloves and
waterproof aprons.
•Respiratory Support-
GOALS OF TREATMENT
• Reduce absorption of the toxin (xenobiotic)
• Enhance elimination
• Neutralize toxin.

Reduce Absorption
• Removal from surface of skin, eyes and hair
• Emesis induction
• Gastric lavage
• Activated charcoal administration and cathartics
• Dilution—milk/other drinks for corrosives
• Whole bowel irrigation
• Endoscopic or surgical removal of ingested chemical
• Skin decontamination—important aspect—not to be neglected:
– Remove contaminated clothing
– Wash with soap and water (soaps containing 30% ethanol advocated).
Decontamination
Gastric Decontamination
• Gastric lavage
• Activated charcoal 25 g 2 hourly
• Sorbitol as cathartic.
Gastric Lavage
• Gastric lavage decreases absorption by 42% if done at 20 minutes and by 16%
if performed at 60 minutes
• Performed by first aspirating the stomach and then repetitively instilling and
aspirating fluid
• Left lateral position delays spontaneous absorption
• No evidence that a larger tube is better
• Simplest, quickest and least expensive way—funnel
• Choice of fluid is tap water: 5–10 mL/kg
• Preferably done on awake patients
• Presence of an ET tube does not preclude aspiration, though preferred if
Glasgow coma scale is low
• No human studies in OP poisoning showing benefit of gastric lavage.
•Specific Treatment-
•Atropine reverses excessive muscarinic stimulation and is effective for
treatment of salivation, bronchial hypersecretion, wheezing, abdominal
cramping, and sweating.
•However, it does not interact with nicotinic receptors at autonomic
ganglia and at the neuromuscular junction and has no effect on muscle
weakness.
•Repeat atropine (2 mg IM, or 1 mg IM for infants) at 5- to 10-min
intervals until secretions have diminished and breathing is comfortable
or airway resistance has returned to near normal.
Treatment: Atropine
Anticholinergic Agents
• Atropine has beneficial effects on central nervous system (CNS)
Atropinization: Targets
• Adequacy of atropinization
• Mandatory targets:
– SBP greater than 90 mm Hg
– Heart rate about 110/minute
– Clear lung fields.
• Other targets:
– Pupils mid position
– Bowel sounds just present
• Targets on subsequent days:
– Day 2: HR greater than 100/minute
– Day 3: HR greater than 90/minute
– Subsequent days: At least 80/minute.
Atropinization: Dose
What dose to use?
• Several recommendations > 20 mg atropine
• 0.02–0.08 mg/kg over 1 hour would take 4 hours to give 20 mg atropine to a 70
kg male.

Anticholinergic Dose
• 1–2 mg initial bolus dose
• Double dose every 5 minutes if targets not met
• In 20 minutes can achieve atropinization for a dose of 25 mg.
•Oxime Therapy
➢Pralidoxime (2-PAM, Protopam) is a specific antidote that reverses
organophosphate binding to the cholinesterase enzyme; therefore, it is
effective at the neuromuscular junction as well as other nicotinic and
muscarinic sites.
➢ It is most likely to be effective if started very soon after poisoning, to
prevent permanent binding of the organophosphate to cholinesterase.
Administer 1–2 g intravenously as a loading dose, and begin a continuous
infusion (200–500 mg/h titrated to clinical response).
➢Pralidoxime is of questionable benefit for carbamate poisoning,
because carbamates have only a transitory effect on the cholinesterase
enzyme.
•Anticonvulsants
❑Nerve agent–induced seizures do not respond to the usual
anticonvulsants used for status epilepticus, including
phenytoin, phenobarbital, carbamazepine, valproic acid, and
lamotrigine.
❑Diazepam for convulsions: (0.2 to 0.5 mg IV for infants <5
years: 1 mg IV for children >5 years; 5 mg IV for adults).
Drugs used in myasthenia gravis
Myasthenia gravis (MG) is a neuromuscular disorder
characterized by weakness and fatigability of skeletal
muscles due to auto-antibodies that inactivate nicotinic
acetylcholine receptors.
Pathophysiology-
In MG, the fundamental defect is a decrease in the number of
available AChRs at the postsynaptic muscle membrane by
three distinct mechanisms:
(1) accelerated turnover of AChRs by a mechanism involving
cross-linking and rapid endocytosis of the receptors;
(2) blockade of the active site of the AChR, i.e., the site that
normally binds ACh; and
(3) damage to the postsynaptic muscle membrane by the
antibody in collaboration with complement.
Diagnosis of Myasthenia gravis-
❑History of diplopia, ptosis, weakness in characteristic distribution
,worse with repeated activity, improved by rest.
❑ Laboratory testing :Anti-AChR radioimmunoassay: ~85%
positive in generalized MG; 50% in ocular MG; definite diagnosis if
positive; repetitive nerve stimulation; decrement of >15% at 3 Hz:
highly probable;
❑ Edrophonium chloride (Tensilon) 2 mg + 8 mg IV; highly probable
diagnosis if unequivocally positive.
Q. How will you differentiate between Myasthenia gravis & cholinergic crisis?

❖The edrophonium test for evaluation of possible myasthenia gravis is performed by


rapid intravenous injection of 2 mg of edrophonium chloride, followed 45
seconds later by an additional 8 mg if the first dose is without effect; a positive
response consists of brief improvement in strength, unaccompanied by lingual
fasciculation (which generally occurs in nonmyasthenic patients).

❖An excessive dose of an anti-ChE drug results in a cholinergic crisis. The


condition is characterized by weakness resulting from generalized depolarization
of the motor endplate; other features result from overstimulation of muscarinic
receptors. The weakness resulting from depolarization block may resemble
myasthenic weakness, which is manifest when anti-ChE medication is insufficient.
Treatment-
The most useful treatments for MG include anticholinesterase
medications, immunosuppressive agents, thymectomy, and
plasmapheresis or intravenous immunoglobulin (IVIg).
1)Anticholinesterase-
➢ Pyridostigmine, neostigmine, and ambenonium are the standard
anti-ChE drugs used in the symptomatic treatment of myasthenia gravis.
➢ All can increase the response of myasthenic muscle to repetitive
nerve impulses, primarily by the preservation of endogenous ACh.
2) Immunosuppression

❑Immunosuppression using glucocorticoids, azathioprine,


cyclosporine and tacrolimus is effective in nearly all patients
with MG.
❑Cyclosporine preferentially inhibits antigen-triggered signal
transduction in T lymphocytes.
❑ Azathioprine is a purine antimetabolite inhibit de novo
purine synthesis ; then inhibit cell proliferation & lymphocyte
functions.
Other Immunosuppressive Drugs
Mycophenolate mofetil, azathioprine, cyclosporine,
tacrolimus, and occasionally cyclophosphamide are effective
in many patients, either alone or in various combinations.

Glucocorticoid Therapy-
❑Glucocorticoids, when used properly, produce improvement
in myasthenic weakness in the great majority of patients.
❑They inhibit production of NR-antibodies. The initial
dose should be relatively low (15–25 mg/d) to avoid the early
weakening; then dose is increased stepwise.
2) Removal of antibodies by plasmapheresis (plasma exchange) is
another therapeutic approach.
3) Immunoglobulin- The indications for the use of IVIg are the same
as those for plasma exchange: to produce rapid improvement to help
the patient through a difficult period of myasthenic weakness or prior
to surgery.
4) Thymectomy
Thymectomy should be considered in myasthenia associated with a
thymoma or when the disease is not controlled adequately by anti-ChE
agents and steroids.
➢Glaucoma is characterized by an increase in intraocular
pressure which exhibits a characteristic progressive optic
nerve cupping and visual field loss and finally blindness.

➢Glaucoma classified in to congenital and acquired-


primary and secondary depending on the presence factors
contributing to the pressure rise.
➢The primary glaucoma is subdivided into narrow
angle/closed angle/acute congestive and wide angle/open
angle/chronic simple glaucoma.
Types of Glaucoma
There are a variety of different types of glaucoma.
The most common forms are:
1) Primary Open-Angle Glaucoma
2) Normal Tension Glaucoma
3) Angle-Closure Glaucoma
4) Acute Glaucoma
5) Pigmentary Glaucoma
6) Exfoliation Syndrome
7) Trauma-Related Glaucoma
Who is at Risk?
•People over the age of 45.
•People who have a family history of glaucoma.
•People with abnormally high intraocular pressure (IOP)-
High IOP is the most important risk factor for glaucomatous
damage.
•People of African descent-
African-Americans have a greater tendency for developing
primary open-angle glaucoma than do people of other races.
•People who have:
o Diabetes
o Myopia (nearsightedness)
o Regular, long-term Steroid/Cortisone use
o A previous eye injury
Diagnosing Glaucoma:
The Tonometer, Visual Field Test, Ophthalmoscopy
Groups/Drugs
1.Beta-blockers:
Timolol(0.25%,0.5% b.d.)
Betaxolol(0.5%)
Levobunolol (0.5% daily or b.d)
Carteolol(1%, 2% b.d)
Metipranolol (0.1%, 0.3% b.d)
Alpha-1 Alpha 2 Beta-1 Beta-2
Located in the Inhibitory Receptors are Located in the
arterioles, dilatorreceptors are located in the ciliary
papillae andlocated in the myocardium epithelium and
muller muscle ciliary bronchi
epithelium
Stimulation gives Stimulation Give rise to Stimulation
rise to results in tachycardia and causes increased
hypertension, increase in the increased cardiac aqueous
mydriasis and lid facility of output when production via
retraction, aqueous outflow stimulated increased cAMP
constrict cilliary and
vessels and bronchodilation
reduce aqueous
formation
Mode of action:
 Betablockers reduce IOP by decreasing aqueous
secretion and therefore useful in all types of
glaucoma.

 Current pharmacotherapies are targeted to


decrease the production of aqueous humor at the
ciliary body and to increase outflow through the
trabecular meshwork and uveoscleral pathways.
 Carteolol facilitiates ocular perfusion and retinal
blood flow in addition to decreasing formation of
aqueous humor.
 It also protects the optic nerve from damage. For
better effect they can be combined with brimonidine
or latanoprost.
Side effects:
 Ocular- dryness of eye, corneal punctate epithelial
erosions and occasional allergy.
 Systemic- tend to occur during first week of
administration (e.g., bradycardia, hypotension
due to β1 blockade; bronchospasm due to β2
blockade; miscellaneous-sleep disorders,
hallucinations, confusion, depression, fatigue,
headache, nausea, dizziness, decreased libido.
Advantages-
 No change in pupil size hence no diminution of vision
in cataract patients and in dim light
 No induced myopia
 No fluctuations of IOP
 Convenient dosing schedule
Contraindications:
 Include congestive heart failure, 2nd or 3rd degree
heart block, bradycardia, asthma and obstructive
airways disease.
 Q& A. β-blockers should not be used at bed-

time because they may cause a profound drop

in BP while the individual is asleep, thus

reducing optic disc perfusion and potentially

causing visual deterioration.


 Q &A. Betaxolol is preferred over timolol in asthma
patients because of selective β1 blocking action and
in addition may exert protective on retinal neurons
by increasing optic disc flow, probably because of
calcium channel blocking effect on the
microcirculation of the disc.
2. Alpha -2 agonists
 They decrease IOP by both decreasing aqueous secretion
and enhancing outflow.

 Because the drugs cross the B-B-B they should not be used in
children.

 Brimonidine – a clonidine congener, highly selective,


lipophilic α2 agonist; also has a neuroprotective effect. It
exhibits additivity with β-blockers.

 Side effects- allergic conjunctivitis, acute granulomatous


uveitis, xerostomia, drowsiness, fatigue, and sedation.
 Apraclonidine – is a polar congener of clonidine which does
not cross B-B-B. 0.5%, 1% is mainly used after laser surgery on
the anterior segment to offset an acute rise in IOP.

 It is not suitable for long-term use because of tachyphylaxis


and a high incidence of local side-effects (itching, lid dermatitis,
follicular conjunctivitis, mydriasis, eyelid retraction and
xerostomia).

 Dipivefrine- it is prodrug of adrenaline, penetrates cornea,


longer acting and better tolerated than Adr.
 3. Prostaglandin analogues:
 Due to their once-daily dosing, low incidence of systemic
side effects, and potent intraocular pressure lowering effect,
prostaglandin analogs have largely replaced β-adrenergic
receptor antagonists as first-line medical therapy for glaucoma.
The prostaglandin analogs consist of latanoprost,

travoprost, bimatoprost, and unoprostone.


 Latanoprost and travoprost- are PGF2α analogues that act as
selective FP prostanoid receptor agonists; both enhance
aqueous humor outflow through the uveoscleral route.
Pressure lowering effect is superior to timolol.

 Bimatoprost- is a synthetic prostamide analogue structurally


similar to PGs and promotes outflow through both uveoscleral
and trabecular routes.

 Unoprostone- is a structural analogue of PG F2α that has no


affinity for PG receptors. It appears to promote aqueous
outflow through the trabecular meshwork.
Side-effects of Prostaglandin analogues:
 Ocular- conjunctival hyperaemia, foreign body sensation,
eyelash thickening, iris hyperpimentation, hyperpigmentation
of periorbital skin and conjunctiva, cystoids macular oedema,
and anterior uveitis (rare).

 Syatemic- occasional headache, precipitation of migraine


in susceptible patients, skin rash and mild upper respiratory
tract symptoms. These preparations should not be used in
pregnancy because animal studies have shown potential
teratogenic effects.
4. Topical carbonic anhydrase inhibitors-
 They are chemically related to the sulphonamides.

 Dorzolamide and brinzolamide both work by inhibiting


carbonic anhydrase (isoenzyme II), which is found in the
ciliary body epithelium. This reduces the formation of
bicarbonate ions, which reduces fluid transport and thus IOP.

 Dorzolamide- 2% t.i.d. as monotherapy or b.d. as adjunctive


treatment.

 Side-effects are allergic blepharoconjuctivitis and a transient


bitter taste.
 Systemic carbonic anhydrase inhibitors-
 Acetazolamide (dose 250mg-1000mg in divided dose)

 The onset of action is within 1hour, with a peak at 4 hours and


duration up to 12 hours.

 Available as 250 mg tabs, capsules and 500 mg inj vials.

 Dichlorphenamide (dose 50-100mg)

 Methazolamide (dose 50- 100mg), longer duration of action.


 Sytemic side-effects-
Paraesthesiae (tingling of the fingers, toes, hands, fee and
occasionally mucocutaneous junctions) is a universal finding,
malaise, gastrointestinal complex (gastric irritation, abdominal
cramps, diarrhea and nausea), renal stone formation, Stevens-
Johnson syndrome(rare) and blood dyscrasias (rare).
5. Miotics-
 In primary open angle glaucoma(POAG) parasympathomimetic
drugs reduce IOP by contraction of ciliary muscle, which
increases the facility of aqueous outflow through the trabecular
meshwork.
 In primary angle closure glaucoma (PACG) contraction of
sphincter papillae and the resultant miosis pulls the peripheral
iris away from the trabeculum, thus opening the angle.
Perparations-
 pilocarpine drops- 1%, 2%, 3%, 4% is used q.i.d as
monotherapy.
 Carbachol- 3% t.i.d is a good alternative to pilocarpine in
resistant cases.
 Ocular side-effects include- miosis, brow ache,
myopic shift, exacerbation of symptoms of cataract,
visual field defects and diffuse superficial corneal
haze.

6. Anti-cholinesterases:
 Reversible- physostigmine, demecarium
 Irreversible- ecothiophate, isoflurophate
 Mechanism of actions is same as pilocarpine.
 Longer acting can cause muscle spasm and systemic side
effects.
 It can induce cataract formation on long term use.
7. Osmotic diuretics:
 They decrease IOP by creating an osmotic gradient between
blood and vitreous so that water is ‘drawn out’ from the
vitreous.

 Glycerol and isosorbide are oral agents and mannitol


(intravenous osmotic agent).

 Clinical uses- when a temporary drop in IOP is required in


acute angle-closure glaucoma and prior to intraocular
surgery.

 Side-effects- cardiovascular overload, urinary retention,


headache, backache, nausea and mental confusion.
Treatment of acute congestive glaucoma
Diagnosis:
 Classical cases there is rapidly progressive unilateral visual
loss with periocular pain and congestion, may be associated
with nausea and vomiting.
Medical treatment:
1.Immediate-
 Patient should be positioned supine to allow the lens to shift
posteriorly.
a) Acetazolamide-500mg i.v and 500mg orally provided there
is no vomiting.
b) Topical
-Dexamethasone q.i.d
-Timolol 0.5% if there is no contraindication.
c) Analgesia and anti-emetics as required.
2. After one hour-
 Pilocarpine 2% q.i.d should be started half to one hour
after commencement of treatment, by which time
reduction of iris ischemia and lowering of IOP allows
the sphincter papillae to respond to the drug.

 Fellow eye is also treated prophylactically with 1%


pilocarpine q.i.d until laser iridotomy is performed.
3. After a further 30 minutes
 Re-check IOP

 If IOP≥ 35mmHg give oral 50% glycerol 1g/kg (with caution


in diabetics) and limit fluid intake for maximum effect.

 If the patient is vomiting or is unable to tolerate oral glycerol


give 20% mannitol(1-2g/kg) i.v over 45 minutes.

 Then Laser iridotomy after iris decongestion or may require


trabeculectomy in unresponsive cases.
Major neurotransmitter in parasympathetic system is (PGI
99)
1)Adrenaline
2) Noradrenaline
3)Acetylcholine
4)Dopamine

The rate limiting step in Acetylcholine synthesis (AIPGME


2000)
1)Choline acetyl transferase activity
2)Choline uptake by nerve endings
3)Transport of Choline
4)Release of Ach from vesicles
Which of the following drug has maximum nicotinic effect
(AIIMS 96)
1)Pilocarpine
2)Methacholine
3)Carbachol
4)Bethanechol
Thank you