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Describe the steps in synthesis, storage, release, termination of acetylcholine

synthesis of acetylcholine
storage and release
receptor binding

cholineacetyltransferase - acetylates choline.

Opening of voltage sensitive calcium channels, allow influx of calcium allowing fusion. Exocytosis delivers acetylcholine into the synapse which binds to cholinoceptors. Acetylcholinesterase: removes the acetyl group.

On presynaptic cells, autoreceptor - involved in feedback regulation.

Heteroreceptors can bind other NTs and contribute to regulation of the fiber.


Differentiate the major types of cholinoceptors

Nicotinic - 5 subunit, ionotropic (ligand gated ion channels), causes depolarization with sodium and potassium flow

Nm - muscle type, end plate receptor, located in skeletal muscle and neuromuscular end plates, have at least 2 alpha subunits for acetylcholine binding, (variety, 2 alpha, rest of 3 are different)

Nn - neuronal type, ganglion receptor
2 alpha, 3 betas, or all alphas, found in Postganglionic cell body, dendrites, some presynaptic cholinergic terminals

Muscarinic - 7 subunit, metabotropic


Name the major types of autonomic receptors and where they are located

M1: CNS neurons, sympathetic postganglionic neurons, some presynaptic sites

*M2: myocardium, smooth muscle, some presynaptic sites

M3: exocrine glands, smooth muscle, vessels

*M4: expressed in CNS, forebrain, striatum, cortex, hippocampus

M5: predominant muscarinic receptor in neurons in VTA and substantia nigra

* opens K+ channels directly (beta subunit)
-rest works through increased IP3 and DAG, with increased intracellular calcium (alpha subunit)


Distinguish between direct acting cholinomimetic agents and indirect-acting agents

indirect-acting cholinomimetic agents inhibit acetylcholinesterase to increase levels of acetylcholine.

Direct acting agents- target the cholinoceptors directly.


Describe the action of cholinesterase inhibitors

So acetylcholinesterase - hydrolyzes the acetylcholine. Ach is attracted to glutamatic acid residue near the serine residue. Hydrolysis of acetylcholine transfers the acetyl group to serine. Hydrolyzed in less than a milisecond


List therapeutic uses for cholinesterase inhibitors

Short acting:
edrophonium •  binds weakly and reversibly to anionic domain of AChE •  rapid renal clearance, brief duration of action
*•  used to diagnose myasthenia gravis (MG)

Intermediate acting inhibitors -
-rivastigmine for treating Alzheimer’s disease
-neostigmine, pyridostigmine, ambenonium, treat MG
-demecarium, physostigmine (physo cross BBB but is used topically)- treats glaucoma

Long-acting inhibitors of acetylcholinesterase: Covalent, not readily reversible
•  organophosphate
•  chemical warfare agents


Recognize the major signs and symptoms of cholinergic excess with treatment

. Muscarinic:
CNS stimulation
•  miosis (pupil constriction)
•  reflex tachycardia
•  bronchoconstriction (fight or flight you want to breath more)
•  excessive GI and GU
smooth muscle activity
•  increased secretory
activity (sweat, airway,
GI and lacrimal glands)
•  vasodilation (sympathetic causes vasodilation of arteries carrying blood to muscles but at same time cause vasoconstriction of arteries carrying blood to unnecessary organs

•  CNS stimulation
(convulsions) followed
by depression
•  neuromuscular end
plate depolarization
(fasciculations, then

Treatment •  if insecticide exposure, decontaminate to
prevent further absorption •  maintain respiration, vital signs •  administer atropine (muscarinic antagonist) •  benzodiazepines for seizures


Cholinesterase inhibitor poisonning DUMBBELSS

Excitation (of skeletal muscle and CNS)*


Understand the mechanism of action of LA’s

Be able to describe the basic chemical structure of LA’s

Understand the effects of pH on the action of LA’s

Drug that reversibly blocks impulse
conduction along nerve axons and other
excitable membranes that utilize voltage gated sodium channels as the primary means of action potential generation.
Block Na+ channels in excitable
membranes without changing resting potential.
Reduce aggregate inward sodium
-Fibers that fire at a faster rate are more susceptible to the effects of local
Repeated depolarizations produce more effective anesthetic binding

This phenomenon is known as Frequency Dependent Block

Local anesthetics are weak bases
Therefore, the more acidic the pH, the
greater ionized, the more basic, the more neutral [B] form

The neutral form is required to get to site of action but charged form is required for activity.


How is capsaicin used as an analgesic?

Vanilloid receptor (VR1) / transient receptor potential (TRPV1) channels found in C fibers are activated by moderate heat (45oC) and capsaicin.

• Repeated application of Capsaicin causes desensitization of C fibers and also
-depletes Substance P to block peripheral sensitization.


Be able to differentiate between amide and ester local anesthetics (LA) and understand their differences in terms of metabolism and allergenicity

Esters: plasma pseudocholinesterase >
PABA and derivatives
- Enzyme deficiency may lead to potentiation of action
-Esters usually have a shorter duration of action
**esters are allergenic due to PABA metabolite

Amides: Liver, cytochrome P450, water soluble metabolites, urinary excretion.
-Low flow states to liver (portal hypertension, CHF, etc.) decreases delivery of LA’s to liver, decreasing amide LA metabolism, increasing lifetime and serum concentration



-stimulant, vasoconstrictor
-used in ENT surgeries because it is a LA and also blocks nasal leakage



A long duration, potent ester primarily used for spinal anesthesia, toxic at relatively low doses
(***exception to short acting ester rule)
-experienced a shortage and basically never made it back to market



Primarily topical
-implicated in MetHb formation



Procaine: (Novocain) quick onset, short duration
-hypersensitivity reactions
TNS implication (rarely



Used to have a bad rep, now a commonly used quick onset, short duration LA
-primarily used now for pregnancies, used for the last part of labor



-the perfect local anesthetic
-transient effect
-low systemic toxicity
-quick onset
-action to span duration of surgery

does have TNS implication



Longer duration than lidocaine

**lowest pKa of injectable LA’s so it has one of the quickest onset
-acts as a vasoconstrictor



Prilocaine: **known associated with methemoglobinemia
-component of EMLA



Excellent long duration LA with devastating potential for cardiac toxicity.
Sensory block>Motor block - great for pregnancies


Bupivacaine SR

Liposomally encapsulated for delivery up to 72 hrs/dose



Single enantiomer long duration
LA with properties similar to bupivacaine but
with less cardiotoxicity; vasoconstrictor



Eutectic Mixture of Local Anesthetic
-Prilocaine/Lidocaine for topical anesthesia


What is the modulated receptor hypothesis?

Modulated Receptor Hypothesis: LA binding is a function of the conformational state of the
channel, i.e., different kinetics/affinities for different conformational states

LA’s have a higher affinity for the receptors in the activated & inactivated states, less affinity for the receptor in the resting state


Understand the concepts of lipophilicity, pKa, and protein binding as they relate to potency, onset of action, and duration of LA’s

The greater the lipophilicity, the greater the potency and duration. However there is also slower onset of action. Often there is a lipid depot surrounding the nerve so there is greater diffusion.

A greater pKa of drug means slower onset of action because it will be more ionized and have difficulty entering cells.

Increased protein binding means increased duration of action


Understand the use of vasoconstrictors as it relates to absorption and duration of LA’s and general pharmacokinetic trends

Absorption is Site dependent
Intercostal (shortest duration), caudal, epidural, brachial plexus, sciatic nerve block (longest duration).

Vasoconstrictors: Epinephrine, Phenylephrine
-decrease absorption irrespective of site of injection
-particularly effective for short and medium acting
drugs. ­ Increases tissue binding responsible for duration of action of long acting drugs.
-Intrinsically analgesic in neuraxial blockade
TEST DOSE: To tell you did not inject intravascularly: Low concentration of epinephrine added
to local; Small dose injected before therapeutic dose; Heart rate increases within 2 minutes (15% increase) if local is injected intravascularly


Understand the adverse effects of LA’s


Systemic toxicity
Local toxicity
Allergic Reactions
Methemoglobin formation

Systemic toxicity: Results from effects of LA on excitable
membranes and tissues other than
target nerves
-Manifest first as CNS toxicity then cardiotoxicity (rule
of thumb)

CNS Toxicity
>Tinnitus, perioral numbness, blurred vision, metallic taste, change in mental state, convulsions.

>Depression of excitability and
(ventricular prolonged QRS) as well as arteriolar dilation (Calcium channel effect)
> Bupivacaine is very cardiotoxic (R+)
> Ropivacaine less toxic (S-)
> Systemic acidosis or hypercarbia ­ increased sensitivity to LA toxicity (their pH is more acidic, trapping the LA in circulation)
>Pregnancy ­ sensitivity to toxic effects **Rescue is by IV Lipid Emulsion (drawing the lipophilic drugs out)

Local injury:
Neural Injury
High concentrations of local for extended periods can lead to nerve tissue destruction via membrane damage, cytoskeletal disruption, etc. but not due to blockade of the Na channel
-Motor and sensory loss are seen (e.g. cauda equina syndrome): If patients with cauda equina syndrome do not receive treatment quickly, adverse results can include paralysis, impaired bladder, and/or bowel control, difficulty walking
-Paralysis and paresis may result
*Transient Neurologic Symptoms (TNS)
Transient pain syndrome associated with spinally administered Lidocaine and certain surgical positions (e.g. lithotomy)
**NOT associated with motor or sensory loss, it just hurts! A self limited neuropathic pain syndrome

>PABA ® hapten formation ® true IgE mediated allergy

-do not form the same metabolites and *Methylparaben, preservative, can cause allergic reactions irrespective of LA type

Prilocaine metabolites (O-toluidine)
act as an oxidizing agent to convert
Hb++ to Hb+++
Benzocaine has also been implicated Chocolate colored blood
Pulse oximeter = 85% saturation w Treatment is with methylene blue


Understand the concept of methemoglobinemia as it relates to LA’s

Prilocaine metabolites (O-toluidine)
act as an oxidizing agent to convert
Hb++ to Hb+++

Benzocaine has also been implicated
Chocolate colored blood
Pulse oximeter = 85% saturation
Treatment is with methylene blue


Describe differential neuraxial & peripheral blockades


Different nerve fibers have different sensitivities to LA's

In clinical practice, incremental increases in local
anesthetic concentration result in progressive
interruption of (in order of sensitivity)
Autonomic/pain fibers
Sensory fibers
Motor fibers

In peripheral blockade, motor fibers are
more peripheral, sensory fibers are
Of the sensory fibers, proximal are outside, distal fibers are inside.

In peripheral blockade, motor block
occurs before proximal sensory loss which occurs before distal sensory loss.


Out the opiates which ones are full agonists (5), partial agonist (1), pure antagonist (3), mixed agonist-antagonists

Pure agonists: Full agonists

Partial agonists

• Pure antagonists

• Mixed agonist-antagonists
-butorphanol (sometimes used to relieve labor pain)
 κ agonists that produce analgesia, but also act as µ antagonists (interfere with morphine, heroin, etc.)


What are the mechanisms of opioids (assuming mew opioid)

Presynaptic neuron
• Inhibits adenylyl cyclase-catalyzed formation of cAMP [cAMP]↓
•Closes Ca2+ channels [Ca2+]↓
→ ↓ synaptic transmission
→ ↓ release of neurotransmitters
that convey pain perception (e.g., ACh, substance P, glutamate)

Postsynaptic neuron
• Opens K+ channels [K+]↑
→ hyperpolarization of cell
• ↓ firing of neuron
• ↓ neuron excitability & pain



Hydrophilic drug, so CNS penetration and exit are slow, slow onset and long duration, T1/2 = 2-4 hr.
• Fairly rapid absorption, wide distribution, rapid hepatic clearance.
 Polar active metabolites cleared by kidney (caution in renal dysfunction).  Heroin (diamorphine), a more lipophilic prodrug of morphine, exhibits faster CNS penetration.

analgesia for acute pain
• pain associated with severe injuries, post-surgery, bone/joint/muscle ailments
 major exception: contraindicated in head injuries** (they tend to increase intracranial pressure)
• myocardial infarction (MI) and angina (most important uses of morphine today)
• pulmonary edema (left ventricle hypertrophy - LVH ) - because of vasodilating effects
• cancer patients (fentanyl IM or IV is an alternative if patient becomes tolerant to morphine).



Oral analgesics for moderate, chronic pain.



regional anesthesia (e.g., spinal or epidural anesthesia)

80-100 times more powerful than morphine.
• Lipophilic drug, so very fast CNS penetration, fast onset and short duration, T1/2 < 1 hr.
• Multiple delivery routes: patch, intrathecal, intranasal spray, and buccal mucosa (fentanyl “lollipop”).


Codeine or dextromethorphan

cough suppressant

cough suppressed by d-isomers of opioids (e.g. dextromethorphan) which have no analgesic activity


Diphenoxylate or loperamide

.for relief from diarrhea (preferred due to lower BBB penetration).



for relief of opioid-induced constipation.


Vicodin, Percocet

Hydrocodone/acetaminophen (Vicodin)

Oxycodone/acetaminophen (Percocet) are two widely prescribed orally active opioid formulations for moderate to severe pain.

 Dosage is monitored by the need to limit acetaminophen (APAP) to <4 g/day in normal person (much
lower doses for alcoholics and for patients with impaired liver function).  Over past decade, the number of overdose deaths from prescription opioids has increased sharply
(Opioid Crisis).


Describe respiratory depression

Opioids decrease the brain's response to CO2 in the respiratory center.

This increase arterial CO2 which causes vasodilation in the brain.

This is why there is an increase in ICP.

-Subnormal drive to breathe, despite normal respiratory rate.
-Effects are dose-dependent: Very high doses may cause irregular breathing and apnea.

-Respiratory depression is the major toxicity of opioids and nearly always the cause of death from overdose.

Equi-analgesic doses of all opioids produce equivalent amounts of respiratory depression. (this is the consistency)

 Difficult to reverse respiratory depression w/o losing some analgesic effects.

However, do not give O2, give naloxone, an opioid antagonist.


What are the acute clinical effects of opioids

11. PBU His M N C My CS E R A

EFFECTS - all "u" opioid agonists


(decrease release of GABA in neuron, relieves inhibition resulting in release of dopamine in neighboring neuron)

4. COUGH suppression
(Depression of cough centers in the medulla.
-Different molecular mechanism from analgesia or respiratory depression.
- cough suppressed by d-isomers of opioids (e.g. dextromethorphan) which have no analgesic activity.
- codeine or dextromethorphan is the preferred agent, rather than morphine.

5. MIOSIS (pupil constriction): Miosis caused by stimulation of Edinger-Westphal (parasympathetic) nucleus of the oculomotor nerve.  Miosis (pinpoint pupils) is a visible signature of opioid overdose.
 Reversed by naloxone, atropine.
*one exception is meperidine (demerol) which produces mydriasis

GI: Intestine and Stomach
• ↓peristalsis in small and large bowels, constipation, cramping.
• Chronic administration of opioids frequently requires laxatives.
• Methylnaltrexone approved for treatment of opioid-induced constipation.
Note: Opioids are useful for treatment of diarrhea. Diphenoxylate (Lomotil®) and loperamide (Imodium®) are preferred due to their lack of central effects (not CNS absorbed).

7. Nausea and Vomiting
 Stimulation of the chemoreceptor trigger zone *(CTZ) in the area postrema - activates vomiting center.
 Emetic effects caused by stimulation of vestibular apparatus - ambulatory patients more likely to vomit than
those lying quietly.

8. Muscle Rigidity (skeletal tonus)
• Large IV doses can cause generalized stiffness of skeletal muscle.
• Most common with fentanyl and related opioids.
• May play a role in some overdose fatalities.

9. Histamine Release
• Full agonists (e.g. morphine, fentanyl) can cause non-immunologic release of histamine,
inducing vasodilation and hypotension. • May cause skin redness, urticaria (hives, rash), and pruritus (itchy skin) near injection site. • Not an allergic reaction - true allergic responses to opioids are rare.

Can induce spasmotic effects on smooth muscle along the biliary tree
and sphincter of Oddi.
• Can precipitate biliary colic (gall bladder attack).
c. Urinary Tract • Anti-diuretic effect can cause urinary retention.

11. Effects on Pregnancy and the Neonate
• Opioids are sometimes used sparingly to relieve labor pain (e.g., fentanyl, butorphanol, meperidine). • All opioids cross the placenta, thus may cause respiratory depression in baby. • Chronic use may cause physical dependence in utero and life-threatening neonatal withdrawal after delivery. • Treatment of choice for opioid addicted mother & newborn: methadone.
Effects on Pregnancy and the Neonate


Describe the chronic effects of opioid

12. Opioid Tolerance
• Reduction in effect with repeated dosing (need higher dose to produce same effect).
• Cross-tolerance to other opioids (additivity effect).
• Tolerance develops rapidly (2-3 wks) to analgesia, *respiratory depression, euphoria.
• No tolerance to miosis and constipation – they occur immediately with 1st dose.

Clinical Characteristics: • Heroin addicts or methadone maintenance patients may have little euphoria from high doses but continue
to experience constipation and miosis. • Terminal cancer patients requiring high doses for analgesia are also tolerant to respiratory depression, but
they frequently require laxatives for constipation.

13. Physical Dependence
• Giving opioid antagonist (e.g., naloxone) to physically dependent person causes abrupt withdrawal
(abstinence) syndrome - usually not life-threatening to adult.
• Symptoms stop when small dose of opioid is given.
• Withdrawal symptoms: sweating, rhinorrhea (runny nose), vomiting, diarrhea, piloerection (goose bumps),
mydriasis, shaking chills, drug seeking behavior.
• Management of withdrawal: Supportive care, methadone.
• Distinction between physical dependence (natural need for higher doses for analgesia) and psychological
dependence (addiction, craving a “high”). Mild physical dependence is common in clinical setting.

14. Opioid overdose (intoxication)
Classic triad (MAR-means to spoil)
Apnea, coma
Respiratory depression



-can occasionally cause seizures due to CNS stimulating effects of its metabolite normeperidine



only partial agonist

Buprenorphine (alternative to methadone)
• Partial agonist at µ receptor - higher doses do not increase effects, ↑ margin of safety.
• Long-lasting: T½ >24 hrs, less likely to cause respiratory depression.
• Prescribed as buprenorphine/naloxone combo (Suboxone®), given orally as a sub-lingual tablet or film (don’t swallow).
• The naloxone is added to make the combo “abuse resistant”.



Antagonist of all opioid receptors (µ, κ, δ).
Blocks effects of heroin, morphine, methadone, etc. • Prescribed for patients after opioid detoxification to prevent relapse.
• To detoxify patient, Methadone or Buprenorphine/Naloxone dosage is slowly tapered to wean patient off drug.
• Once sufficiently detoxified (withdrawal free), patient is often prescribed Naltrexone PO for relapse prevention.

• Long-acting opioid antagonist used for maintenance therapy and relapse prevention once detoxified.
• Orally active
• Not recommended for emergency overdose treatment.



Intravenous Naloxone (Narcan) is widely used for emergency opioid overdose/intoxication.
• Pure, competitive antagonist at µ, κ, and δ receptors.
• Rapidly reverses opioid overdose when injected IV or IM, but it has short duration (T1/2 ~ 1 hr). Gives
immediate relief from acute respiratory depression, but can induce severe withdrawal symptoms – not life-
threatening to adult. Multiple or continual dosing may be required due to its short T1/2.
• Not orally active.
• Naloxone is added to many abuse-prone opioid drugs (e.g., oxycodone, buprenorphine) to render them
“abuse resistant”.

Mechanism: naloxone’s effects are minimal when taken orally with oxycodone or buprenorphine due to its poor absorption but will induce rapid withdrawal symptoms if oxycodone/naloxone or buprenorphine/naloxone is injected for a ‘high’.


Nalorphine, pentazocine, nalbuphine, butorphanol

Act as κ agonists to produce analgesia, and as µ antagonists.

Developed in search for analgesics with less abuse potential and lower respiratory depression.

Clinical Characteristics of Mixed Agonist-Antagonists:
• Effective analgesics for moderate to severe pain.
• Limited toxicity (reduced respiratory depression or smooth muscle effects). • Decreased abuse potential, but also decreased patient acceptance due to side effects (dysphoria)- a state of unease or generalized dissatisfaction with life .

• Drawback: As µ antagonists, they can precipitate acute withdrawal in heroin or morphine addicts.


What is the treatment of shingles

An antiviral (like acyclovir) and local anesthetic lidocaine.



a commonly used anti-glioma chemotherapy agent.

MGMT (methylguanine-DNA-methyltransferase) removes the DNA adduct formed by DNA's reaction

So the more methylated the MGMT gene, the more vulnerable a tumor will be to tenzolomide


succinylcholine: clean up crew gets shock while cleaning up "SUCKS grafity"

succinylcholine: a nicotinic agonist
less readily hydrolyzed than ACh prolongs channel opening leads to muscle relaxation administered parenterally
charge limits penetration to CNS

Prolonged agonist occupancy prevents recovery of the membrane potential and the muscle relaxes

It is the only DEPOLARIZING NMJ blocking agent.


M2 & M3

M2: smooth muscle, MYOCARDIUM - opens K+ channels, inhibition of adenylyl cyclase

M3: smooth muscle, EXOCRINE glands, vessels - IP3, DAG, intracellular calcium increases.

so think muscle, two, three, plant the tree

1,4,5 - makes you feel alive


M1, M4, M5

All are expressed in the CNS!

M1: sympathetic postganglionic neurons - increases IP3, DAG and intracellular calcium

M4: forebrain especially, striatum, cortex, hippocampus - opens K+ channels, inhibits adenylyl cyclase

M5: VTA and substantia nigra - increases IP3, DAG and intracellular calcium


Sweat glands are sympathetic nervous system (evidenced by Horner's syndrome). Then why would muscarinic antagonists lead to "dry as a bone" presentation?

Sweat glands are special! Despite being sympathetic they feature M3 (muscarinic) receptors with an acetylcholine NT. So anti-muscarinic drugs will interfere with sweat.


What is edrophonium

It is a short acting reversible inhibitor of acetylcholinesterase.

binds weakly and reversibly to anionic domain of AChE
•  rapid renal clearance, brief duration of action
•  used to diagnose myasthenia gravis (MG)
-on an exam, a patient could be currently treated for MG. She is either undertreated or overtreated leading to too much acetylcholine and causing refractory NMJ receptors. A small dose of edrophonium, if she improves that means she needs more acetylcholine.
Or exacerbates the crisis. Cholinergic excess.

-it removes muscle weakness symptoms for 5-15 min so its not useful for treatment.


What are signs of cholinergic excess?


CNS stimulation - seizures
Reflex tachycardia
Excess GI and GU smooth muscle activity

increased secretory activity (sweat, airway, GI and lacrimal glands, vasodilation)

Treatment •  if insecticide exposure, decontaminate to
prevent further absorption
•  maintain respiration, vital signs
•  administer atropine (muscarinic antagonist) + pralidoxime (organophosphate poisoning treatment)
•  benzodiazepines for seizures



alpha agonist

-dilator muscle of eye has alpha receptors, this is to facilitate increase in pupil size similar to effects of tropicamide.



In age related macular degeneration, there is neovascularization mediated by VEGF which is leaky and can cause blindness.

Bevacizumab is an antibody that soaks up all the free vegf.


Bethanechol: "Beth the construction worker"

Muscarinic agonist:

-increases secretion of the gut (cement spilling out). "Do not obstruct", used for non-obstructive GI issues, post op ileus. It can also be used for urinary retention since it activates the detrusor muscles.


Pilocarpine (pile o carp),

dripping water,

Pilocarpine increases salivation (dry mouth caused by Sjogren's syndrome).

Can also be used for glaucoma. (activating the ciliary body) "net".

Also causes miosis- important for acute glaucoma.


Carbachol varenicline

-glaucoma treating agent: constricted hood blocking carbon fumes

it is a muscarinic and nicotinic agonist.




Pyridostigmine is the drug of choice for Myasthenia gravis - an autoimmune disease targetting nicotinic receptors.

They increase acetylcholine at NMJ's so it can outcompete with the antibodies.

Neostigmine is not as widely used for this. It can also treat ileus and reversal of neuromuscular blockade.


Physostigmine (phys ed)

acetylcholinesterase with central effects - works through competitive effects.

-treats atropine in wonderland: atropine overdose (mad as a hatter, hot as a hare, blind as a bat)

Belladonna flower -nightshade, which contains naturally occurring atropine.

Jimson week (gym) - also overdose of atropine (gardeners mydriasis)


DUMBBELS - sweaty kid struggling with weights, too weak to lift them.

diarrhea, urination, miosis, bronchospasm, bradycardia, lacrimation, salivation

Cholinesterase inhibitor toxicity effects

Important is that cholinesterase inhibitors can also activate nicotinic receptors which with over activation causes flaccid paralysis

Commonly - organophosphate poisoning. Parathion, malathion,. Muscarinic and nicotinic symptoms. CNS involvement follows rapidly causes convulsions.

Person brought to ER, after gardening, he has bradycardia, tearing excessively, and can't breath. Acute organophosphate have to recognized immediately. Aging organophosphate+acetylcholinesterase will become irreversible. Pralidoxime


PraLIDoxime + Atropine

regenerates acetylcholinesterase to reverse cholinergic toxicity induced by organophosphate including flaccid paralysis. However it will NOT reverse the symptoms of CNS. because it can't enter

Atropine an muscarinic antagonist "alice was here". It can't reverse the paralysis since it only acts muscarinic


Donepezil, galantamine, rivastigmine

All three penetrate the CNS to treat alzheimers, "brain puzzle"

Alzheimers GALA , REVERSE the STIGMA, DONE with the puzzle.

With extra acetylcholine, these elderly patients can have serious side effects.