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Autonomic Pharmacology

Afferent pathways carry sensory signals which way?

Towards the CNS

Which way do efferent pathways carry motor commands?

Away from the CNS out to the muscles and glands

Autonomic

Involuntary

Somatic

Voluntary

Sympathetic

Fight or flight

Parasympathetic

Rest and digest

The autonomic nervous system is mainly activated in

the spinal cord, brain stem, hypothalamus, and portions of the cerebral cortex (limbic cortex)

Somatic System

Parasympathetic

Sympathetic

Innervate all innervated structures of the body except skeletal muscle, synapse may be outside CNS, form extensive peripheral plexus, preganglionic neurons- myelinated, postganglionic neurons - nonmyelinated, Innervated tissue has some degree of spontaneous activity in the absence of innervation

Autonomic characteristics

Innervate skeletal muscle, synapse always within CNS, no peripheral plexus, myelinated, skeletal muscle does not contract without innervation

Somatic characteristics

Short preganglionic neuron and long postganglionic neuron

sympathetic neurons

Long preganglionic neuron and short postganglionic neuron

Parasympathetic neurons

Sympathetic neurons exit the CNS through

thoracic and lumbar vertebrae

Parasympathetic neurons exit the CNS through

Cranium and sacral vertebrae

Main autonomic neurotransmitter

ACh, NE, Epi, D

Acetylcholine is the neurotransmitter in

preganglionic neurons, postganglionic parasympathetic neurons, a few sympathetic neurons (sweat glands)

Norepinephrine is the neurotransmitter in

most postganglionic sympathetic neurons

Sympathetic postganglionic neurons that innervate sweat glands use what as a neurotransmitter

Acetylcholine

The cells of the adrenal medulla are analogous to

postganglionic cells of the sympathetic nervous system

Cells of the adrenal medulla release

epinephrine and norepinephrine into the bloodstream

Parasympathetic

Sympathetic

Sympathetic

Sympathetic

Somatic

Adrenaline

Noradrenaline

Dopamine

Acetylcholine

Enzyme turns tyrosine into dopa

tyrosine hydroxylase

tyrosine hydroxylase turns tyrosine into

Dopa

Aromatic L-amino acid decarboxylase turns dopa into

dopamine

dopamine beta-hydroxylase is the enzyme that turns what into what

dopamine into norepinephrine

phenylethanolamine-N-methyltransferase turns what into what

Norepinephrine into epinephrine

Norepinephrine turns into epinephrine only where

Adrenal medulla and a few epinephrine-containing neuronal pathways in the brainstem

Norepinephrine is cleared from the synapse primarily by reuptake into the neuron that released it

Reuptake 1

Norepinephrine is cleared by uptake into the postsynaptic cell

reuptake 2

Origin of preganglionic neuron in sympathetic nervous system

thoracic/lumbar

Origin of preganglionic neuron in the parasympathetic nervous system

cranial/sacral

Nicotinic receptor is used as a receptor for ganglionic neurotransmitter in what system

Sympathetic and parasympathetic

Receptors present on effector cells innervated by postganglionic neurons sympathetic

alpha/beta adrenergic

Receptors present on effector cells innervated by postganglionic neurons parasympathetic

muscarinic

Parasympathetic primary mechanism of terminating neurotransmitter signal

reuptake

Sympathetic primary mechanism of terminating neurotransmitter signal

enzymatic hydrolysis

pupils constrict, stimulate saliva, slow heartbeat, constrict airways, stimulate activity of stomach, stimulate gallbladder, stimulate activity of intestines, contract bladder

Parasympathetic

Dilate pupils, inhibit salivation, increase heartbeat, relax airways, inhibit activity of stomach, inhibit gallbladder, inhibit activity of intestines, secrete epinephrine and norepinephrine, relax bladder

Sympathetic

ANS receptors - cholinergic

muscarinic (m1,m2,m3,m5,m5) and nicotinic (nn and nm)

ANS receptors - adrenergic

alpha-adrenergic (alpha 1 and 2) and Beta-adrenergic (beta 1, 2, 3)

Sympathetic activity receptors in organs

adrenergic excepts for in sweat glands

Parasympathetic activity receptors in organs

muscarinic

Autonomic regulation

reflex arcs, presynaptic autoreceptors, postsynaptic regulation

Reflex arcs

Homeostatic response that is important to adrenergic drugs (beta blockers)

Presynaptic autoreceptors

alpha 2 inhibits NE release and M2 inhibits ACh release

Postsynaptic regulation

controls number of receptors and hyperpolarization

Baroreceptors

pressure-sensing neurons

Acetylcholine receptors are subdivided into

nicotinic and muscarinic receptors

Indirect acting cholinomimetics

AChE inhibitors

Direct acting cholinomimetics

muscarinic agonists and nicotinic agonists

Direct-acting Anticholinergics

Muscarinic and nicotinic antagonists

Nicotinic antagonists

Ganglionic blockers, NMJ blockers

Ganglionic Blockers (Nn) act at the autonomic ganglia to interrupt neurotransmission by

blocking nicotinic neuronal receptors to prevent acetylcholine from binding

Neuromuscular Junction Blockers (NMJ blockers/Nm)

Competitively block/depolarize nicotinic muscle receptors found at the endplate of skeletal muscle fibers (somatic)

Muscarinic Antagonists

block muscarinic acetylcholine receptors

acetylcholine agonists and antiacetylcholineesterases

Increase the amount of acetylcholine

Types of Cholinergic drugs

Ganglionic blockers, muscarinic antagonists, acetylcholine agonists, antiacetylcholineesterases, NMJ blockers

Direct acting Cholinergic drugs

Similar effect to ACh itself, effect depends, will bind to and activate muscarinic or nicotinic receptors directly

Indirect-acting Cholinergic drugs

Inhibit acetylcholinesteraseincrease endogenous ACh levels leading to enhanced cholinergic receptor activation

Muscarine

a plant alkaloid that mimics the effects of ACh at select cholinergic sites. From Amanita muscaraia and Inocybes

M2 Muscarinic receptor found in

Heart, nerves, smooth muscle

M33 Muscarinic receptor found in

Glands, smooth muscle and eyes

Pharmacology of muscarinic receptors

parasympathetic activity with no systemic therapeutic applications

Muscarinic Agonists - Choline esters

acetylcholine, methacholine, carbachol. bethanechol

Muscarinic Agonists - Alkaloids

Muscarine and Pilocarpine

Choline esters ADME

Poorly absorbed, Do not cross BBB, Metabolized by cholinesterases

Alkaloids ADME

Well absorbed, widely distributed, Metabolized by P450 (Cevimeline)

Bethanechol uses

urinary retention

Bethanechol ADE

GI distress, sweating, hypotension

Bethanechol contraindications

airway disease ulcer

Pilocarpine uses

Xerostomia and Glaucoma

Muscarinic Poisoning DUMBELSS

Pilocarpine Diarrhea, Urination, Miosis, Bradycardia, Bronchoconstriction, Excitation, Lacrimation, Salivation, Sweating

Bethanechol (Urecholine) PC

Muscarinic agonist

Bethanechol (Urecholine) PK

Poor absorption, no cross BBB

Bethanechol (Urecholine) MOA

Acts on muscarinic GPCRs on parasympathetic effector organs

Bethanechol (Urecholine) physiology

Urinary effects

Bethanechol (Urecholine) Clinical uses

urinary retention

Bethanechol (Urecholine) adverse effects

GI distress, sweating, hypotension

Bethanechol (Urecholine) Contraindications

asthma, ulcer

Effect of muscarinic agonists on eye

Miosis (pupil constriction)

Effect of muscarinic agonists on heart

Bradycardia (decreased heart rate)

Effect of muscarinic agonists on lung

Bronchoconstriction and increased secretion

Effect of muscarinic agonists on GI tract

increased motility and secretion

Effect of muscarinic agonists on Bladder

increased voiding

Effect of muscarinic agonists on glands

Increased sweating, salivation, lacrimation

Methacholine uses

Asthma

Carbachol uses

Miosis for surgery

Cevimeline uses

Xerostomia