Autonomic Pharmacology

midterm 1 pharm

What does the autonomic nervous system ensure?

ensures that the internal environment functions optimally even when the external environment changes

Membrane Potential

- Needed in excitable cells (nerve & muscle)

- Result from a difference in electrical charge across the plasma membrane of a neuron

- Changes in membrane potential above a threshold lead to action potential

Action Potential

- sudden reversal of electric charge across the membrane of a resting neuron

- begins when neuron receives signal from another cell

- Signal causes Na+ channels to open, allowing Na+ to flow into cell = positively charged

- start in cell body, travel down the axon, & end at the axon terminal

synapse

- Space between the axon terminal of one cell & dendrites

- Neurotransmitters travel across synaptic cleft & bind to receptors on the postsynaptic membrane

The Somatic Nervous System

- Responsible for carrying motor and sensory information to and from the central nervous system

- Made up of nerves that connect to the skin, sensory organs, and all skeletal muscles

Acetylcholine & the Neuromuscular Junction

Peripheral Nervous System

Neurons and ganglia outside of the brain and spinal cord

General Autonomic Nervous System Properties

- controls glands, cardiac & smooth muscle

- Regulates unconscious processes that maintain homeostasis

- BP, body temperature, respiratory airflow

- Visceral reflexes

Main neurotransmitters of the ANS

acetylcholine (ACh) and norepinephrine (NE)

Preganglionic neuron of ANS

- cell body in brain or spinal cord

- Axon is myelinated fiber that extends to autonomic ganglion

Postganglionic neuron of ANS

- Cell body lies outside the CNS in an autonomic ganglion

Sympathetic neuron chain

Parasympathetic neuron chain

Cholinergic neurons release...

acetylcholine (ACh) from preganglionic neurons & from parasympathetic postganglionic neurons; can excite of inhibit depending on receptor

Nicotinic receptors

- found on dendrites and cell bodies of ANS cells at the NMJ

- Ion channels (Ionotrophic)

Muscarinic receptors

- plasma membranes of all parasympathetic effectors

- G-protein coupled (Metabotrophic)

Adrenergic neurons release...

norepinephrine (NE) from postganglionic sympathetic neurons only (excites or inhibits depending on receptor)

What adrenergic receptors cause excitation?

Alpha1 (α1) and Beta1 (β1)

What adrenergic receptors cause inhibition?

Alpha2 (α2) and Beta2 (β2)

What adrenergic receptors inc thermogenesis (brown fat)?

Beta3 (β3)

What is acetylcholine synthesized from?

- Acetyl CoA (mitochondria)

- choline (dietary)

- Catalyzed by cholineacetyl transferase (ChAT)

When enzyme metabolizes ACh?

Acetylcholinesterase (common drug target)

Where are nicotinic receptors found?

- ganglions

- skeletal muscle (NMJ)

- neurons in CNS

What are some sympathetic targets of ACh?

eccrine sweat glands and blood vessels in skeletal muscle

Where do you find muscarinic receptors?

at parasym target organs (effectors)

Nicotinic Acetylcholine Receptor (AChR)

- has 5 polypeptide subunits

- receptors vary in subunit structure, agonist sensitivity, & distribution

- mediate FAST synaptic transmission

Muscarinic AChRs

- M1-M5

- GCPRs

- Slower synaptic transmission via intracellular signaling cascade

Direct Acting of Cholinergic Agonists/Parasympathomimetics

drug acts right on postsynaptic receptor

Indirect Acting of Cholinergic Agonists/Parasympathomim

- Inhibit Acetylcholinesterase enzyme, which breaks down acetylcholine (reversibly or irreversibly)

- AKA anticholinesterases

- Inc amount of ACh

- Ex) Neostigmine (Bloxiverz) & Pyridostigmine (Mestinon)

Cholinergic effect on eye

miosis

cholinergic effect on cardiovascular

dec heart rate

cholinergic effect on respiratory

Bronchial constriction and increased secretions

cholinergic effect on GI

Increased motility and relaxation of sphincters (inc defecation)

cholinergic effect on genitourinary

Relaxation of sphincter sand bladder wall contraction

cholinergic effect on glands

inc. secretions

Esters of choline =

structurally related to ACh (see -chol- in name)

Alkaloids of choline =

not related to ACh (usually plant derivatives); Main reason for distinction is that alkaloids, due to structure, are NOT metabolized by cholinesterases (ex: pilocarpine)

BETHANECHOL (Urecholine)

- choline ester

- Short duration of action (several minutes)

- Used to stimulate bladder or GI muscle

CARBACHOL (Miostat)

- choline ester

- Intraocularly to produce miosis during ophthalmic surgery

- Can also decrease IOP after surgery

PILOCARPINE (Salagen)!

- plant alkaloid from small shrub Pilocarpus

- Greater affinity for muscarinic receptors than for nicotinic

- Ocular: Miosis (pupil constriction), glaucoma

- direct acting

Neostigmine (Bloxiverz) & Pyridostigmine (Mestinon)!

- reversible anticholinesterases (inc ACh/cholinergic)

- Used to reverse the effects of nicotinic antagonists like curare

- Used to treat myasthenia gravis

Aricept (DONEPEZIL)!

- indirect acting cholinergic drug by inhibiting AChE

- tx for Alzheimer's pts (they have low lvls of ACh)

- reversible

Reversible Inhibitors of AChE

- compete w/ acetylcholine for active site on cholinesterase

- include the quaternary amines and the carbamates

- include drugs w/ names ending in "-stigmine" & "-nium"

Irreversible inhibitors of AChE

- phosphorylate the enzyme & inactivate it

- Widely used as insecticides (commonly referred to as nerve gases); Organophosphates are lipid soluble & rapidly cross membranes, including skin & blood-brain barrier

Toxicity of Cholinergic Stimulants =

- D = diarrhea

- U = Urination

- M = miosis

- B = brachycardia

- B = Brochoconstriction

- E = Excitation (paralysis, ataxia, seizures)

- L = lacrimation

- S = Salivation & sweating

Cholinergic Toxidrome

- Muscarinic Symptoms: salivate, lacrimate, urinate, defecate, GI cramps, vomiting

- Nicotinic Symptoms: muscle cramps, tachycardia, weakness, twitching, fasiculation

Cholinergic Antagonists/Parasympatholytics

antagonize the effects of acetylcholine (most directly to the receptors, but others block ACh release)

Muscarinic blockers

Relax smooth muscle, decrease gland secretions, increase heart rate

Nicotinic blockers

Relax skeletal muscle during surgery

Muscarinic Antagonists Effects (Anticholinergic Toxidrome)

- dry mouth (no salivation)

- mydriasis

- flushing, inhibits sweating

- inc heart rate

- bronchodilation, inhibit secretions

- GI: reduced motility & secretions

- urinary retention

- Drowsiness, hallucinations, coma (CNS fx)

Uses of Muscarinic Antagonists

- dilate pupils

- tx for COPD

- Prevent salivation during surgery

- ntispasmodics, antinausea

Neuromuscular Blockers

- Competitive neuromuscular blocking used to produce skeletal muscle relaxation

- Bind ALL nicotinic receptors (at the neuromuscular junction & autonomic ganglia)

- Depolarizing = bind receptor & open ion channel, resulting in depolarization of the end plate

- Non-depolarizing = bind receptor, but do not open ion channel

Succinylcholine (Quelicin) Phases

1. Activates ACh receptors, but chronic depolarization at the muscle end-plate leads to inactivation of voltage-gated Na+ channels & 'flaccid paralysis' (short acting)

2. After chronic exposure to succinylcholine, Ach receptors desensitize (longer acting)

Succinylcholine (Quelicin)!

- Paradoxically causes persistent membrane depolarization that inactivates (desensitizes) Na+ channels & blocks neuromuscular (NM) transmission

- depolarizing neuromuscular blocker

Non-Depolarizing Nicotinic Antagonists

- Pancuronium and D-tubocurarine (curare)

- Muscle relaxation for surgery

- competitive antagonists at nicotinic receptor

- Selectivity is not good

Why do we want to co-administer a muscarinic antagonist with a neuromuscular blocker?

We want to avoid too much ACh from getting to muscarinic receptors to prevent Cholinergic Toxidrome

How can effects of neuromuscular blockers be reversed?

add a cholinesterase inhibitor (increases amount of ACh available to compete with antagonist)

Botulinum toxin (Botox)

- breaks down SNAREs

- inhibits acetylcholine releasefrom somatic nerves

- Can treat problemscaused by muscle spasms