NeuropharmacologyNeuropharmacology

By By

Takele BeyeneTakele BeyeneDepartment of Biomedical SciencesDepartment of Biomedical Sciences

C ll f V t M di i & A i lt C ll f V t M di i & A i lt College of Vet. Medicine & Agriculture College of Vet. Medicine & Agriculture

Addis Ababa UniversityAddis Ababa Universityyy

Basic Anatomy and Physiology of NSBasic Anatomy and Physiology of NS

Two parts of the nervous system (NS)CNS (central): brain and spinal cord( ) pPNS (Peripheral):

Afferent (sensory) neurons (SN)Efferent (motor) neurons (MN) = Somatic NS and Efferent (motor) neurons (MN) = Somatic NS and

Autonomic NsBasic unit of the nervous system = neuron

Sensory, Associative, Motor Parts of the neuron

Cell b d Dendrite A nCell body, Dendrite, AxonAfferent neurons, which carry nerve impulses into the CNS from sensory end organs in peripheral tissues, and

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y g p p ,Efferent neurons, which carry nerve impulses from the CNS to effector cells in peripheral tissues.

Topics to be covered Topics to be covered Topics to be covered Topics to be covered

I.I. Pharmacology of Autonomic & Somatic Nervous Pharmacology of Autonomic & Somatic Nervous I.I. Pharmacology of Autonomic & Somatic Nervous Pharmacology of Autonomic & Somatic Nervous SystemSystem

II.II. Drugs acting on Central Nervous SystemDrugs acting on Central Nervous SystemGeneral and Local Anesthetics (techniques and General and Local Anesthetics (techniques and types)types)

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I. Pharmacology of Autonomic and Somatic I. Pharmacology of Autonomic and Somatic Nervous SystemNervous SystemNervous SystemNervous System

Learning ObjectivesLearning Objectives

Anatomy and functions of the ANSAnatomy and functions of the ANS

Neurotransmitters in ANS

Cholinergics and Anticholinergics

Adrenergics and AntiadrenergicsAdrenergics and Antiadrenergics

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Introduction to ANSIntroduction to ANSIntroduction to ANSIntroduction to ANS

ANS also called the visceral, vegetative, or, g ,involuntary nervous system

distributed widely throughout the body and regulatesdistributed widely throughout the body and regulatesautonomic functions

consists of nerves, ganglia, and plexuses

innervate the heart blood vessels glands otherinnervate the heart, blood vessels, glands, othervisceral organs, and smooth muscle in various tissues.

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Visceral Afferent FibersVisceral Afferent FibersVisceral Afferent FibersVisceral Afferent Fibers

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Visceral Afferent Fibers….cont’d• Two main sensory systems:

Cranial (parasympathetic) visceral sensory system– Cranial (parasympathetic) visceral sensory systemand

– spinal (sympathetic) visceral afferent systemspinal (sympathetic) visceral afferent system

Cranial visceral sensory system carriesCranial visceral sensory system carriesmechanoreceptor & chemosensory information

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Central Autonomic ConnectionsHypothalamus generally are regarded as principal loci of integration of ANS functions, which include regulation of:

B d t tBody temperatureWater balanceCarbohydrate and fat metabolismBlood pressureEmotionsSleep Respiration, and Reproduction

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Peripheral Autonomic System (PAS)Peripheral Autonomic System (PAS)

T l di i i Two large divisions: (1) the sympathetic or thoracolumbar outflow and (2) the parasympathetic or craniosacral outflow(2) the parasympathetic or craniosacral outflow

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Divisions of the PAS…cont’d

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Autonomic Nervous System(ANS)Autonomic Nervous System(ANS)Sympathetic (Adrenergic): “fight or flight”

Increases heart rate, respiration rate, and blood flow to pmuscles; decreases GI function; causes pupillary dilationp p yPreganglionic synapse: ACh; postganglionic synapse: epi or norepi

Parasympathetic (Cholinergic): “homeostatic”Brings heart rate, respiration rate, and blood flow to

l b k l l l muscles back to normal levels; returns GI function to normal; constricts pupils to normal sizePre- and postganglionic synapse: ACh

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Antagonistic ControlControl

• Most internal organs areinnervated by both branches ofinnervated by both branches ofthe ANS which exhibitantagonistic control

A great example is heart rate.A great example is heart rate.An increase in sympatheticstimulation causes HR toincrease whereas an increase in

th ti ti l tiparasympathetic stimulationcauses HR to decrease

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Exception to the dual innervation rule:Sweat glands and blood vessel smooth muscle are

only innervated by sympathetic and rely strictly on.

Exception to the antagonism rule:

Sympathetic and parasympathetic workcooperatively to achieve male sexual function.

Parasympathetic is responsible for erection whilesympathetic is responsible to ejaculation.

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NEUROTRANSMISSIONNEUROTRANSMISSIONNEUROTRANSMISSIONNEUROTRANSMISSION

Conduction reserved for the passage of an impulseConduction- reserved for the passage of an impulsealong an axon or muscle fiber;

Transmission- the passage of an impulse across asynaptic or neuro-effector junction.

Very few drugs (Local anesthetics) modify axonalconduction in the doses employed therapeuticallyconduction in the doses employed therapeutically.

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Cholinergic transmission

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Adrenergic Transmission

16Steps in the enzymatic synthesis of dopamine, norepinephrine, and epinephrine

Divisions of the PAS s o s o t e S Acetylcholine is neurotransmitter:-

All preganglionic autonomic fibersAll preganglionic autonomic fibers,All postganglionic parasympathetic fibers, andA few postganglionic sympathetic fibersA few postganglionic sympathetic fibersCholinergic fibers use Ach

Adrenergic fibers comprisemajority of postganglionic sympathetic fibers;majority of postganglionic sympathetic fibers;transmitter is norepinephrine (noradrenaline)

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Skeletal MuscleSkeletal Muscle

Stimulation of a motor nerve results in the release of AChThe combination of ACh with nicotinic ACh receptors inducesThe combination of ACh with nicotinic ACh receptors inducesan immediate, marked increase in cation permeabilityAbout 50,000 Na+ ions traverse the channelThe channel-opening process is the basis for the localizeddepolarizing

which triggers the muscle AP leads to contractionwhich triggers the muscle AP leads to contraction

Autonomic EffectorsAutonomic EffectorsffffStimulation of autonomic effector cells occurs on activation of muscarinic acetylcholine receptors.

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Autonomic Nervous System DrugsAutonomic Nervous System DrugsAutonomic Nervous System DrugsAutonomic Nervous System DrugsAutonomic nervous system drugs work either by:

acting like neurotransmitters or acting like neurotransmitters or by interfering with neurotransmitter release

Two groups of drugs affect the parasympathetic Two groups of drugs affect the parasympathetic nervous system

CholinergicAnticholinergic

Muscarinic antagonistsNi ti i t i tNicotinic antagonists

Two groups of drugs affect the sympathetic nervous system: system:

Adrenergic and antiadrenergics19

I. Cholinergic Drugs I. Cholinergic Drugs /P th i ti //P th i ti //Parasympathomimetics//Parasympathomimetics/

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Cholinergic DrugsCholinergic DrugsMimic the action of the parasympathetic nervous system

A. Muscarinic Agonists /Direct Acting Direct Acting CholinomimeticCholinomimeticssCholinomimeticCholinomimeticss

CholinomimeticCholinomimetic alkaloids: alkaloids: Muscarine, Pilocarpine, p

Ach and Ach and CholineCholine estersestersAcetylcholine, Methacholine, Carbachol, B h h lBethanechol

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B. Acetylcholinesterase Inhibitors / indirect acting cholinergic agonists// indirect acting cholinergic agonists/

2 1 Reversible ACE Inhibitors2 1 Reversible ACE Inhibitors2.1. Reversible ACE Inhibitors2.1. Reversible ACE InhibitorsCarbamates: Neostigmine, Physostigmine, Rivastigmine,Ambenonium, galatamine, Edrophonium,Tacrine, donepezil

2 2 I ibl ACE I hibit2 2 I ibl ACE I hibit2.2. Irreversible ACE Inhibitors2.2. Irreversible ACE InhibitorsOrganophosphates:

Malathion, parathion, Echothiophate, IsoflurophateMalathion, parathion, Echothiophate, Isoflurophate

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Malathion and Parathion

Pralidoxime (2 PAM) is a mechanism based antidote for poisoningPralidoxime (2-PAM) is a mechanism based antidote for poisoningAnticholinestrase poisoning is reversed by

Atropine- counteract the muscarinic action andPralidoxime- reactivate AChE

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Pralidoxime- reactivate AChE

Summary of cholinergics

AcetylcholineBethanecholCarbacholCDirect acting

Cholinergics

CevimelinePilocarpine

AmbenomiumDonepezil

Direct acting

pEdrophoniumGalantamineNeostigminePhysostigmineP id i i

Indirect acting (reversible)

PyridostigmineRivastigmineTacrine

Indirect acting EchothiophateIsoflurophate

g(irreversible)

(according to Lippincott´s Pharmacology, 2006)24

II. Anticholinergic Drugs II. Anticholinergic Drugs /P h l i //P h l i //Parasympatholytics//Parasympatholytics/

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Anticholinergic DrugsAnticholinergic DrugsInhibit the actions of ACh by occupying the acetylcholinereceptorsreceptorsCompetitive (reversible) antagonists of Ach

Pharmacologic effects opposite of the muscarinic agonists

i i iAntagonistic responses include:decreased contraction of GI and urinary tract smooth muscles,dilation of pupils,p p ,reduced gastric secretion,decreased saliva secretion.

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Anticholinergic DrugsAnticholinergic DrugsExamples include:

Solanaceous AlkaloidsSolanaceous AlkaloidsAtropine and Scopolamine

Semi-syntheticsHomatropine, metscopolamine

Synthetic congenersClidi i T l i P h li I iClidinium,Telenzepine, Propantheline, IpratropiumBenztropine, etc

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Indications Antimuscarinics

Preanesthetics= Used preoperativelyAtropine, hyoscine

GITGITRelax smooth m/s-

propantheline, hyoscine, clindinium, dicycloaminepropantheline, hyoscine, clindinium, dicycloamineFacilitate endoscopy-

HyoscineIrritable bowel syndrome-Irritable bowel syndrome

dicycloaminePeptic ulcer-

pirenzepine, telenzepinep p p

Ophthalmic- to dilate the pupilAtropine, scopolamine,tropicamide

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III NICOTINIC ANTAGONISTSIII NICOTINIC ANTAGONISTSIII. NICOTINIC ANTAGONISTSIII. NICOTINIC ANTAGONISTS

T b lTwo subclasses:

1 Skeletal neuromuscular blocking agents and1. Skeletal neuromuscular blocking agents and 2. Ganglionic blocking agents.

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1. Skeletal neuromuscular blocking 1. Skeletal neuromuscular blocking agentsagentsagentsagents

A. Depolarizing AgentSuccinylcholine/ suxamethoniumSuccinylcholine/ suxamethoniumDecamethonium

Initially depolarizes like Ach but persistent depolarization of y p p pnicotinic receptors at NMJ leads to repolarization

Decrease Ach release/ lm/s relaxation

Concurrent use of AChE inhibitors aggravate itToxicity is not reversed by use of AChE inhibitors to increase of Toxicity is not reversed by use of AChE inhibitors to increase of Ach Action is terminated by plasma cholinesterase

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y p

Skeletal neuromuscular blocking agentsSkeletal neuromuscular blocking agents

B. Non-depolarizing agent= stabilizing= competitive blocking agentsco pet t ve b oc g age ts

Short acting: Mivacurarium

I di A i Intermediate Acting: Vecuronium, Rocuronium, Atracurarium,

Long acting: Tubocororium, pancuronium, gallamine

C i i l di l A h d d l i i f h Competitively displace Ach and prevent depolarization of the endplate.

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Tubocurarine and derivativesTubocurarine and derivatives

Plant alkaloid from Chondodendron tomentosumPlant alkaloid from Chondodendron tomentosum.Causes muscle paralysis (arrow poison).Rapid onset of actionRapid onset of action

Metocurine is a semi-synthetic analog of tubocurarine.Metocurine is a semi synthetic analog of tubocurarine.More potent than the parent compound.

Therapeutic Use: As a muscle relaxant in various surgical procedures.

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Botulinum Toxin (Botox)

Toxin produced by the bacterium Clostridium botulinumCauses food poisoning; Large doses can be fatalCauses food poisoning; Large doses can be fatalPrevents Acetylcholine release from the nerve terminalProduces flaccid paralysis of skeletal musclep yInhibition lasts from several weeks to 3 to 4 months.

Therapeutic Uses:Therapeutic Uses:Administered locally, via im or intradermal injections, tocontrol muscle spasms and to facilitate muscle

l i ( f k )relaxation (eye; face; neck etc.)Dermatological / Cosmetic Uses in human:

To treat facial wrinkles (forehead; under the eyes etc.)( ; y )Prevent excessive sweating (palm; armpit etc)

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2. Ganglionic blocking agents2. Ganglionic blocking agents2. Ganglionic blocking agents2. Ganglionic blocking agentsA. NicotineA. Nicotine

at low dose Stimulate ganglia initially like Ach byat low dose Stimulate ganglia initially like Ach bydepolarizing the excitatory postsynaptic membranes.At high dose, block the ganglia b/c of persistentd l i idepolarization

B Hexamethonium Trimethaphan B Hexamethonium Trimethaphan MecamylamineMecamylamineB. Hexamethonium, Trimethaphan, B. Hexamethonium, Trimethaphan, MecamylamineMecamylamineImpair transmission

Compete with Ach for nicotinic receptorTrimethaphan

Block the channel after it opensHexamethonium

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Hexamethonium

Adrenergic DrugsAdrenergic DrugsSimulate the action of the sympathetic nervous system

Examples include: pepinephrine, norepinephrine, isoproterenol, dopamine,dobutamine, phenylpropanolamine, isoetharine, albuterol,terbutaline, ephedrine, and xylazine, p , y

Adrenergic receptors are divided into two major typesaccording to drug potency on the receptorsg g p y p

Alpha-(α-) adrenergic receptorsE > NE >> isoproterenolp

Beta-(β-) adrenergic receptorsisoproterenol > E > NE

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isoproterenol > E > NE

αα--Adrenergic ReceptorsAdrenergic Receptors

α1 α2 Type “Vascular” “Presynaptic”

Distribution Blood vessels, GIT, sphincters, iris radial, liver

Autonomic nerve terminals, blood vessels, pancreatic islets, platelets

Receptor- GqPCR, linked to activation of GiPCR, linked to inhibition ofReceptor Transduction

GqPCR, linked to activation of PLC-DAG-IP3

GiPCR, linked to inhibition of adenyl cyclase-c.AMP

Agonist Profile

E=NE>>>ISOP E=NE>>> ISOP Profile

Selective Agonists

Phenylephrine & methoxamine Clonidine, α-MeDOPA

Selective Antagonists

Prazocin Yohimbine

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ββ--Adrenergic ReceptorsAdrenergic Receptorsββ Adrenergic ReceptorsAdrenergic Receptors

β β β β1 β2 β3Type “Heart” “Smooth M” “Fat”

Distribution Heart, salivary glands Blood vessel, GIT, uterus, Skeletal

Fat tissues uterus, Skeletal muscle, Liver,

Receptor - Transduction

Gs-PCR, linked to activation of adenyl cyclase-c.AMP-PKA cascade

Agonist Profile

ISOP >E=NE ISOP>E>>NE ISOP=NE>E

Selective Agonists

Dobutamine Salbutamol, terbutaline

BRL 37344 Agonists terbutalineSelective

Antagonists Atenolol Butoxamine

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Classification of Adrenergic Receptors

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Classification of Adrenergic Receptors (2)Classification of Adrenergic Receptors (2)

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Adrenergic Blocking AgentsAdrenergic Blocking AgentsAdrenergic Blocking AgentsAdrenergic Blocking AgentsBlock the effects of the adrenergic neurotransmitters

Examples of alpha-blockers include:phenoxybenzamine prazosin and yohimbinephenoxybenzamine, prazosin, and yohimbine

Examples of beta-blockers include: Examples of beta blockers include: propranolol, metoprolol, and timolol

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Sites of Actions of Anti-adrenergic Drugs

VMC (α2 ) Adrenergic Nerve terminal

Anti adrenergic Drugs

Ganglia

terminal

BVHeart

Effectors cell( α & β)

1. Central blockers

2. Ganglionic blockers

3. Adrenergic Nerve terminal Blockers

4. Adrenergic Receptor

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gBlockers• Alpha Blockers• Beta Blockers

Summary of ANSSummary of ANS

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