Autonomic Crap

Question 1

Acetylcholinesterase Inhibitors (Reversible)

Answer 1

This group of drugs inhibits AChase which allows the
actions of ACh to persist. Thus, these drugs have a
cholinomimetic action which can be exerted at either
nicotinic or muscarinic receptors. Toxicity of these drugs
is complex due to potentiation of ACh at both ganglionic
and postganglionic sites, but generally reflects excessive
activation of muscarinic receptors.

Question 2

Physostigmine

Answer 2

a. mechanism of action: is a tertiary amine that is a
substrate for AChase where it forms a stable complex
that reversibly inactivates the enzyme
therapeutic use: treatment of anticholinergic
toxicity, i.e., atropine, TCAs (IV, IM); open-angle
glaucoma (ophthalmic)
c. can enter the CNS and cause convulsions

Question 3

Pyridostigmine, Neostigmine

Answer 3

a. therapeutic use: used to treat myasthenia gravis (an
autoimmune disease where antibodies attack nicotinic
receptors at the neuromuscular junction); reversal of
non-depolarizing blocking agents (tubocuraine)
b. are quaternary amines so have less potential to enter
CNS and cause convulsions
MG is an autoimmune disease where antibodies to NM receptors
are produced; it causes weakness in skeletal muscles especially in the facial area

Question 4

Edrophonium

Answer 4

a. therapeutic use: used to diagnose myasthenia
gravis; as a curare antagonist
b. has a short duration of action (10-20 min.) and IV
injection leads to a rapid increase in muscle strength

Question 5

Donepezil, Rivastigmine, Galantamine

Answer 5

a. therapeutic use: used to treat mild to moderate
Alzheimer’s disease; Donepezil is used most
commonly
b. drugs readily enter the CNS

Question 6

Alzheimer’s

Answer 6

Alzheimer’s is a neurodegenerative disorder characterized by progressive loss of memory and other cognitive functions. Patients lose cholinergic neurons in the cortex (Meynert’s nucleus).  ACh is the main strategy.

Question 7

Acetylcholinesterase Inhibitors (Irreversible)

Answer 7

These drugs are of little use therapeutically. Most were
originally developed by the military as nerve agents.
Examples include sarin, soman, and tabun, and these
agents are lethal to laboratory animals in submilligram
quantities.

Question 8

Acetylcholinesterase Inhibitors (Irreversible) drugs

Answer 8

Parathion and malathion are organophosphates which
are employed as insecticides. These two agents are
actually inactive as given (prodrugs) and are activated by
cytochrome P450 enzymes. In birds and mammals, the
active form of malathion is rapidly hydrolyzed by plasma
carboxylesterases, while this process is much slower in insects. Parathion is much more toxic since it is not
hydrolyzed by carboxylesterases.
Malathion is available as a topical lotion for headlice.
The danger of using these agents is that the binding of
drug to AChase is not easily reversed since it forms a
covalent bond. A chemical reactivator such as the drug
pralidoxime (PAM) can break the bond between the
irreversible anticholinesterase and AChase if given prior
to removal of an alkyl group from the cholinesterase
inhibitor. Once this alkyl group is removed (a process
known as chemical aging) pralidoxime can no longer
remove the drug from AChase.

Question 9

Pealidoxime

Answer 9

Pralidoxime does not enter the CNS so any
AChase inhibitor that got into the CNS is
not removed. Newer nerve agents will age
within seconds and pralidoxime is much
less effective against these drugs.

Question 10

Toxicity of Acetylcholinesterase Inhibitors

Answer 10

DUMBBELSS: diarrhea, urination, miosis,
bronchoconstriction, bradycardia, excitation (of
skeletal muscle and CNS), lacrimation, salivation and
sweating

*toxicity resembles too much parasympathetic
stimulation + sweating + Nicotinic effects

Treatment: atropine +/- pralidoxime

Question 11

Nicotine

Answer 11

a. primarily activates nicotinic receptors
b. nicotine in cigarette smoke is absorbed systemically
through the lungs; although nicotine activates both the
sympathetic and parasympathetic systems, differences in
dominant autonomic tone account for specific organ
effects
c. since PANS dominates most organs, nicotine has
PANS effects
d. SANS dominates blood vessels and sweat glands so
both of these get sympathetic stimulation
e. high doses cause desensitization producing the
opposite effect at various organs

Question 12

Nicotine pharmokinetics

Answer 12

a. nicotine is highly lipid soluble
b. it crosses the placental membrane and is secreted in
the milk of lactating women
c. Note: benzo(a)pyrenes in cigarette smoke act as a
P450 inducer

Question 13

Nicotinic receptors

Answer 13

a. bind acetylcholine and nicotine
b. nicotine initially stimulates and then blocks the
receptor
c. are found in the CNS, adrenal medulla,
autonomic ganglia, and the neuromuscular junction
d. two major subtypes: receptors in autonomic
ganglia (NN), and receptors at skeletal muscle end
plates (NM)

Question 14

Antimuscarinic Agents

Answer 14

These agents block muscarinic receptors. This would
include all parasympathetic impulses but also the
sympathetic impulses mediated via ACh and muscarinic receptors which include the sweat glands. These agents are clinically useful and are used in a variety of situations. These agents have no action on nicotinic receptors.

Question 15

Antimuscarinic Agents info

Answer 15

1. Classification
   a. selectivity for muscarinic receptor subtypes
   b. all muscarinic antagonists currently used clinically
   are non-selective
2. Target organ selectivity
   a. depends on lipid solubility of the drug
   b. drugs with a quaternary nitrogen are polar and
   less likely to penetrate lipid barriers such as the
   blood-brain barrier or the cornea of the eye

Question 16

atropine

Answer 16

a. is a belladonna alkaloid (Atropa belladonna) with
high affinity for muscarinic receptors; it can block
muscarinic receptors in both the central and
peripheral nervous system
b. is the prototypical antimuscarinic drug
c. pharmacokinetics: is a tertiary amine which makes
it lipid-soluble; well distributed into the CNS and other
organs; t ½ = 2 hrs with a duration of 4-8 hrs except in
the eye where effects last 72 hrs or longer

Question 17

Pharmacokinetics of other muscarinic blockers

Answer 17

a. ophthalmology: topical drugs for the eye must be
lipid soluble (tertiary amine)
b. parkinsonism: must be lipid soluble
c. gut, bronchi: not lipid soluble (quaternary
nitrogen)

Question 18

Antimuscarinic Agents moa

Answer 18

a. act as competitive antagonists at muscarinic
receptors
b. the effect of muscarinic antagonists can be
overcome with the addition of muscarinic agonists or
AChase inhibitors

Question 19

Antimuscarinic agent opthalmic

Answer 19

used to dilate the pupil (mydriasis) and to paralyze accomodation; duration of action of atropine (>72 hrs), homatropine (24 hrs), cyclopentolate (2-12 hrs), and tropicamide (0.5-4 hrs)
Muscarinic blockers are useful for dilated eye exams

Question 20

CNS

Answer 20

scopolamine for motion sickness; benztropine,
biperiden, trihexyphenidyl as adjuncts to L-DOPA for
parkinsonism

Clinical Note: Stimulation of muscarinic receptors causes nausea and vomiting;
in motion sickness the main effect of muscarinic blockers is on the vestibular
apparatus

Clinical Note: Parkinson’s disease is caused by loss of dopaminergic neurons;
as a result there is an imbalance in neurotransmitters where dopamine is too
low and ACh is too high

Question 21

Bronchi

Answer 21

parenteral atropine for reducing airway
secretions during surgery; ipratropium and tiotropium
for asthma and COPD
Both asthma and COPD are associated with bronchoconstriction;
blocking muscarinic receptors causes bronchodilation

Question 22

Gut

Answer 22

dicyclomine is used as an adjunct in PUD and

for irritable bowel syndrome

Question 23

Bladder

Answer 23

tolterodine, oxybutynin, and glycopyrrolate,
to reduce urgency and in mild cystitis to reduce bladder
spasms following urologic surgery
Clinical Note: Urinary incontinence is often treated with muscarinic blockers

Question 24

Toxicity of Muscarinic Antagonists

Answer 24

“dry as a bone, red as a beet, hot as a pistol, mad as
a hatter, blind as a bat”
Blockade of thermoregulatory mechanisms (sweating) may cause hyperthermia or “atropine fever” (“hot as a pistol”); this is potentially lethal in infants; “dry as a bone” because sweating, salivation, and lacrimation are all significantly reduced or stopped
Acute angle-closure glaucoma, especially in the elderly
4. Urinary retention, constipation, blurred vision (“blind as a bat”)
5. CNS effects: sedation, amnesia, delirium,
hallucinations (“mad as a hatter”)
Cardiovascular effects: dilation of the cutaneous
vessels of the arms, head, neck, and trunk; this is known as “atropine flush” (“red as a beet”) and may be diagnostic of overdose with these drugs

Question 25

Nicotinic Antagonists

Neuromuscular Blockers

Answer 25

All of these drugs are structurally similar to acetylcholine.
Succinylcholine, for example, is composed of two molecules of
acetylcholine linked end-to-end. Several of these drugs are
built off of a steroid-like nucleus. All drugs have one or two
quaternary nitrogens making them unable to effectively enter
the CNS due to poor lipid solubility.

Question 26

Non-depolarizing moa

Answer 26

tubocurarine is considered the prototype even though it is no longer used; competitive inhibitors of ACh binding to NM receptors; drugs bind to one of the alpha subunits on the NM receptor; antidotes include AChase inhibitors such as neostigmine or
pyridostigmine (ACh)

Question 27

Non-depolarizing

therapuetic use

Answer 27

surgical relaxation especially for intra-
abdominal or intrathoracic procedures; tracheal intubation
during general anesthesia; control of ventilation in patients
with ventilatory failure; seizures to control motor activity
(not to stop the seizure)

Question 28

Non-depolarizing pharm

Answer 28

drugs are classified by duration of
action; mivacurium has the shortest duration but a slower
onset of action compared to SCh; atracurium is
spontaneously inactivated to a metabolite called
laudanosine which may cause seizures; atracurium has
largely been replaced by an isomer called cisatracurium
which produces less laudanosine; rocuronium has the most
rapid onset time (1-2 minutes)

Question 29

non depolarizing intermediate

Answer 29

Cisatracurium

Rocuronium

Question 30

non depolarizing long

Answer 30

Pancuronium

Question 31

non depolarizing SE

Answer 31

muscarinic block for pancuronium
(tachycardia); histamine release for mivacurium
(hypotension and reflex tachycardia)

Question 32

non depolarizing general features

Answer 32

during anesthesia, administration of
non-depolarizing NM blockers initially causes motor weakness followed by skeletal muscles becoming flaccid
and inexcitable to electrical stimulation; smaller muscles
are paralyzed first and the diaphragm is usually last to be
affected (but first to recover)

Question 33

Depolarizing moa

Answer 33

succinylcholine (SCh) is the only drug in this
category; it works just like ACh and binds to both alpha
subunits on the NM receptor to open the ion channel and
cause depolarization of the motor end plate and muscle
contraction

Question 34

SCh phases

Answer 34

phase I: depolarizing, inc by Achase inhib, muscle contraction then flaccid paralysis

phase II: desensitizing, little/ no affect of Achase inhib, membrane repolarizes but cannot easily depolarized

Question 35

depolarizing use & kinetics

Answer 35

Therapeutic use: same as for non-depolarizing but
especially useful in tracheal intubation

Pharmacokinetics: transient muscle fasciculations occur in
the chest and abdomen within 30 seconds (gen. anesthesia
and non-depol. drugs can prevent this); arm, neck, and leg
muscles are relaxed by 90 seconds followed by the
respiratory muscles; rapidly hydrolyzed by plasma and
liver cholinesterase so duration is ~10 min.

Question 36

depolarizing SE

Answer 36

SCh can stimulate muscarinic receptors
(bradycardia) and NN receptors; hyperkalemia (especially
in burn pts, head injury and other trauma); muscle pain
(due to initial muscle contraction)

Question 37

depolarizing drug interactions

Answer 37

SCh + inhaled anesthetics = malignant
hyperthermia (rare but life-threatening) is associated
with abnormal release of calcium from skeletal muscle;
treat with dantrolene

Question 38

Dantrolene moa & use

Answer 38

MOA: binds to the ryanodine receptor calcium channel
(RyR1) blocking its opening and preventing calcium release
and muscle contraction
Therapeutic use: malignant hyperthermia; patients at
highest risk for this condition have a genetic alteration in
the RYR1 that results in prolonged release of calcium,
massive muscle contraction, lactic acid production, and
increased body temperature; the risk in these patients is further increased by SCh and inhaled anesthetics

Question 39

Botulinum toxin

Answer 39

a. MOA: blocks ACh release
b. Therapeutic use: local facial injections for wrinkles; spasticity (cerebral palsy); strabismus and
blepharospasm; hyperhidrosis; migraines

Question 40

Centrally-acting Skeletal Muscle Relaxants

Answer 40

These drugs are used for spasticity (sometimes called
spasmolytics) which is characterized by an increase in tonic
stretch reflexes and flexor muscle spasms together with muscle
weakness. Spasticity is often associated with spinal injury,
cerebral palsy, multiple sclerosis, and stroke. These conditions
often involve abnormal function of the bladder and bowel as
well as skeletal muscle.

Question 41

Diazepam (benzodiazepine)

Answer 41

a. MOA: GABAA (Cl- channel) allosteric agonist that causes hyperpolarization via increased Cl-conductance and inhibition of neuronal activity; works centrally to reduce spasticity
b. Other: at doses that produce muscle relaxation it also causes sedation

Question 42

Baclofen

Answer 42

a. MOA: is a GABAB (K+ channel) allosteric agonist that causes hyperpolarization via increased K+ conductance and inhibition of neuronal activity; presynaptically this action reduces calcium influx and prevents neurotransmitter release (glutamate in the brain, and substance P in the spinal cord); postsynaptically it prevents the propagation of action potentials
b. Other: causes less sedation than benzodiazepines

Question 43

Tizanidine

Answer 43

a. MOA: a2 agonist; centrally this action prevents neurotransmitter release (glutamate presynaptically) and propagation of action potentials (postsynaptically)
b. Other: fewer cardiovascular effects than clonidine and methyldopa (both are 2 agonists used for hypertension)
but may cause hypotension and drowsiness

Question 44

Riluzole

Answer 44

sodium channel blocker used for amyotrophic 
lateral sclerosis (ALS, Lou Gehrig’s disease); slows disease progression and ↑ survival