autonomic sforstudents
TRANSCRIPT
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