ANS Pharmacology

Cholinergic

refers to neurons that use acetylcholine as their synaptic transmitter

Cholinergic Neuron Pathway

1. Choline comes into the cell
2. ACh is formed
3. ACh is put into a vesicle
4. ACh is released into the synaptic cleft

Which enzyme degrades ACh?

Acetylcholinesterase (AChE)

What role does Botox play in the cholinergic neuron?

blocks the release of ACh from the vesicle by blocking fusion with the presynaptic membrane

Risk-Benefit Ratio

major consideration when designing drugs

Cholinomimetics

agents which INCREASE cholinergic signaling

(cholinergic antagonist)

ex: direct and indirect acting

What effects cholinergic agonism?

• Receptor specificity
• Tissue specificity
• Dose response curve

Which receptor will not allow cholinergic agonism?

alpha and beta receptors

Which receptors allow cholinergic activity?

muscarinic and nicotinic receptors

T/F: Cholinergic Agonism = PNS activation

FALSE

Which type of molecule can cross the blood brain barrier?

hydrophobic, usually small

What is the effect of low doses of ACh?

muscarinic stimulation at target organs

Muscarinic Stimulation Effects

• SLUDS
• Decreased HR
• Decreased BP
• Bronchoconstriction
• DUMBBELSS

SLUDS

Salivation
Lacrimation
Urination
Defecation
Sweating

Peripheral Effects

DUMBBELSS

Diarrhea
Urination
Miosis (constriction)
Bronchorrhea (mucus)
Bradycardia
Emesis (vomiting)
Lacrimation
Salivation
Sweating

Peripheral AND Central

Why is sweating an effect of muscarinic stimulation?

the nerve itself is cholinergic with muscarinic receptors

(SNS action but occurs with ACh stimulation)

Why is ACh binding to muscarinic receptors important for medication?

you cannot stimulate the PNS directly to affect blood vessels as they are not innervated; you must administer ACh to cause vasodilation on endothelial cells

Will administered ACh yield central effects?

At higher doses of ACh, what effects do you begin to see?

nicotinic effects at the NMJ, brain, and ganglion

Nicotinic Stimulation Effects

fasciculations (look like shivering) due to toxic levels of cholinergic signaling

Direct-Acting Cholinomimetics

bind directly to and activate muscarinic or nicotinic receptors

ACh receptor agonists

Examples of Direct-Acting Cholinomimetics

• Bethanechol
• Muscarine (natural)
• Pilocarpine (natural)

Bethanechol

ACh + methyl group = muscarinic specific

ester to amide = resistant to AChE

Bethanechol Uses

bladder and bowel motility (urinary retention)

Bethanechol Adverse Effects

• SLUDS
• Bronchoconstriction

What is a contraindication for bethanechol?

asthma -- causes bronchoconstriction with muscarinic activation

What is a sign of too much Bethanechol?

frequent drooling, sweating, urination

Muscarine

muscarinic agonist that does NOT cross the BBB

not used clinically

Is muscarine metabolized?

no -- it is cleared renally

Pilocarpine

muscarinic agonist mainly used to increase secretions

Pilocarpine Effects

• Decreased intraocular pressure (glaucoma)
• Increases salivation (dry mouth)
• Miosis
• Sweating

SNS Effect on the Pupil

binding to alpha 1 receptor to cause dilation

known as mydriasis

PNS Effect on the Pupil

binding to M3 receptor to cause constriction

known as miosis

Patients on hard drugs (meth) commonly exhibit _ of the pupils.

dilation -- major sympathetic stimulation

Nicotine

activates nicotinic cholinergic receptors

neither direct or indirect

activates dopamine reward pathway

Nicotine Effects

• Enhances concentration, memory, problem solving
• Alertness, relaxation
• Suppresses appetite
• Tachyphylaxis
• Central and peripheral

Tachyphylaxis

rapid decrease in response to a drug due to repeated administration

Nicotine Adverse Effects

• Irritability and tremors
• GI
• Increased HR and BP
• Withdrawal syndrome

Acetylcholinesterase (AChE)

works fast at synapses to clear it of ACh

Butyrylcholinesterase

"pseudocholinesterase"

widely distributed to ensure ACh does not persist outside the synapse

Indirect Acting Cholinomimetics

AChE inhibitors

Acetylcholinesterase (AChE) Inhibitors

keep more ACh in the synapse to prolong stimulation

AChE Inhibitor Effects

increases tone at NMJ, increases muscarinic activity, and enhances central cholinergic signaling by increasing the amount of ACh in the synaptic cleft

also used in pesticides and nerve gas

What are some common reasons to use an AChE inhibitor?

Myasthenia gravis, Alzheimer's

Why is AChE inhibitor used for Alzheimer's?

enhances executive function and memory via cholinergic signaling

ex: Donepezil

Myasthenia Gravis

autoimmune neuromuscular disorder characterized by weakness of voluntary muscles due to antibodies blocking ACh receptors at the NMJ

Why is AChE inhibitor used for Myasthenia gravis?

MG patients have muscle weakness; inhibiting AChE will increase available ACh in the synaptic cleft

Reversible AChE Inhibitors

quaternary amines that bind AChE, cleave it, and inactivate it

longer half life than older agents, causing it to be taken less frequently (1-2x a day)

Reversible AChE Inhibitors Examples

neostigmine, pyridostigmine, and carbaryl

(quaternary amines)

Why do Reversible AChE Inhibitors have no CNS actions?

cannot cross the BBB due to charge

Uses for Reversible AChE Inhibitors

• MG
• Glaucoma (muscarinic receptors increase aqueous outflow to decrease eye pressure)

Which Reversible AChE Inhibitor has the longest half life?

pyridostigmine

Adverse Effects of Reversible AChE Inhibitors

rare at therapeutic doses but can be seen in the elderly and children with high exposure

Irreversible AChE Inhibitors

chemically reacts and modifies AChE in a two-step process

final product is stable and would take way too long to undo without the proper enzyme

Irreversible AChE Inhibitors Examples

organophosphates and thiophosphates

Irreversible AChE Inhibitor Effects

ALL expected effects of ACh excess:

• SLUDS
• Fasciculations
• Seizures

Which enzyme, if delivered quickly, can reverse AChE inhibition?

pralidoxime (2-PAM)

How does 2-PAM work?

removes the covalent modification after the first step of the reaction and prevents irreversible step

At which point would 2-PAM not work?

after the second (irreversible) step is completed

If someone exposed to chemical agents presents with SLUDS, what is the most rational next step?

treat them ASAP with atropine and 2-PAM

What should be considered in rehab for a patient taking a cholinergic?

• Dyspnea (due to bronchoconstriction)

• Increased urination frequency (especially with abdominal contraction)

• No pupil dilation in low light (increases risk of falling)

• Decreased performance when using nicotine (increases BP and decreases blood O2 carrying due to increased plasma carbon monoxide)

Cholinergic Blockers/Anticholinergics

agents that decrease cholinergic signaling

ganglionic blockers, NMJ blockers, and antimuscarinic drugs

Where do ganglionic blockers act?

at the nicotinic receptor

Where do antimuscarinic drugs act?

muscarinic receptors

Where do neuromuscular blockers act?

nicotinic receptors on skeletal muscle

Effects of Muscarinic Antagonism

• Vasoconstriction
• Pupil dilation
• Decreased salivation
• Bronchodilation
• Increased HR
• Decreased GI tone
• Decreased excretion and urination

Low Dose Muscarinic Antagonism

decreased secretions, dry mouth mainly

Medium Dose Muscarinic Antagonism

• Decreased sweating
• Decreased bladder tone
• Increased HR
• Mydriasis
• Loss of accommodation

High Dose Muscarinic Antagonism

• Decreased GI motility
• CNS effects (memory)

Toxic Dose Muscarinic Antagonism

hallucination and convulsions

Muscarinic Antagonists are commonly given for .

overactive bladders

Why can muscarinic antagonists be an issue in geriatric populations?

memory issues may already exist and can be worsened

Which muscarinic antagonist is given during an eye exam and why?

Scopolamine drops -- dilate the eye by blocking muscarinic receptors in the vestibular system

reason you can't read after an eye exam

Adverse Effects of Scopolamine

drowsiness, dry mouth, blurred vision

can very easily cross BBB and have CNS effects

If you apply a muscarinic antagonist to a patient's eye, what will happen to their pupil size?

increase

Atropa belladonna

poisoning occasionally used for hallucinogenic effects as it crosses the BBB

Symptoms of Atropa Poisoning

same as toxic doses of antimuscarinics -- convulsions and hallucinations

Pneumonic for Atropa

Blind as a bat (dilation)
Red as a beet (increased temperature)
Dry as a bone (decreased sweating)
Mad as a hatter (not thinking well)

Treatment for Atropa Poisoning

AChE Inhibitor

Examples of Muscarinic Blockers

Atropine
Scopolamine
Oxybutynin
Tolterodine
Ipratropium
Tiotropium
Benztropine

Atropine

muscarinic antagonist that blocks muscarinic receptors

Atropine Effects/Uses

• Raises HR (treat bradycardia)
• Improve AV conduction
• Treats organophosphate poisoning

Scopolamine Uses

prevent motion sickness

Tolterodine Uses

treats overactive bladder; better tolerated than oxybutynin

Ipratropium/Tiotropium

treats COPD (bronchodilation)

Tiotropium has a longer half life

Benztropine Uses

Parkinson's Disease

Muscarinic Blocker Adverse Effects

Dry mouth
Confusion

You are working with a pt with a stable spinal cord injury at T10. He is on drugs to reduce spasticity, including tolterodine to treat spastic bladder. You and he begin work with a sliding board transfer from the wheelchair; he urinates involuntarily during his initial attempt. He is embarrassed and states this happened before and requests to end session. What could have happened here (caused this)?

He likely took his medicine right before he came. Schedule the session a couple of hours after he usually takes his medication.

What should be considered in rehab with a patient taking anticholinergics?

• Hyperthemia (inhibition of sweating)
• Increased HR
• Decreased pupil constriction (light sensitive)
• Decreased cognitive activity (especially in older adults)
• Sedation

When working with an older adult taking an anticholinergic that exhibits decreased cognitive ability during the session, what should you do?

maybe do exercise just before the next dose

Indirect Acting ACh Blocker

Botox

Botox MOA

proteases that cleave SNARE proteins, inhibiting muscle spasticity and causing flaccid paralysis

can be stable and active in nerves for weeks to months

Botox Sites of Action

ACh nerve endings:

• PSNS sites (incl. urinary)
• Sweat glands
• Skeletal muscle

Botox Uses

• Cosmetic
• Dystonia
• Chronic pain
• Hyperhidrosis
• BPH
• Overactive bladder (1 yr. effect)

Adrenergic Neuron Pathway

1. Tyrosine transported into the cell
2. Tyrosine hydroxylated to DOPA
3. DOPA decarboxylated to dopamine
4. Half of DA is turned to NE in storage vesicles
5. NE leaves vesicles and it methylated to Epi
6. Ca++ causes the release of NE

Metyrosine

blocks NE synthesis

Tetrabenazine

prevents storage of NE

Pseudoephedrine & Amphetamine

promote NE release

Cocaine & Antidepressants

inhibit NE reuptake

Phenelzine

inhibit NE metabolism