PHAR 428

Ya Fatou Njie-Mbye, Ph.D.

Spring, 2018

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 Acetylcholinesterase (AChE)
functions to terminate the action of
acetylcholine (ACh) at the junction of
cholinergic nerve endings on their
postsynaptic sites or effector organs.

 Drugs that inhibit AChE are called

anticholinesterase agents (AChE
Inhibitors).

Golan 3rd /4th Edition

ANTICHOLINESTERASE AGENTS (AChE Inhibitors)
MOA
 Bind to and inhibit acetylcholinesterase (AChE),
preventing hydrolysis of ACh.
 The neurotransmitter accumulates in synapse, and
thus is capable exerting excessive stimulation of
cholinergic receptors in CNS and PNS
 Use extensively as toxic agents in the form of
insecticides, pesticides and potential chemical warfare
“nerve gas”.
 Some used therapeutically or in clinical trials for
treatment of Alzheimer’s (at smaller doses).

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ANTICHOLINESTERASE AGENTS (AChE Inhibitors)
Structural classes and their Pharmacological properties
• Compounds containing a quaternary ammonium group do not penetrate cell membranes readily :
- poorly absorbed from GI tract or across the skin
- at moderate doses are excluded from the CNS by blood-brain barrier
- some compounds act preferentially at neuromuscular junctions of skeletal muscles as
both AChE inhibitors and direct agonists
 Lipid soluble agents (organophosphates):
- well absorbed after oral administration and have ubiquitous effects at both peripheral
and central sites
- well absorbed in skin
- volatile agents readily transferred across the alveolar membrane
- have high risk of toxicity
- excreted almost entirely as hydrolyzed products in urine
- hydrolyzed by plasma and liver esterases
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ANTICHOLINESTERASE AGENTS (AChE Inhibitors)
Pharmacological Actions
• Stimulation of muscarinic receptors responses at autonomic effector organs.
• Stimulation , followed by depression or paralysis of all autonomic ganglia and
skeletal muscle (nicotinic actions).
• Stimulation, with occasional subsequent depression, of cholinergic receptor sites
in the CNS.
 Pharmacological actions of AChE inhibitors on autonomic effector cells in CNS,
as well as excitatory actions on autonomic ganglia are blocked by atropine.
 Site of therapeutic importance are CNS, eye, intestine and neuromuscular
junction (NMJ) of skeletal muscle.

Note: other actions are of toxicological consequences

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ANTICHOLINESTERASE AGENTS (AChE Inhibitors)
Pharmacological Actions
 Eye
- applied locally to the conjunctiva AChE inhibitors can cause conjunctival
hyperemia and constriction of pupillary sphincter muscle (miosis),
accommodation of lens to near vision, lowering of intraocular pressure
(IOP)
 GI Tract
- Increased secretion of gastric acid, enhanced gastric contractions
 Neuromuscular junction
- contraction of skeletal muscles
 Other sites
- Low doses of AChE inhibitors augment secretory responses (lacrimal glands,
sweat, salivary, bronchial, gastric and intestinal)
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 ANTICHOLINESTERASE AGENTS (AChE Inhibitors)
Therapeutic Uses
 Current uses of AChE inhibitors is limited to four conditions of the periphery:
• Atony of smooth muscle of the intestinal tract and urinary bladder
- potentiates parasympathetic action (Increase in smooth muscle motility and tone, secretion of
gastric acid)
• Glaucoma
- potentiates parasympathetic action (Decrease IOP by increasing aqueous humor outflow)
 Myasthenia gravis
- AChE increases concentration of endogenously releases Ach thereby increasing ACh signaling (Improve
muscle weakness)
• Reversal of the paralysis of competitive neuromuscular blocking drugs
- AChE increase AChE increases concentration of endogenously releases increasing ACh signaling

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ACETYLCHOLINESTERASE INHIBITORS
 Reversible
A. Neostigmine methylsulfate (BLOXIVERZ)
- Reversible inhibits AChE
- Poorly absorbed in GI after oral administration and does not enter CNS
- Destroyed by plasma esterases, and excreted in the urine (half life of 1-2 hrs)
- Can stimulate contractility prior to paralysis in skeletal muscle
- Therapeutic use as an antidote for non-depolarizing neuromuscular blocking
agents post-op.
- Adverse effects include bradycardia, nausea, vomiting , dry mouth, headache,
dyspnea, pruritus, hypotension
- Precautions include pregnancy, nursing mothers, renal or hepatic impairment,
cardiovascular conditions
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ACETYLCHOLINESTERASE INHIBITORS
 Reversible
B. Pyridostigmine (MESTINION; REGONOL) Ambenonium (MYTELASE)
- Actions are longer than Neostigmine
- Like Neostigmine it is poorly absorbed in GI, destroyed by plasma esterases, and excreted in the urine (half life of 1-2 hrs)
- Adverse effects include GI upset (diarrhea), urinary urgency, increased salivation and bronchial secretions, muscle
cramps, miosis and diaphoresis, fasciculation and weakness.
- Use in chronic management of myasthenia gravis (MESTINION; MYTELASE)
- Use as a reversal agent to the neuromuscular blocking effects of non-depolarizing muscle relaxants (REGONOL)
- Precautions include bronchial asthma, pregnancy, nursing mothers

C. Donepezil (ARICEPT; NAMZARIC), Rivastigmine (EXELON), Galantamine (RAZADYNE)

- Treatment of Alzhiemer type dementia
- Mild to moderate dementia associated with Parkinson Disease (EXELON)
- Adverse effects include nausea, diarrhea, vomiting, insomnia, muscle cramp, fatigue, anorexia, severe skin reactions,
headache
- Precautions include peptic ulcer, asthma or COPD, monitor for GI bleeding, pregnancy, nursing mothers, cardiac
conduction conditions

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ACETYLCHOLINESTERASE INHIBITORS
 Toxicity
- In addition to cases of accidental intoxication from the use and manufacture of
organophosphorous compounds as agricultural insecticides, these agents have been used
frequently as homicidal and suicidal purposes.
- Acute intoxication are manifested by muscarinic and nicotinic signs and symptoms
- Systemic effects appear within minutes after inhalation of vapors or aerosols
- The onset of symptoms is delayed after GI and percutaneous absorption
- Atropine in sufficient doses effectively antagonizes the actions of muscarinic receptor sites.
Large doses needed to cross blood-brain barrier.
- Pralidoxime is used in treatment of poisoning due to pesticides and chemicals (eg nerve
agents), as well as in the control of over dosage by AChE inhibitors used in treatment of
myasthenia gravis. MOA: can reactivate inhibited AChE.
- Other treatments include , supportive measures such as oxygen supply, artificial respiration,
Diazepam can also be used to reduce persistent convulsion.
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 Cholinergic Receptor Antagonists
 Antimuscarinic Agents
 Ganglionic blockers
 Neuromuscular-blocking Agents

Figure 5.2 Lippincott’s 12

 Cholinergic Receptors
 Two types:
I. Muscarinic receptors (mAchRs)
- 7 transmembrane helix G-protein coupled receptor
- located on ganglia of PNS, & autonomic effector organs innervated by postganglionic
parasympathetic nerves
- also located within the CNS
- five subtypes; M1-M5
II. Nicotinic receptors (nAchRs)
- Ligand gated ion channels
- located in the peripheral autonomic ganglia, adrenal medulla, skeletal muscle, CNS
and neuromuscular junction
- 2 subtypes [muscle type (NM), neuronal type (NN]

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Signal Transduction-Nicotinic Receptor

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Ganglionic Neurotransmission
 Neurotransmission in autonomic ganglia is a complex process
involving multiple neurotransmitter-receptor systems.
 The primary event involves release of ACh and rapid depolarization
of postsynaptic membranes via the activation of neuronal nicotinic
(Nn) receptors by Ach.

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GANGLIONIC STIMULATING DRUGS

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GANGLIONIC STIMULATING DRUGS
 Drugs that stimulate cholinergic receptor sites on autonomic ganglia have
been useful in analyzing the mechanism of ganglia function.
 Ganglionic agonists have limited therapeutic use.
 Divided in two groups:
A. Drugs that are specific to the nicotinic sites (include nicotine)
B. Muscarinic receptor agonists such as muscarine and methacholine

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 GANGLIONIC STIMULATING DRUGS
1. Nicotine
 Natural liquid alkaloids, colorless and volatile base
 Readily absorbed from the respiratory tract, buccal membrane and skin
 Limited absorption in stomach. Rapidly eliminated by kidney. The rate of urinary excretion diminishes when the urine is alkaline. (also excreted in milk of
lactating women who smoke)
 Medical significance because its toxicity, presence in tobacco, and propensity for conferring a dependence on its user.
 Can stimulate and desensitize receptors. Both sympathetic and parasympathetic ganglia are stimulated.
• In low doses causes ganglionic stimulation by depolarization, however at high doses causes ganglionic blockade

 Pharmacological Action
- Pharmacological effects include effect on CNS (release of neurotransmitters), influence on HR, BP, release of Epinephrine, variable effects on GI motility
and secretion.
• Increase HR by excitation of sympathetic ganglia or paralysis of parasympathetic cardiac ganglia
• Slow HR by paralysis of sympathetic or stimulation of parasympathetic cardiac ganglia
• Complex peripheral effects; stimulation of sympathetic ganglia and adrenal medulla increases BP and HR. Stimulation of parasympathetic ganglia
increases motor activity of the bowel…at high doses BP falls and activity ceases in GI and bladder musculature

 Therapeutic use in smoking cessation. (reduce craving of nicotine and inhibition of the reinforcing effects of nicotine)
 Toxicology
- acute poisoning from nicotine can occur from accidental ingestion (insecticide sprays, exposure to tobacco in children). Onset of symptoms
include, nausea, salivation, vomiting diarrhea, mental confusion, hearing and visual disturbances. Death may results within minutes from respiratory
failure
- To treat for toxicity, vomiting maybe induced or gastric lavage can be performed. A slurry of activated charcoal is then passed through the tube and left in
the stomach. Respiratory assistance and treatment of shock may be necessary
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Nicotine

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GANGLIONIC BLOCKERS

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GANGLIONIC BLOCKERS
 specifically act on nicotinic receptors of both parasympathetic and sympathetic autonomic
ganglia
 Block entire output of the ANS at the nicotinic receptor
 Are rarely uses therapeutically, but serve as a tool in research studies
1. Nicotine
• Stimulates ganglia by an ACh-like action then blocks them by causing a persistant
depolarization
2. Trimethaphan and Mecamylamine
• Use in treatment of hypertension in the 1950s and 1960s
• Competes with ACh for ganglionic nicotinic receptors
3. Hexamethonium
 Blocks channel after it opens; this action shortens the duration of current flow because the
open channel becomes occluded or close.
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Golan 3rd Edition
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Neuromuscular Blocking Agents

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Neuromuscular Blocking Agents
 Block cholinergic transmission between motor nerve endings and
nicotinic receptors on neuromuscular endplate of skeletal muscle
 Structural analogs of ACh, that act as antagonist (competitive/non-
depolarizing type) on the end plate of the NMJ
 Clinically used during surgery for producing complete muscle relaxation
 Also useful in orthopedic surgery and in facilitating tracheal intubation
• Examples of Non-depolarizing (competitive) blockers; Tubocurarine
(not use clinically), Vecuronium, rocuronium bromide (ZEMURON)

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Figure 9-4 Golan

Fig 5.9 Lippincotts

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Neuromuscular Blocking Agents
 Neuromuscular Blocking agents (depolarizing type acts as agonist at
receptor)
- structural analogs of ACh
- illicit effects similar to ACh, by depolarizing plasma membrane of
muscle fiber
- more resistant to degradation by AChE
 Succinylcholine is the only depolarization agent in use today

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Neuromuscular Blocking Agents
 Depolarizing Agent [Succinylcholine (ANECTINE;QUELICIN)]
- high affinity for nicotinic receptor and resistant to AChE
- used during surgery for the induction of paralysis (depolarizing
blockade), and in electroconvulsive shock
- Adverse effects include hyperthermia, apnea, hyperkalemia

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Neuromuscular Blocking Agents
 Pharmacological Properties
- Action on organ systems
• Skeletal muscle
- competitive antagonists bind the nicotinic ACh receptor of the motor end-plate and thereby competitively block the
binding of ACh
- depolarizing agents depolarize the membrane by opening channels in the same manner is Ach. However, have longer
duration due to resistance to AChE. This results in a brief period of repetitive excitation that may elicit transient and
repetitive muscle excitation (fasciculations), followed by block of neuromuscular transmission and flaccid paralysis (
called phase 1 block)
• CNS
- Tubocurarine and other quaternary neuromuscular blocking agents are virtually devoid of central effects at clinical
doses due to inability to penetrate blood-brain barrier
• Autonomic ganglia and muscarinic sites
- Neuromuscular agents show variable potencies in producing ganglionic block
- ganglionic blockade by Tubocurarine and other stabilizing drugs are reversed or antagonized by anti-
aetylcholinesterase agents
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Neuromuscular Blocking Agents
 Pharmacokinetics Properties
- Quaternary ammonium neuromuscular blocking agents are very poorly absorbed in GI
- Rapid onset achieved with intravenous administration
• Clinical use include as a muscle relaxant (relaxation of skeletal muscle, particularly of the
abdominal wall to facilitate operative manipulations), control of muscle spasm and rigidity
• Synergism and Antagonism
- Important pharmacological interactions of these drugs are with certain general anesthetic,
certain antibodies, calcium channel blockers, and anti- acetylcholinesterases (AChE inhibitors)
- Neostigmine use in treatment of over dose (antagonizes only the skeletal muscle blocking action
of the competitive blocking agents)
- Atropine is administered to counteract muscarinic stimulation
 Toxicology
- Untoward responses of the neuromuscular blocking agents include prolonged apnea,
cardiovascular collapse, alterations in body temperature, electrolyte imbalance, reduced renal
function ….

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