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Pharmcol201 2005: Lecture 16

Pharmcol201 2005: Lecture 16

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PHARMCOL201 2005: Lecture 16
Lecture 16Lecture 16
ANS Lecture 3ANS Lecture 3NoradrenergicNoradrenergicTransmissionTransmission
Chapter 11, 5 Chapter 11, 5 
th th 
Edition, Rang,Edition, Rang,Dale and Ritter.Dale and Ritter.
Learning ObjectivesLearning Objectives
Describe the classification ofDescribe the classification ofadrenoceptorsadrenoceptors, their, theireffectors and second messengerseffectors and second messengersDescribe the synthesis, storage and release of NADescribe the synthesis, storage and release of NAand Adrenaline and points where drug action (withand Adrenaline and points where drug action (withexamples) can occur.examples) can occur.Describe the mechanism by whichDescribe the mechanism by whichNA’sNA’sactions areactions areterminated and the key enzymes involved in itsterminated and the key enzymes involved in itsmetabolismmetabolismDescribe the actions ofDescribe the actions ofadrenoceptoradrenoceptoragonists onagonists onsmooth muscle, the heart and metabolism.smooth muscle, the heart and metabolism.Describe, with examples, the key clinical uses ofDescribe, with examples, the key clinical uses ofadrenoceptoradrenoceptoragonists & antagonists.agonists & antagonists.Differentiate direct and indirect actingDifferentiate direct and indirect actingsympathomimeticssympathomimeticsDescribe and predict the effects of drugs that inhibitDescribe and predict the effects of drugs that inhibitNA uptake transportersNA uptake transporters
Chemistry of the PeripheralChemistry of the PeripheralNervous SystemNervous System
NA
SYMP.
SMOOTH MUSCLECARDIAC GLANDS
SYMP.
SWEAT GLANDS PILOERECTOR
ACh
N
AChACh
N
M
SynthesisSynthesis
TyrosineDOPADopamineNoradrenaline
Tyrosine hydroxylase Dopa decarboxylase Dopamine-
  
-hydroxylase
Methyl tyrosine
-
used in thetreatment of phaeochromocytoma
Methyl dopa
-
false substrate, decarboxylatedand hydroxylatedto form
-methyl NA a falsetrasmitter, which is not a substrate for MAO,so accumulates and displaces NA from vesicles-less active on
-1 receptors-more active on
-2.USED AS AN ANTIHYPERTENSIVE
-ve
Carbidopa-
used as an adjunct therapy in PDDoes not enter the brain
-ve
NAATP
Ca
2+
Ca
2+
NAATP
α2
ACcAMPGidepolarisationCa
2+
inVesicleexocytosisRelease of NAand ATP (1:4)Action at post-and pre-synapticreceptorsStorage and Release
Uptake and DegradationUptake and Degradation
NoNosynapticallysynapticallylocalisedlocalisedenzyme to degrade NAenzyme to degrade NA(or other(or othercatecholaminescatecholamines))Action is terminated by REUPTAKEAction is terminated by REUPTAKEUPTAKE IUPTAKE I: High affinity system with a relatively: High affinity system with a relativelylowlowmaxmiummaxmiumrate of uptake (neuronal)rate of uptake (neuronal)UPTAKE 2UPTAKE 2: Low affinity for NA, but high: Low affinity for NA, but highmaximum rate: Smooth muscle, cardiac muscle,maximum rate: Smooth muscle, cardiac muscle,endothelium (nonendothelium (non--neuronal)neuronal)
 
PHARMCOL201 2005: Lecture 16
MetabolismMetabolismAdrenoceptorAdrenoceptorAgonistsAgonists
Subtype selective drugs exist:Subtype selective drugs exist:--
αα
11--agonistsagonists –  – phenylephrinephenylephrine,,oxymetazolineoxymetazoline--
αα
22--agonistsagonists--clonidineclonidine –  – cause fall in bloodcause fall in bloodpressure partly due to decreased NApressure partly due to decreased NArelease,major central actions.release,major central actions.--
ββ
11--agonistsagonists –  – dobutaminedobutamine –  – increased cardiacincreased cardiaccontractility, but causecontractility, but causedysrhythmiasdysrhythmias--
ββ
22--agonistsagonists –  – salbutamolsalbutamol –  – bronchodilaterbronchodilater--asthmaasthma
Agonists ofAgonists of
αα
1 on Smooth1 on SmoothMuscleMuscle
NANA
αα
11
Gq/11Gq/11
IP3IP3
CaCa
2+2+
contractioncontractionMain effect is on vascular smooth muscleMain effect is on vascular smooth muscle
decreased vascular compliancedecreased vascular compliance
increased central venous pressureincreased central venous pressure
increased peripheral resistanceincreased peripheral resistanceIncreased systolic and diastolic arterial pressure,Increased systolic and diastolic arterial pressure,triggeringtriggeringbaroreceptorbaroreceptorreflexesreflexes
reflexreflexbradycardiabradycardiaand inhibition of respirationand inhibition of respiration
Agonists ofAgonists of
ββ
--receptors onreceptors onSmooth MuscleSmooth Muscle
Produce relaxation of smooth muscleProduce relaxation of smooth muscle--
ββ
22

cAMPcAMP
PKAPKA
inhibition of MLCKinhibition of MLCK
inhibits contractioninhibits contraction--
ββ
2 agonists e.g.2 agonists e.g.salbutamolsalbutamolare used in theare used in thetreatment of asthma (treatment of asthma (brochodilationbrochodilation), or to cause), or to causerelaxation of uterine smooth muscle duringrelaxation of uterine smooth muscle duringprematureprematurelabourlabourAdrenaline is used in anaphylactic reaction toAdrenaline is used in anaphylactic reaction tohelp breathinghelp breathing
HeartHeart
ββ
--receptor activationreceptor activation
Heart rate (Heart rate (chronotropicchronotropic))
Force ofForce ofcontactioncontaction((inotropicinotropic))
Cardiac outputCardiac output
Oxygen consumptionOxygen consumptionClinically: adrenaline iv for cardiac arrestClinically: adrenaline iv for cardiac arrestDalbutomolDalbutomol((
ββ
1 agonist) IV in1 agonist) IV incardiogeniccardiogenicshockshock
MetabolismMetabolism
Beta agonists encourage the conversion of energyBeta agonists encourage the conversion of energyinto freely available fuels causing an increase ininto freely available fuels causing an increase inplasma concentration of glucose and free fatty acids.plasma concentration of glucose and free fatty acids.
 
PHARMCOL201 2005: Lecture 16
AlphaAlphaAdrenoceptorAdrenoceptorAntagonistsAntagonists
NonNon--selective
selective
--antagonistsantagonists
 –  – HaloalkylaminesHaloalkylamines((egegphenoxybenzaminephenoxybenzamine))
1
1--selective antagonistsselective antagonists
 –  – PrazosinPrazosin,
2,
2--selective antagonistsselective antagonists –  – YohimbineYohimbine –  – Ergot derivativesErgot derivatives
NonNon--Selective
Selective
--AR AntagonistsAR Antagonists
PhenoxybenzaminePhenoxybenzamine(irreversible)(irreversible) –  – usedusedto treatto treatpheochromocytomapheochromocytomabut nonbut non--specific for alphaspecific for alphaadrenoceptorsadrenoceptors(also(also5HT, His & Ach)5HT, His & Ach)PhentolaminePhentolamine –  – binds to both alpha 1 andbinds to both alpha 1 andalpha 2.alpha 2.These drugs cause a fall in blood pressureThese drugs cause a fall in blood pressurebutbutbaroreceptorbaroreceptorreflexive increase inreflexive increase incardiac output and heart rate.cardiac output and heart rate.
αα
--1 Selective Antagonists1 Selective Antagonists
PRAZOSINPRAZOSINCauseCausevasodilationvasodilationand a fall in arterialand a fall in arterialpressure (pressure (hypotensivehypotensive))Used in the treatment of mildUsed in the treatment of mildhypertension.hypertension.Major side effectsMajor side effects--postural hypotension,postural hypotension,impotenceimpotence
αα
--2 Selective Antagonists.2 Selective Antagonists.
e.g.e.g.YohimbineYohimbine(naturally occurring(naturally occurringalkalkalaloidoid))BlockBlockpresynapticpresynaptic
--2 receptors, therefore2 receptors, thereforeincrease release of NAincrease release of NA--sympathomimeticsympathomimeticAlso block postAlso block post--synaptic
synaptic
--2 receptors so2 receptors soresponses are complexresponses are complex
 –  – Dominant effectsDominant effects--vasodilationvasodilation, drop in blood, drop in bloodpressure.pressure.
No therapeutic use but useful pharmacologicalNo therapeutic use but useful pharmacologicaltooltool
ββ
--AdrenoceptorAdrenoceptorAntagonistsAntagonists
PropranololPropranolol(
1 and
2)(
1 and
2)AtenololAtenolol
1
1--selective antagonistselective antagonistEffects depend on the degree of sympatheticEffects depend on the degree of sympatheticactivityactivity--very little effect at rest. Most importantvery little effect at rest. Most importanteffects are on the cardiovascular system and oneffects are on the cardiovascular system and onbronchial smooth musclebronchial smooth musclePropranololPropranolol--at rest, very little change in heartat rest, very little change in heartrate, cardiac output or blood pressure. But therate, cardiac output or blood pressure. But theeffects of exercise on these variables is reduced.effects of exercise on these variables is reduced.
Cardiac EffectsCardiac Effects
Beta blocker use lowers blood pressure inBeta blocker use lowers blood pressure inpatients with hypertension.patients with hypertension.complex mechanism involving:complex mechanism involving:
 –  – Reduction in cardiac outputReduction in cardiac output –  – Reduced sympathetic activityReduced sympathetic activity –  – Reduction ofReduction ofreninreninrelease from the kidneyrelease from the kidney –  – Central actionsCentral actions
Beta blockers do not cause hypotension inBeta blockers do not cause hypotension innormotensivenormotensivepatients.patients.

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