Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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Important regulator of the activities of heart andperipheral vasculature, especially in responses toexercise and stress

Drugs that mimic the actions of epinephrine arecalled sympathomimetic drugs or adrenergic drugs

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α1 •Post synaptic•Smooth muscles•Salivary glands and liver cells

Mydriasissphincter contractionConstipationand Urinary retentionGland-secretionLiver-glycogenesis

α2 Presynaptic-adrenergic orcholinergic nerve cellsPost synaptic- brain, βpancreatic cellsExtra junctional- blood vesselsand platelets

Reduces release of norepinephrine (as anegative feedback mechanism)bradycardia, hypotensionCentral sympathetic outflow isdecreased

β1 Heart and juxtraglomerularapparatus

Contraction Increased heart rate

β2 Bronchi, uterus, liver, GIT, Eyes Relaxation Bronchodilation, urinaryretention, constipation, uterusrelaxation

β3 Adipocyes Lipolysis and thermogenesis

Receptors Agonists Antagonists

α1 PHENYLEPHRINEMETHOXAMINE

PRAZOCINTERAZOCINTAMSULOCIN

α2 OXYMETAZOLINECLONIDINE

YOHIMBINEROUWOLSCINE

β1 DOBUTAMINEXAMOTEROL

ATENOLOLACEBUTALOL

β2 TERBUTALINESALBUTAMOL

BUTOXAMINE

β3 BRL37344 CYANOPINDALOL

D1 FENOLDOPAM SCH23390

D2 BROMOCRIPTINE SULPIRIDE

Directly actingdrugs

On α –receptorsE.g.. phenylephrine

On β- receptorsEgg. isoprenaline

On both α, β-receptors

Eg. Adrenaline/epinephrine

Indirectly actingdrugs

Eg.Tyramine

Mixed actingdrugs

Indirect action on lowdose, direct action on

high dose

Eg. AmphetamineDexamphetamine

MethamphatamineEphedrine

Vasopressor agents-α1 receptor agonist- noradrenaline, phenylephrine, methoxamine,mephantermineCardiac stimulants-Nonselective- adrenaline, isoprenalineβ1 receptor agonist- prenalterol, dopamine, dobutamineBronchodilators-Nonselective- adrenaline, isoprenalineSelective β2 agonist-salbutamol,terbutaline,salmeterol,formoterolNasal decongestant-α1- receptor agonist- phenylephrine, pseudoephedrine,phenylpropanolamineα2 receptor agonist- oxymetazoline, xylometazoline,naphazoline

Uterine relaxantsSelective β2 agonist- isoxsuprine, ritodrine,salbutamol, terbutaline, orciprenalineCNS stimulants

Amphetamine, methamphetamine, dexamphetamine,ephedrineAnorectic agentsFenfluramine, dexfenfluramine, Sibutramine

Potent stimulant of alpha and beta receptorsComplex actions on target organs

Adr: α1 +α2+ β1+ β2 and weak β3 actionNA: α1 +α2+ β1+ β3 and no β2 action

Iso: β1+ β2 + β3 action but no α action

Tyrosine tyrosine hydroxylase DOPADOPA DOPA decarboxylase dopamineDA DA β-decarboxylase NENE is taken up and stored in granulesNE not stored in storage granules are called as mobilepool (MAO can metabolize these)NE releases via exocytosis as Ca++ enters.NE attaches to receptors in the post-synaptic neuron

Sympathetic nerves take up amines and release them asneurotransmitters

Axonal uptake or Uptake I is a high efficiency system, morespecific for NA By norepinephrine transporter (NET) Located in neuronal membrane Inhibited by Cocaine, TCAD, Amphetamines

Vesicular uptake- By vesicular monoamine transporter (VMAT-2) Also capture DA for synthesis of NA Inhibited by Reserpine

Extraneuronal uptake is less specific for NA Located in smooth muscle/ cardiac muscle By extraneuronal amine transporter Inhibited by steroids/ phenoxybenzamine No Physiological or Pharmacological importance

NE can be transported back into the pre-synaptic neuron(reuptake). Enzymes involved in metabolism are

Mono Amine Oxidase (MAO)Intracellular bound to mitochondrial membranePresent in NA terminals and liver/ intestine

Catechol-o-methyl-transferase (COMT)Neuronal and non-neuronal tissueActs on catecholamines and byproducts

End product of EPI metabolism VMA-vanilyl mandelic acidEnd product of DOPA metabolism HVA-homovallinic acidNE can activate the presynaptic receptors (α-2 for negativefeedback)

1. Phosphorylation of agonist occupied receptor by Gprotein coupled kinase (GRK) family– Homologousdesensitization

2. Phosphorylation of β receptor by protein kinaseactivated by second messenger cAMP.

This activated PK can phosphorylate any structurallysimilar receptor not occupied by agonist-----Heterologous desensitization

Two types of drugs, which involve:

Displacement of stored catecholamines from the pre-synaptic nerve (AMPHETAMINE AND TYRAMINE)Inhibition of reuptake of catecholamines alreadyreleased (COCAINE)MAO INHIBITOR-SELEGILINECOMT INHIBITOR-TOLCAPONE, ENTACAPONE

Some drugs have both direct and indirect actions.Both types of sympathomimetics, direct and indirect,ultimately cause activation of adrenoceptors, leading tothe characteristic effects of catecholamines

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Plant alkaloid, resembling adrenaline peripherallyCentrally – Increased alertness, anxiety, insomnia, tremor andnausea in adults. Sleepiness in childrenEffects appear slowly but lasts longer (t1/4-6 hr)Tachyphylaxis on repeated dosingUsed as bronchodilator, mydriatic,

in heart block,mucosal vasoconstriction& in myasthenia gravis.

It is a normal by-product of tyrosine metabolism in thebodyAlso found in high concentrations in fermented foodssuch as cheese and fish.If administered parenterally, it has an indirectsympathomimetic action caused by the release ofstored catecholamines.Just like amphetamines, it increases the number ofcatecholeamines at the synapse.

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In patients treated with MAO inhibitors (drug used inDepression and Parkinson’s disease) – causes anincrease in NE levels.

Cheese, liquor, dry sausage, yogurt, raisins, liver,pickle

Effect of tyramine is greatly intensified, leading tomarked increases in BP and HR – hypertensive crisis, “Cheese syndrome” Arrhythmia or Stroke

Patients taking MAO inhibitors must be very carefulto avoid tyramine-containing foods.

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Mainly acts on β1 ↑ Ca+ influx in cardiac cells.HR ----- ↑ +ve chronotropic effect .Pace maker ac vityof both SA node & purkinje fibers is ↑Contractility --↑↑ +ve inotropic effect, relaxa on isaccelerated.Excitability & Automaticity --- ↑Conduction velocity.---- ↑in AV node & Refractoryperiod is ↓Stroke volume ---- ↑ & cardiac output ---- ↑.Work load ---- ↑↑ oxygen demand.Mechanical efficiency of heart is decreased.

Cardiovascular System

A relatively pure 1 agonist such as phenylephrineincreases peripheral arterial resistance

This leads to a dose-dependent rise in bloodpressure

A relatively pure β agonist such as isoproterenoldecreases peripheral resistance by activating β2receptors (smooth muscle relaxation )

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Cutaneous, Mucous membrane & renal beds (α1 )constrictedBV going to liver & Skeletal muscle mainly dilated (β2 )

Coronary (Mainly β2 ) ----- dilatedCerebral ---- no significant change, related to systemicblood pressure.Action most marked on arterioles and precapillarysphincters.

Catecholamines do not cross the BBB effectivelySome drugs i.e. amphetamine/cocaine does cross theBBB and produces stimulant effectsStarts with reducing fatigue and progresses asanorexia, euphoria and insomniaVery high doses-aggressiveness, marked anxiety andconvulsions

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The radial pupillary dilator muscle of the iris contains1 receptors

Activation causes mydriasis and β stimulants also have important effects on

intraocular pressure. agonists decreases the outflow of aqueous humor

from the eye and β antagonists (timolol) decreasethe production of aqueous humor.

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Bronchial smooth muscle contains β2 receptors thatcause bronchodilation

The blood vessels of the upper respiratory tractmucosa contain α1 receptors. Decongestants are α1agonists, causes vasoconstriction.

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The bladder base, urethral sphincter, and prostatecontain 1 receptors that mediate contraction andtherefore promote urinary retention.

β are found in the Uterus causing smooth musclerelaxation.

Used and misused as a CNS stimulantAmphetamine easily enters the CNSIt has marked stimulant effects on mood and alertnessand a depressant effect on appetite.Its peripheral actions are mediated primarily throughthe release of catecholamines

Methamphenidate (N-methylamphetamine) is verysimilar to amphetamine with a higher ratio of centralto peripheral actions .Lipolysis from Beta3

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Indications of amphetamine include:Causes released of stored NE from the pre-synapseinto the synapse.Narcolepsy & ADHDObesitySide effects: Insomnia, Decreased appetite

Uses:1.Anaphylactic Shock 1:1000

0.5 ml for adults IM0.3ml for child 6-12 years

May be repeated after 10-20 minutes . Avoid I/V because fatal ventricular fibrillation may occur.

Cardiac arrest2. Control of local bleeding-1:100003.Increases local anesthestic action (byvasoconstriction)1:200000Cardiac arrest

Contraindications:HyperthyroidismHTNArrhythmias

Selective, synthetic and direct α1 –agonistAdministered orally, parenteraly & topically (eye, nose)Long duration of actionResistant to MAO and COMTPeripheral vasoconstriction leads to rise in BPReflex bradycardiaProduces mydriasis and nasal decongestionUsed in shock as pressor agentSinusitis & Rhinitis as nasal decongestantMydriatic in the form of eye drops and lowers intraocularpressureDoes not cross BBB, so no CNS effectsActions qualitatively similar to noradrenalineADRs: Photosensitivity, conjunctival hyperemia andhypersensitivity

-methyldopaDoesn’t cross placentaUses:HypertensionGestational HTNChronic HTN during Pregnancy

Oxymetazoline and XylometazolineHigher affinity for 1 than 2 (partial 2 agonist)Also causes vasoconstriction.Used as a nasal decongestant

Cocaineis a local anesthetic with a peripheralsympathomimetic actionThe action results from inhibition of transmitterreuptake at pre-synapse.Readily enters the CNS and produces anamphetamine-like effect that is shorter lasting andmore intense.The major action of cocaine in the central nervoussystem is to inhibit dopamine reuptake into neuronsin the "pleasure centers" of the brain.Increased epinephrine leads to systemic symptomsof sympathetic effects.

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Orally effective very potent long acting β-receptoragonist and has little effect on receptors.Leads to an increase and Heart rate (β1) with adecrease in blood pressure (β2)This lead to a marked increase in cardiac outputassociated with a fall in diastolic and mean arterialpressureUses- uterine relaxant for threatened abortion anddysmenorrheaADR- tachycardia, flushing and hypotension

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In small doses (2-5 μg/kg/minute), it stimulates D1-receptors in renal, mesenteric and coronary vesselsleading to vasodilatation Renal vasoconstriction occurs in CVS shock due to

sympathetic over activity Increases renal blood flow, GFR and causes

natriuresis

Moderate dose (5-10 μg/kg/minute), stimulates β1-receptors in heart producing positive inotropic andlittle chronotropic actionsReleases Noradrenaline from nerves by β1-stimulationDoes not change PR and HRGreat Clinical benefit in CVS shock and CCFHigh dose (10-20 μg/kg/minute), stimulates vascularadrenergic α1-receptors – vasoconstriction anddecreased renal blood flowUSES-

Hypovolaemic shockCardiac failure

Derivative of DopamineMOA:

Acts on both alpha and beta receptors but more prominentlyin β1 receptorDoes not act on D1 or D2 receptorsRacemic mixture of dobutamine used clinically

(-) dobutamine- α1 agonist(+) dobutamine- α1 antagonist

- 8-10 times β1 agonistSo benefit of racemic mixture-Increase in force of contractionand cardiac output with little change in heart rate andperipheral resistanceHalf life- 2minSo IV infusion- 2.5-10 µg/kg/min

Uses: Clinically give in dose of 2.5-10 µg/kg/min IVinfusion

Short term emergency treatment of cardiac failure inpt of MI, after cardiac surgery, in pt of CCF.

Limitations-Short half life- so IV infusion is requiredTolerance develops within few days- so used forshort termDysrhythmias- less chances

Avoided in- HT, cardiac Dysrhythmias

Agonist to postsynaptic α2A adrenoceptors in brain,stimulationsuppresses sympathetic outflow andreduces blood pressure

High dose activates peripheral presynapticautoreceptors on adrenergic nerve ending mediatingnegative feedback suppression of noradrenalinerelease

Overdose stimulates peripheral postsynaptic α1adrenoceptors & cause hypertension byvasoconstriction

Clonidine reduces blood pressure

Abrupt or gradual withdrawal causes reboundhypertensionOnset may be rapid (a few hours) or delayed for aslong as 2 days and subsides over 2-3 daysNever use Clonidine with β-adrenoceptor blockers

Short acting : Salbutamol, Metaproterenol,Terbutaline, pirbuterolSelective for β2 receptor subtypeUsed for acute inhalational treatment ofbronchospasm.Onset of action within 1 to 5 minutesBronchodilation lasts for 2 to 6 hoursDuration of action longer on oral administrationDirectly relax airway smooth muscleRelieve dyspnea of asthmatic bronchoconstrictionLong acting: Salmeterol,

Antioxytocics or tocolytic agentsβ2 agonists relax uterusUsed by i.v. infusion to inhibit premature labourIsoxsuprine, Terbutaline, Ritodrine, SalbutamolTachycardia & hypotension occur

Use minimum fluid volume using 5% dextrose as diluentsRitodrine: 50 μg/min, increase by 50 μg/min every 10minutes until contractions stop or maternal heart rate is140 beats/minute.Continue for 12-48 hours after contractions stop

Short acting (rescue drugs): Albuterol, Terbutaline Long acting (maintenance drugs): Salmeterol Inhaled Beta agonists is used in Asthma. Causes

smooth muscle relaxation at the bronchus(bronchodilation)

Adverse drug effects: Tachycardia, tremors,palpitations

Destroyed in the gut wall by MAO & COMT so notgiven orally.Given S/C ,I/M, by inhalation ,Topically on Mucousmembrane, eye .I/V inj avoided ---risk of fatal ventricular fibrillation.S/C not used in shock Poor absorption due tovasoconstriction.Metabolites excreted in urine

Cardiac arrhythmias: due to increased automaticity ofectopic pace makers, specially in patient on Digoxin.Anginal pain: increased work load & oxygen demand;specially in patients with atherosclerosis.Cerebral hemorrhage: Due to marked rise in bloodpressure.Pulmonary edema may be produced.CNS A/E: Only at high doses, does not cross BBB attherapeutic doses.

Disturbing Reactions like fear, apprehension, anxiety,Restlessness, Headache ,Tremors.

Hyperthyroidism: chance of cardiac dysrhythmiasDiabetes: Risk of HyperglycemiaBeta blockers: Marked effect on alpha receptors--- Risein blood pressure.With Inhalational General anesthetics:Inhalational General anesthetics sensitize the heart toaction of epinephrine---- risk of Cardiac arrhythmiasC/I- hypertension, hyperthyroidism, angina pectoris

1. CNS stimulation2. Mydriatic agents3. Nasal decongestion4. Hypovolemic shock as vasopressor agents5. Anaphylactic shock/reaction6. Appetite suppressant7. Cardiac Resuscitation8. Along with Local anesthetics (LA)9. Topical Hemostatic10. Status Asthmatics11. Tocolytic agents

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