AUTONOMIC PHARMOCOLOGY DRUGS

Direct-acting Cholinomimetics

- Bind to and activate either muscarinic or nicotinic receptors directly

- Similar in effect to ACh itself

- Effects depend on route of administration, pharmacokinetics, and receptor selectivity/expression

Indirect-acting Cholinomimetics

- Inhibit acetylcholinesterase

- Increase endogenous ACh levels leading to enhanced cholinergic receptor activation

- Effects larger under conditions of increased cholinergic activity and acetylcholine storage/release

Direct-acting Cholinomimetics Classes

- Muscarinic Agonists

- Nicotinic Agonists

Bethanechol (URECHOLINE) Use

Urinary Retention

Bethanechol (URECHOLINE) Class

direct-acting muscarinic agonist

Bethanechol (URECHOLINE) MOA

acts on muscarinic GPCRs on parasympathetic effector organs

- contracts urinary muscle to release urine

Bethanechol (URECHOLINE) adverse effects

- GI distress

- Sweating

- Hypotension

**All due to INC parasympathetic activity

Bethanechol (Urecholine) contraindications

asthma, ulcer

**due to the fact that parasympathetic activity decreases HR and BP

Indirect-acting Cholinomimetics Classes

AChE inhibitors

Bethanechol (Urecholine) PK

A: Poorly absorbed

D: Do not cross BBB

M: Cholinesterases

donepezil

• Pharmacologic class

• Physiologic effects

• Clinical uses

• Pharmacokinetics

• Adverse effects

Class: AChE Inhibitors

Effects: CNS

- Low Dose = Stimulation

- High Dose = Convulsions, Coms

Clinical Use: Alzheimer's Dementia

PK:

- A: good

- D: CNS --> through BBB

- M: AChE

- E: Renal (Kidneys)

AEs:

- Bradycardia

- GI Distress

malathion

• Pharmacologic class

• Physiologic effects

• Clinical uses

• Pharmacokinetics

• Adverse effects

Class: AChE Inhibitors

Effects:

Uses: Head lice

Pharmacokinetics:

- A: Rapid

- D: Widespread —> Penetrate CNS

- M: Malathion —> Maloxon —> Inactive

- Irreversible (Humans can metabolize)

AChEI's Primary sites of activity:

- Stimulation of muscarinic receptor activity at autonomic effector organs (atropine-sensitive)

- Stimulation - paralysis of autonomic ganglia and skeletal muscle (nicotinic activity)

- Stimulation - depression of cholinergic receptor activity in the CNS

AChEI compounds with ____________________ are poorly absorbed, do not cross BBB, act primarily at NMJ

4 degree ammonium

AChEI __________________ compounds are well absorbed, cross BBB, exert both peripheral and central actions

Lipid-soluble

Clinical uses of ACHEs

Peripheral

- GI / Urinary Smooth Muscle Atony (Contraction)

- Glaucoma (Dec eye pressure)

- Myasthenia Gravis (Dec muscle activity)

- Reversal of neuromuscular activity

- Anticholinergic Intoxication

Central

- Alzheimer's Dementia (suppression of neurological activity)

rivastigmine

• Pharmacologic class

• Physiologic effects

• Clinical uses

• Pharmacokinetics

• Adverse effects

Class: AChE Inhibitors

Effects: CNS

- Low Dose = Stimulation

- High Dose = Convulsions, Coms

Clinical Use: Alzheimer's Dementia

PK:

- A: good

- D: CNS --> through BBB

- M: AChE

- E: Renal (Kidneys)

AEs:

- Bradycardia

- GI Distress

neostigmine

• Pharmacologic class

• Physiologic effects

• Clinical uses

• Pharmacokinetics

• Adverse effects

Class: AChE Inhibitors

Effects:

- Initial muscle contraction

- Later fasciculations --> Paralysis

Use: Myasthenia Gravis (Muscle Disease)

PK:

- A: poor

- D: local

- M: AChE

- E: Renal

sarin

• Pharmacologic class

• Physiologic effects

• Clinical uses

• Pharmacokinetics

• Adverse effects

Class: AChE Inhibitors

Effects:

Use: Nerve Gas

PK: Irreversible

AEs:

- Extreme cholinergic crisis

- Death

Cholinergic Crisis Therapy

Artificial Respiration

Decontamination

Atropine & Pralidoxime

Diazepam

Cholinergic Crisis Prevention

Atropine & Pralidoxime

Cholinergic Crisis Causes

Pesticide Use (malathion)

Nerve Gas Agents (Sarin)

Cholinergic Crisis Signs:

DUMBBELLS

Diarrhea

Urination

Miosis

Bradycardia

Bronchoconstriction

Excitation (Muscle + CNS)

Lacrimation (the flow of tears)

Salivation

Sweating

CNS Involvement (Confusion, ataxia, convulsion, coma)

DUMBBELLS

Diarrhea

Urination

Miosis

Bradycardia

Bronchoconstriction

Excitation (Muscle + CNS)

Lacrimation (the flow of tears)

Salivation

Sweating

Pralidoxime is most effective at the _____________

NMJ - cannot penetrate CNS

Pralidoxime is ineffective in the CNS due to N+, so it is given with Atropine

Pralidoxime Use

organophosphate poisoning

- cholinergic crisis

caused by Pesticide Use (malathion) & Nerve Gas Agents (Sarin)

Belladonna Class & MOA

muscarinic antagonist

block receptors in the muscles of the eye that constrict pupil size

Belladonna Use

Increase pupil size

MOA of Antimuscarinics

Bind to muscarinic receptors with high affinity

Competitively inhibit activity of ACh

- Competitive Inhibitor: Binds to the same site as the endogenous ligand (ACh) and blocks the pathway

Atropine Drug Class

muscarinic antagonist

Uses of Antimuscarinics

• Muscarinic poisoning

• Anticholinesterase poisoning/cholinergic crisis:

- Insecticide/pesticide exposure

- Nerve gas exposure (high doses needed)

• Hyperhidrosis (excessive sweating)

• Parkinson's disease and drug-induced parkinsonism

• Anesthesia

Antimuscarinic Contraindications

Relative, not absolute

• Glaucoma

• BPH (may increase urinary retention)

• Peptic ulcer (especially nonselective agents)

• Geriatric patients (may impair memory/cognition)

Atropine Fever

Due to decreased sweating with atropine which increases internal temperature

NMJ Blockers Uses

• Used during surgical procedures and in the ICU to produce muscle paralysis

• Adjuncts during general anesthesia to relax skeletal muscle (abdominal)

• Facilitation of endotracheal intubation

NMJ Blockers block ____________________

nicotinic receptors at NMJ (NM)

Non-depolarizing NMJ Blockers MOA

Competitive antagonists of ACh binding to Nm receptors

- Keeps the channel closed and prevents ACh from binding

Non-depolarizing NMJ Blockers can be reversed by _________________

AChE Inhibitors

Succinylcholine MOA

- Depolarizing Nm blocker

- Stimulates Nn and Cardiac M receptors

**Depolarizing NMJ Blocker

Competitive antagonists of ACh binding to Nm receptors

- Opens the channel and keeps it open

- Initial muscle excitation followed by prolonged paralysis (depolarizing blockade)

Succinylcholine Drug Class

Depolarizing NMJ Blocker

Succinylcholine is ___________________ resistant

AChE resistant

Depolarizing NMJ Blocker MOA

Opens the channel and keeps it open

- Initial muscle excitation followed by prolonged paralysis (depolarizing blockade)

Succinylcholine AEs

- Arrhythmias

- Hyperkalemia (Due to no sodium moving in due to no action potential, so K+ cannot move out of the cell)

- Increased IOP (Intraocular pressure)

Pancuronium MOA

Non-depolarizing NMJ Blocker

- Competitive antagonists of ACh binding to Nm receptors

- Keeps the channel closed and prevents ACh from binding

Pancuronium DOA

Long DOA (increased with renal dysfunction)

Pancuronium dosage must be altered if ______________

the patient has renal dysfunction because the drug is renally eliminated

- Will stay in the body longer if pt has renal impairment

Pancuronium AEs

Tachycardia (M-mediated)

Reversal of Non-depolarizing NMJ Blockers

AChE Inhibitors antagonize the blockade produced by non-depolarizing agents (neostigmine + atropine)

- SUGAMMADOX (BRIDION)

Mecamylamine (VECAMYL) is indicated in

severe hypertension

Mecamylamine (VECAMYL) MOA

Non-depolarizing blockade of Nn receptors at the ganglion

Mecamylamine (VECAMYL) Physiological Effects

Both sympathetic and parasympathetic effects

• Sedation, tremor, mental status change

• Cycloplegia, moderation dilation

• Hypotension, tachycardia

• Decreased motility/constipation

• Urinary retention, impaired sexual function

• Dry mouth, anhidrosis

Nicotine MOA

Initial Nicotinic Receptor Stimulation

- More CNS and Nn than Nm

- Depolarization & action potential generation

High doses stimulate more Nn and Nm receptors

Subsequent depolarizing blockade

- Neurons stop firing, skeletal muscle relaxes

- Postsynaptic cell unresponsive

Varenicline MOA

alpha7 nAChR full agonist

alpha4beta2 partial agonist

effects restricted to CNS

Varenicline effects are restricted to ___________

CNS

Nicotine Use

Smoking Cessation

Nicotine AEs & Contraindications

Nausea

Vomiting

Diarrhea

Increased BP

Seizures

Varenicline Use

Smoking Cessation

Varenicline AEs & Contraindications

Nausea

Insomnia

Exacerbation of psychiatric illness

Neonicotinoids

These chemicals mimic the acetylcholine neurotransmitter and are highly neurotoxic to insects, their use has been linked to bee population collapse

alpha-1:

vessels

phenylephrine drug class & effects

alpha-1 agonists

- nasal decongestant

Effects:

- contraction of vessels (vasoconstriction) —> INC TPR (total peripheral resistance)

- increased BP

alpha-2:

postsynaptic CNS, presynaptic autonomic

clonidine drug class & effects

alpha-2 agonists:

- hypertension

Effects:

- reduced sympathetic outflow

- presynaptic inhibition

- DEC mean BP

prazosin drug class & effects

alpha-1 antagonists

- hypertension

- BPH

Effects:

- Vessels: dilation —> DEC BP

- Eye: Miosis

- Prostate: Relaxation

yohimbine drug class & effects

alpha-2 antagonists:

Effects:

- presynaptic autonomic

- tachycardia

yohimbine use

used in veterinary medicine to reverse the effects of xylazine in dogs and deer

beta-1:

heart

Dobutamine drug class & effects

beta-1 agonists

- cardiogenic shock/heart failure

Effects:

- INC force & rate of contraction

beta-2:

lungs, vessels, uterus

Albuterol drug class & effects

beta-2 agonists

- asthma

Effects:

Smooth muscle relaxation (bronchodilation)

beta-3:

+ agonists: Mirabegron

detrusor relaxation

bladder

Mirabegron drug class & effects

beta-3 agonists

- urinary incontinence

Effects:

detrusor relaxation

isoproterenol drug class & effects

non-selective beta agonists

- bradycardia

Effects:

- vasodilation —> DEC TPR

- cardiac: increased contractility —> INC HR & cardiac output

- decreased mean BP

metoprolol drug class & effects

beta-1 antagonists:

- hypertension

Effects:

DEC force & rate of contraction —> DEC BP & HR

butoxamine drug class & effects

beta-2 antagonists:

Effects:

- smooth muscle contraction (bronchoconstriction)

propranolol drug class & effects

beta 1 = beta 2 antagonist

Effects:

- DEC HR & BP

- Bronchoconstriction

First Generation Beta Blockers

Not selective between beta 1- and beta 2-adrenergic receptors

Second Generation Beta Blockers

Selective for beta 1-adrenergic receptors

Third Generation Beta Blockers

Have effects other than beta adrenergic receptor blockade

Some are selective for beta-1 adrenergic receptors, while others block both beta 1- and beta 2-adrenergic receptors

Epinephrine drug class and effects

alpha/beta agonists (alpha = beta)

- Indication: Anaphylaxis

Effects:

- Cardiac: increased contractility —> INC HR & cardiac output

- Increased mean BP

Norepinephrine drug class and effects

alpha/beta agonists - (alpha >>> beta - no beta-3)

- Indication: Shock/Severe HTN

Effects:

- Positive chronotrope (INC HR), positive inotrope (INC blood pumped by heart) - overcome by baroflex

- Increased BP

reflex bradycardia

low heart rate caused by the baroreceptor reflex

reflex bradycardia seen in what sympathomimetic?

norepinephrine bc it primarily affects alpha 1 and alpha 2 greater than beta 1

labetalol

alpha/beta antagonists

Effects:

- DEC HR & cardiac output

- DEC BP

- Eyes: Miosis

- Bronchoconstriction

- Prostate: Relaxation