AUTONOMIC PHARMACOLOGY

Enrico Ian L. Deliso, MDXU-JPRSM

Autonomic Nervous System (ANS)

• Sympathetic (thoracolumbar) division• Parasympathetic (craniosacral) division

Organization of the ANS

Characteristic Sympathetic Parasympathetic

Origin of preganglionic T1 – T12; L1-L3 CN III, VII, IX, X; S2 – S4

Length of pre-ganglionic axon

Short Long

Neurotransmitter in the Gaglion

ACh ACh

Receptor in ganglion Nicotinic Nicotinic

Length of post-ganglionic axon

Long Short

Neurotransmitter in effector organ

Norepinephrine (except sweat glands-Ach)

Ach

Receptor in effector organs α1,α2,β1,β2,β3 Muscarinic

Enteric Nervous Sytem

• is a large and highly organized collection of neurons located in the walls of the gastrointestinal system

• it is sometimes considered a third division of the ANS• Consist of

– Myenteric plexus (Auerbach)– Submucous Plexus (Meissner)

Uninnervated Receptors

• Respond to autonomic transmitters and drugs but receive no innervation

• Examples:– Muscarinic receptors on endothelium of blood vessels

Cotransmitters

• In the nerve terminals, autonomic nerves has vesicles that contain other transmitter molecules in addition to the main agents

• Involves in the modulation of the synaptic transmission

• Examples:– ATP, enkephalin, VIP

CHOLINERGIC PHARMACOLOGY

Acetylcholine (Ach)

• Primary transmitter in all the automonic ganglia and at the synapses between parasympathetic postganglionic neurons and the effector cells

• Primary transmitter at the somatic system (NMJ)

Cholinergic Drug Effects

• Not very useful, because their effects are not sufficiently selective

• Botulinum toxin, a very large molecule that diffuses slowly, for relatively selective drug effect

Receptor Name

Typical Locations Result of Ligand Binding

Muscarinic

M1

 

CNS neurons, sympathetic postganglionic neurons, some presynaptic sites

Formation of IP3 and DAG, increased intracellular calcium

Muscarinic

M2

Myocardium, smooth muscle, some

presynaptic sites; CNS neurons

Opening of potassium channels, inhibition of adenylyl cyclase

Muscarinic M3

Exocrine glands, vessels (smooth muscle and endothelium); CNS neurons

Like M1 receptor-ligand binding

 Muscarinic

M4 

CNS neurons; possibly vagal nerve endings Like M2 receptor-ligand

binding 

Muscarinic M5

Vascular endothelium, especially cerebral

vessels; CNS neurons  

Like M1 receptor-ligand binding

Nicotinic NN

Postganglionic neurons, some presynaptic cholinergic terminals

Opening of Na+, K+ channels, depolarization

Nicotinic NM

Skeletal muscle neuromuscular endplates Opening of Na+, K+ channels, depolarization

Organ Response

EYES

Sphincter muscle of iris Contraction (miosis)

Ciliary muscle Contraction for near vision

HEART

Sinoatrial node Decrease in rate (negative chronotropy)

Atria Decrease in contractile strength (negative inotropy). Decrease in refractory period

AV node Decrease in conduction velocity (negative dromotropy). Increase in refractory period

Ventricles Small decrease in contractile strength

BLOOD VESSELS

Arteries Dilation (via EDRF). Constriction (high-dose direct effect)

Veins Dilation (via EDRF). Constriction (high-dose direct effect)

LUNG

Bronchial muscle Contraction

Bronchial gland Stimulation

GI

Motility Increase

Sphincters Relaxation

Secretion Stimulation

URINARY BLADDER

Detrussor contraction

Trigone and sphincter relaxation

GLANDS

Sweat, salivary, lacrimal, nasopharyngeal secretion

CHOLINOCEPTOR-ACTIVATING & CHOLINESTERASE-INHIBITING DRUGS

Cholinomimetic Drugs

• Indirect-acting– Edrophomium (short acting)– Carbamates (intermediate to long-acting)– Organophosphates (very long acting)

• Direct-acting– Muscarinic• Choline Esters• Alkaloids

– Nicotinic

DIRECT ACTING CHOLINOMIMETICS

Direct acting Cholinomimetics, MUSCARINIC

DRUG CLINICAL USE TOXICITIESCHOLINE ESTERSAcetylcholine NONE All

parasympathomimetic effects: diarrhea, urinary urgency

Bethanechol Bladder and bowel atony

Pilocarpine Sjogren’s SyndromeGlaucome

ALKALOIDSMuscarine Alkaloid in mushroom Mushroom poisoning

Direct acting Cholinomimetics, NICOTINIC

DRUG CLINICAL USE TOXICITIES

NICOTINE (full Nn agonist) Smoking cessationInsecticide

Generalized ganglionic stimulation: hypertension, tachycardia, nausea, vomiting, diarrheaMAJOR overdose: convulsions, paralysis, coma

VARENICLINE (partial Nn agonist)

Smoking cessation HPN, sweating, sensory disturbance, diarrhea, polyuria, menstrual disturbance

SUCCINYLCHOLINE (selective Nm agonist)

Neuromuscular Relaxation Initial Muscle spasms and postoperative pain

Muscarinic Toxicity

• CNS stimulation• EYE: miosis• LUNGS: bronchoconstriction• GIT/GUT: excessive smooth muscle activity• Increase secretory activity of glands• vasodilation

Reflex compensation for muscarinic toxicity

• Transient bradycardia followed by reflex tachycardia if administered by IV

• Reflex tachycardia for all other routes

Nicotinic Toxicity

• Ganglionic stimulation• Blockade of the Neuromuscular end plate

depolarization – leading to paralysis• CNS toxicity: stimulation (convulsions) followed

by CNS depression

INDIRECT ACTING CHOLINOMIMETICS

MOA of indirect acting cholinomimetics

• Bind to the cholinesterase and undergo prompt hydrolysis

• Amplify Ach effects wherever it is released• No significant actions at uninnervated sites

where Ach is not normally released

Indirect acting cholinomimetics

DRUG CLINICAL USE TOXICITIES

ALCOHOLS

Edrophonium Reversal of nondepolarizing neuromuscular blockade;Diagnosis of Myasthenia; Differentiate myasthenic and cholinergic crisis

Increased parasympathetic effects, nausea, vomiting, diarrhea, urinary urgency

CARBAMATES

Neostigmine Reversal of nondepolarizing neuromuscular blockade;Treatment of MG;Bladder atony

Like edrophonium but longer duration

Pyridostigmine Treatment of MG

Physostigmine Antidote to atropineGlaucoma

Like edrophonium but longer duration plus CNS effects

Myasthenia Gravis

• Autoimmune destruction of nicotinic Ach receptors– Fluctuating muscle weakness– Ocular symptoms– Bulbar symptoms– Proximal muscle weakness

• Myasthenic crisis– Worsening of symptoms– EDROPHONIUM improves muscle strength

• Cholinergic crisis– Excessive activation of cholinoreceptors– EDROPHONIUM weakens muscle strength

Indirect acting cholinomimeticsDRUG CLINICAL USE TOXICITIES

SPECIAL CARBAMATES

RivastigmineGalantamineDonepezilTacrine

Alzheimer’s disease Nausea and Vomiting

ORGANOPHOSPHATES

Parathion Insectecide only Highly Dangerous; ALL parasympathetic effects plus muscle paralysis and coma

Malathion Insecticide and scabicide Safer than parathion

SarinTabun

Nerve gasTerrorist threat

Rapidly lethal

CHOLINORECEPTOR BLOCKERS AND CHOLINESTERASE REGENERATORS

Anticholinergic Drugs

• Antimuscarinic– M1-Selective (Pirenzepine)– Non-selective (Atropine)

• Antinicotinic– Ganglion Blockers (Hexamethomium)– Neuromuscular Blockers (Tubucurarine)

• Cholinesterase regenerators– Oximes (Pralidoxime)

Nonselective Muscarinic AntagonistDrug Clinical Use Toxicities

AtropineCyclopentolateTropicamide

MydriaticCycloplegicAntidote for cholinesterase inhibitor toxicity

All Parasympathetic effects plus sedation, delirium, hyperthermia and flushing

Scopolamine Motion sicknessBenztropineBiperidenTrihexyphenidyl

Anti-ParkinsonismAcute dystonia

IpratropiumTiotropium

COPD

Oxybutynin Urinary UrgencyPostoperative bladder spasms

GlycopyrrolateDicyclomine

AntispasmodicTransient Hypermotility

Selective Muscarinic Antagonist

DRUG CLINICAL USE TOXICITIES

M1 Selective

PirenzepineTelenzepine

PUD Excessive Parasympathetic Effects

M2 Selective

TolterodineDarifenacinFesoterodineSolifenacin

Urinary UrgencyStress incontinence

Excessive Parasympathetic Effects

Contraindications to Muscarinic Blockers

• Infants• Hyperthermia due to decrease sweating• Acute angle closure glaucoma• BPH

Ganglion Blockers

• Competitive pharmacologic antagonists at the nicotinic Ach receptors

• First successful agents for the treatment of HPN but were abandoned because its adverse effects are so severe

Ganglion Blockers

DRUG CLINICAL USE TOXICITIESHexamethonium Hypertension (not

used)Complete blockade of ALL autonomic effects: Postural HypotensionDry mouthBlurred visionConstipationSevere sexual dysfunction

Trimethaphan Hypertensive urgenciesControlled Hypotension

Mecamylamine Smoking cessationTourette’s syndrome

Neuromuscular Blockers

• Important for producing complete skeletal muscle relaxation in surgery

• Classification:– NONDEPOLARIZING (Tubocurarine,

Pancuronium, Atracurium, Vecuronium)– DEPOLARIZING (Succinylcholine)

ADRENERGIC PHARMACOLOGY

Norepinephrine

• Primary transmitter at the sympathetic postganglionic neuron-effector cell synapses in most tissues

• Except:– Sweat glands – Ach

Sites of Autonomic Drug Actions

STEPS INHIBITORS

CHOLINERGIC ADRENERGIC

Synthesis Hemicholinium Metyrosine

Storage Vesamicol Reserpine

Release Botulinum Guanethidine

Termination

Metabolism Neostigmine MAOI’s, COMTIs

Reuptake NONE Cocaine, TCAs

Drug effects on Adrenergic Transmission

• Other drugs promote catecholamine release

• Used in treatment of several diseases (Pheochromocytoma, Hypertension)– Block sympathetic but NOT parasympathetic

functions

SYMPATHOMIMETICS

ADRENERGIC AGONIST• DIRECT ACTING

– ALPHA AGONIST• NONSELECTIVE• ALPHA 1 SELECTIVE• ALPHA 2 SELECTIVE

– BETA AGONIST• NONSELECTIVE• BETA 1 SELECTIVE• BETA 2 SELECTIVE

• INDIRECT ACTING– RELEASERS– REUPTAKE INHIBITORS

MOA OF SYMPATHOMIMETICS

• Direct activation of adrenoceptors• Indirect activation by increasing concentration

of available catecholamines in the synapse– Release of stored catecholamines– Inhibits the reuptake process

Nonselective Direct Acting Catecholamines

DRUG ACTIVITY CLINICAL USE TOXICITIES

Epinephrine α1,α2,β1,β2,β3 AnaphylaxisHemostasis

Excessive sympathomimetic effects: HPN, arrythmia, stroke, MI, pulmonary edema

Norepinephrine α1,α2,β1 Neurogenic ShockLast resort in shock

Extreme vasospasm, tissue necrosis, excessive BP increase, arrythmia and infarction

Dopamine D1, D2α1,α2,β1,β2,β3

Shock, Heart Failure Cardiovascular disturbance, arrythmias

Isoproterenol β1,β2,β3 Acute asthma

Selective α1 Agonist

DRUG CLINICAL USE TOXICITIES

Phenylephrine DecongestantMydriaticNeurogenic Hypotension

HPNStrokeMI

Methoxamine Paroxysmal atrial tachycardia

Midodrine Chronic orthostatic hypotension

Selective α2 Agonist

DRUG CLINICAL USE TOXICITIESClonidine Hypertension Rebound

hypertensionSedation

Methyldopa Pre-eclampsia Hemolyttic AnemiaSedation

ApraclonidineBrimonidine

Glaucoma

Selective β1 Agonist

DRUG CLINICAL USE TOXICITIESDobutamine Heart failure

ShockCardiac stress testing

Tachycardia ArrythmiaTachyphylaxis

Selective β2 Agonist

DRUG CLINICAL USE TOXICITIES

AlbuterolMetaproterenolTerbutaline

Acute BronchospasmAsthma RELIEVER

TachycardiaTremors

SalmeterolFormoterol

Asthma CONTROLLER

Ritodrine Premature Labor

Dopamine

• Low Dose (1-5 mcg/kg/min)– Vasodilation in the splanchnic and renal vascular

beds via D1 receptors

• Medium Dose (5-15 mcg/kg/min)– Increased renal blood flow, hear rate, cardiac

contractility and cardiac output via βreceptors

• High Dose (>15 mcg/kg/min)– Increased BP and vasoconstriction viaαreceptors

Indirect Acting Sympathomimetics

DRUG CLINICAL USE TOXICITIESAmphetamineMethamphetamine

AnorexiantWeight reductionADHDNarcolepsy

AddictionParanoiaAggresionInsomniaArrythmiaHPNConvulsions

Ephedrine NarcolepsyIdiopathic postural hypotensionEnuresis

TachycardiaHypertension

Pseudoephedrine decongestant

Indirect Acting Sympathomimetics

DRUG CLINICAL USE TOXICITIES

Cocaine Local AnestheticIntrinsic Hemostatic Action

AddictionHPNArrythmiasSeizures

Tyramine Found in fermented Foods (cheese)

Hypertensive Crisis when taken together

PhenelzineTranycypromine

Mood Disorders

ADRENORECEPTOR BLOCKERS

Adrenoreceptor Antagonists

• Alpha blockers– Nonselective• Irreversible (Phenoxybenzamine)• Reversible (Phentolamine)

– Alpha 1 selective (Prazosin)– Alpha 2 selective (Yohimbine)

• Beta Blockers– Nonselective (propranolol)– Beta 1 Selective (Atenolol)– Beta 2 Selective (Butoxamine)

Nonselective Alpha Blockers

DRUG CLINICAL USE TOXICITIESPhenoxybenzamine (irreversible and long acting)

Pheochromocytoma, carcinoid, mastocytosis, Raynaud’s phenomenon

Orthostatic Hypotension, Reflex TachycardiaGI irritation

Phentolamine (reversible, short acting)

Pheochromocytoma, antidote to alpha 1 agonist overdose, local vasoconstrictor, rebound HPNED

Selective Alpha 1 Blockers

DRUG CLINICAL USE TOXICITIESPrazosinDoxazosinTerazosin

HPNBPH First Dose orthostatic

Hypotension,Little reflex tachycardia

TamsulosinSilodosin

Urinary HesitancyUrinary RetentionBPH

Selective Alpha 2 Blockers

DRUG CLINICAL USE TOXICITIES

YohimbineRauwolscine

Research applicationED (obsolete)

TachycardiaGI upset

Mirtazapine Depression SomnolenceHypercholesterolemiaIncrease appetite

Nonselective Beta BlockersDRUG CLINICAL USE TOXICITIES

Propranolol AnginaArrythmia HPN, Essential Tremors, Migraine prophylaxis, Variceal Bleeding

Excessive beta blockade:BronchospasmAV blockHeart failure, CNS sedation, masks hypoglycemia in DM patients, ED

Nadolol Longest half life

Pindolol Partial agonist activity

Timolol Galucoma Lacks anesthetic effect

Labetalol Partial agonist activityHPN (pre-ec)Pheochromocytoma

Combined alpha and beta blockade

Carvedilol Heart Failure

Selective Beta 1 BlockersDRUG CLINICAL USE TOXICITIES

Atenolol HPNAnginaArrythmia

Like PropranololLess danger of bronchospasm

Betaxolol Glaucoma

Esmolol Shortest half lifeSVT, Thyrotoxicosis

Acebutolol Partial Agonist activity, SVT

Metoprolol Arrythmia, heart failure

Nebivolol Like atenolol Vasodilation

Selective Beta 2 Blockers

DRUG CLINICAL USE TOXICITIES

Butoxamine Research application

bronchospasm

ORGAN EFFECT

SYMPATHETIC PARASYMPATHETIC

Pupils Mydriasis Miosis

Heart rate Tachycardia Bradycardia

Heart Contractility Increased Decreased

Blood Vessels

Skin, Splanchnic Vasoconstriction No effect

Skeletal Vasodilation No Effect

GI

Motility Decreased Increased

Secretion Decreased Increased

Bladder Relaxation Contraction

Uterus Relaxation (beta 2)Contraction (alpha 1)

Contraction (M3)

Penis Ejaculation erection

ORGAN EFFECT

SYMPATHETIC PARASYMPATHETIC

Sweat glands Increase sweating (Ach)

No effect

Liver GluconeogenesisGlycogenolysis

No effect

Fat cells Lipolysis No effect

Kidney Increase renin release

No effect