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Adrenergics : 

Adrenergics Dr.S.P.Dhanya

Autonomic Nervous System : 

Autonomic Nervous System

Slide 3: 

Transmitters: Acetylcholine: ALL preganglionic neurons ALL parasympathetic postganglionic neurons Norepinephrine (= Noradrenaline): MOST sympathetic postganglionic neurons Exceptions: Sweat glands (Acetylcholine); Renal arteries (Dopamine) Epinephrine (= Adrenaline): Adrenal medulla upon sympathetic impulses (no ganglion!)

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preganglionic postganlionic

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Action Potential Na+ Ca2+ ACH Acetylcholinesterase Na+ Sympathetic Ganglionic Synapse Preganglionic neuron Postganglionic neuron Nicotinic Receptor

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Action Potential Ca2+ NE Sympathetic Organ Synapse G Effector Organ Postganglionic neuron Adrenergic Receptor

Adrenergic Neurons : 

Adrenergic Neurons Na+ Tyrosine Ca++ Receptor MAO  Dopamine Dopa Dopamine is converted to epinephrine

Slide 9: 

Termination of (nor)epinephrine action: Reuptake into presynaptic nerve ending Predominant mechanism active transport; inhibited by Cocaine Catechol-O-methyltransferase (COMT) In the cytoplasm of post-junctional cells Monoamino-oxidase (MAO) In mitochondria of nerve and post-junctional cells Presynaptic a2-receptors Negative feedback that inhibits norepinephrine release

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Na+ Pharmacologic manipulation of the adrenergic system Presynaptic neuron H+ Effector organ Ca2+ Na+ Tyrosine Tyrosine Dopamine DA NE (-) Uptake 2 Uptake 1 Na+, Cl- NE NE NE NE b a1 a2 NE MAO

Receptors and signal transduction in the ANS : 

Receptors and signal transduction in the ANS Adrenergic Receptors a1A b3 Two Families: Alpha and Beta Based on affinity to adrenergic agonists

Adrenergic Receptors : 

Adrenergic Receptors Alpha affinity: epinephrine≥ norepinephrine>> isoproteranol Beta affinity: Isoproteranol>epinephrine> norepinephrine Isoproteranol

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Adrenergic receptors: Alpha 1 most vascular smooth muscles Activate PLC b => Ca++ => Contraction Alpha 2 mostly presynaptic Inhibit adenylate cyclase (Gai) Beta 1 mostly heart Activate adenylate cyclase Beta 2 respiratory and uterine smooth muscle Activate adenylate cyclase Beta 3 mostly adipocytes Activate adenylate cyclase => lipolysis (Dopamine)

What do these receptors do? : 

What do these receptors do? Alpha 1 Vasoconstriction, ↑ BP, ↑ tonus sphincter muscles Alpha 2 Inhibit norepinephrine, insulin release Beta 1 Tachycardia, ↑ lipolysis, ↑ myocardial contractility Beta 2 Vasodilation, bronchodilation, ↓insulin release

Adrenergics : 

Adrenergics These are drugs with action similar to adrenaline or sympathetic stimulation

Direct acting sympathomimetics : 

Direct acting sympathomimetics

Catecholamines : 

Catecholamines Drugs having a catechol nucleus They are substrates for MAO and COMT

Receptor selectivity : 

Receptor selectivity

Pharmacological actions : 

Pharmacological actions Adrenaline increase cardiac output force of contraction Velocity of conduction Heart rate Oxygen consumption Diastole is abbreviated

Blood vessels-alpha 1 : 

Blood vessels-alpha 1 Constriction of vessels of skin, mucous membrane, splanchnic ,renal except skeletal vasculature( as there are beta 2 receptors) When adr is given--- depending on dose Very low dose-vasodilatation Moderate dose-stimulate alpha 1 and beta 2 receptors-----rise followed by fall in BP-BIPHASIC Very large dose-increase in BP

Dale’s vasomotor reversal : 

Dale’s vasomotor reversal Pretreatment with alpha blocker------------adrenaline will cause only depressor response

Cardiovascular effects of sympathomimetics : 

Cardiovascular effects of sympathomimetics TIME (min)

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Bronchi-dilatation Uterus-relaxation Git-inhibits motility Urinary bladder-relaxes detrusor, contracts trigone Eye-mydriasis Intraocular tension-decrease aqueous humor production Vasoconstriction of ciliary vessels reduced secretory activity of ciliary epithelium(alpha2) Enhance trabecular flow(beta20 Aument uveoscleral outflow to some extent

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Skeletal muscle-increase Ach release-asynchrony Lipolysis, decrease peripheral utilization of glucose, increase lactic acidosis Sweat glands-increase secretion Increase salivation Enhance renin release through beta1 Enhance platelet arggregation Glycogenolysis-hyperglycemia,lipolysis Mainly reduction of insulin and increase in glucagon

Routes : 

Routes Adrenaline-s.c,i.m,i.v,nebulisation Noradrenaline-not used clinically Isoprenaline-s.l,i.v,i.m Dopamine-i.v Fenoldopam-i.v Dobutamine-i.v Acidic pH-increase stability of catecholamines Dextrose/normal saline + ascorbic acid

Adverse effects : 

Adverse effects Therapeutic doses-palpitation, tachycardia,tremolousness High-alarming increase in BP,VF Contraindications Coronary artery disease Hypertension Along with halothane hyperthyroidism

Uses : 

Uses Anaphylaxis 0.5 ml of 1/1000 solution given i.m or 1/10,000 solution given slow i.v Not given sc as absorption –unrelaible-shock Oxygen inhalation Put patient flat on floor Hydrocortisone(to prevent late phase) Physiological antagonist

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2. Bronchial asthma 3.Cardiac arrest/complete heart block 4. As a styptic-local hemostatic agent-alpha 1 mediated vasoconstriction 5.Used in high dilution along with local anaesthetic-TIME SYNERGISM Drug remains at site due to asoconstriction Smaller dose is required Systemic absorption and toxicity is decreased 6. Epistaxis

Other catecholamines : 

Other catecholamines Noradrenaline Of historical importance Important in CNS

isoprenaline : 

isoprenaline Cause fall in BP Formerly used in bronchial asthma

Dopamine : 

Dopamine Effect of dopamine dose dependent Very short duration of action Metabolised by COMT No oral action Given iv-0.2-1mg/mt Used in cardiogenic shock/ septic shock and severe cardiac failure-raise BP and urine output

Dose : 

Dose 2-5 microg/kg/mt---i.v—D1—splanchnic vasodilatation, prevent renal shutdown 5-10 microg/kg/mt—i.v----D1+β1-dilate splanchnic,increase cardiac output- Ideal for cardiogenic shock 10-20microg/kg/mt-i.v---β1-increase cardiac output >20 microg/kg/mt-i.v---α 1

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4. Dobutamine Dopamine derivative Act on α and β receptors Positive inotropic inotropic agent in pump failure-MI/cardiac surgery,short term management of CHF 5.Dopexamine In cardiac failure 6.Fenoldopam In hypertensive crisis

Non catecholamines : 

Non catecholamines No catechol nucleus Act on alpha or beta receptor directly Resistant to inactivation by MAO/COMT Cross blood brain barrier

Indirectly-acting sympathomimetics:Amphetamine,Tyramine : 

Indirectly-acting sympathomimetics:Amphetamine,Tyramine Promote release of NE via reverse action of plasma membrane transporter 2 C H N H 2 C H 3 A m p h e t a m i n e Extracellular Intracellular amphetamine NE NET

Amphetamine : 

Amphetamine Structurally related to ephedrine D isomer has effect on CNS L isomer has effect on CVS Orally effective and is long acting

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Raise SBP and DBP Contracts sphincter of bladder Increase concentration, attention span Suppress appetite Weak antiemetic, anticonvulsant and analgesic Psychological dependence and tolerance

Adverse effects : 

Adverse effects Restlessness, dizziness, tremor, talkativeness, insomnia Headache , palpitation, cardiac arrhythmia Nausea, vomiting, diarrhoea,anorexia

uses : 

uses ADHD Narcolepsy Obesity Methamphetamine, Methylphenidate, Dexmethylphenidate, Pemoline are other agents used in ADHD

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Na+ Indirect-acting sympathomimetics: Transporter blockers Cocaine Antidepressants H+ Effector organ Ca2+ NE Uptake 1 Na+, Cl- NE NE NE NE b a1 NE 2 NE NE Desipramine Venlafaxine

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Na+ H+ Effector organ Ca2+ NE NE NE NE NE b a1 2 NE NE Cocaine NE NE NE NE NE

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Na+ Indirect-acting sympathomimetics: MAO Inhibitors H+ Effector organ Ca2+ NE Na+, Cl- NE NE NE NE b a1 NE MAO 2 3 Phenelzine Selegiline

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Na+ H+ Effector organ Ca2+ NE Na+, Cl- NE NE NE NE b a1 NE MAO 2 3 Phenelzine Selegiline NE NE NE NE NE NE NE NE NE NE NE NE

Mixed-acting sympathomimetics: Ephedrine : 

Mixed-acting sympathomimetics: Ephedrine Promote release of NE via reverse action of plasma membrane transporter Direct action on receptors 2 C H N H 2 C H 3 A m p h e t a m i n e Extracellular Intracellular ephedrine NE NET

Ephedrine : 

Ephedrine Alkaloid-Ephedra vulgaris Mixed action-displacement of NA as well as on α & β receptors Action-increase in cardiac output, heart rate, BP Bronchi-dilatation CNS-increase mental alertness,wards off fatigue, restlessness,euphoria,convulsion Eye-mydriasis

Tachyphylaxis : 

Tachyphylaxis Reduction in response to a drug when it is repeatedly given at short intervals Mechanism-exhaustion of the NA available for displacement from the neuronal pool Other drugs are amphetamine,tyramine

tachyphylaxis : 


Ephedrine/tyramine/amphetamine+ MAO inhibitor-Cheese reaction : 

Ephedrine/tyramine/amphetamine+ MAO inhibitor-Cheese reaction abundantly present in yoghut, cheese,banana etc Ephedrine cause release of catecholamines . MAO inhibitors inhibit breakdown of catecholamines Dangerous levels of NA can result in hypertensive crisis Treatment-alpha blockers

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H+ Effector organ NE NE NE NE NE b a1 NE MAO 3 Phenelzine Selegiline NE NE NE NE NE NE NE NE NE NE NE NE Co-admininstration with other indirect-acting drugs can lead to hypertensive crisis Amphetamine, Tyramine NE NE NE NE NE NE NE

Uses : 

Uses Mild chronic bronchial asthma Hypotension during spinal anesthesia-neurogenic shock Chronic orthostatic hypotension Rhinorrhoea Narcolepsy Fundoscopy Nocturnal enuresis

Adverse effects : 

Adverse effects Nervousness,palpitation,tachycardia,irritability,euphoria,convulsion

Pseudoephedrine : 

Pseudoephedrine Oral and parenteral use for rhinorrhoea Minimal cvs/cns effects No bronchodilator effects Used in allergic rhinitis,blocked eustachian tubes and upper respiratory tract infections

Mephenteramine : 

Mephenteramine Mixed acting Produce cardiac stimulation and vasoconstriction-↑ cardiac output and BP Prevent and treat hypotension due to spinal anesthesia and surical procedures, shoc in myocardial infarction and other hypotensive states

Phenylpropanolamine : 

Phenylpropanolamine Similar to ephedrine Cause vasoconstriction Strong association with stroke Restricted use---dose<100 mg

Direct acting adrenergic receptor agonists: a1 receptors : 

Direct acting adrenergic receptor agonists: a1 receptors Phenylephrine Methoxamine Oxymetazoline Naphazoline Xylometazoline Diacylglycerol Activate Protein C a2

Phenylephrine : 

Phenylephrine Selective Raise BP Nasal decongestant-topical/oral Fundoscopy in elderly

Methoxamine : 

Methoxamine Selective Used as pressor agent

Oxymetazoline Xylometazoline Naphazoline : 

Oxymetazoline Xylometazoline Naphazoline Alpha agonists Produce local vasoconstriction Longer duration of action Cause initial stinging sensation(naphazoline) Avoid reuglar use for long period as it can cause Atrophic rhinitis anosmia Impair mucociliary function

Direct acting adrenergic receptor agonists: a2 receptors : 

Direct acting adrenergic receptor agonists: a2 receptors Clonidine Apraclonidine Methyldopa Guanabenz Guanfacine Tizanidine Brimonidine dipivefrine -Dependent Activity

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Decreased sympathetic tone Decr. HR Decr. Contractility Decr. Renin release Decr. Vasoconstriction

Other uses : 

Other uses Menopausal hot flushes Opiate, alcohol, nicotine withdrawal Decrease diarrhoea in diabetic autonomic neuropathy Intrathecally as an analgesic

Alpha methyl dopa : 

Alpha methyl dopa Prodrug Decraboxylated and hydroxylated to false neurotransmitter-----alphamethylNE Act on alpha2 Drug of choice in pregnancy induced hypertension

Adverse effects : 

Adverse effects hepatitis, Hemolytic anemia, thrombocytopenia Hyperprolactinemia, gynecomastia, galactorrhoea Flu like illness Cause sedation , forgetfullness, dryness of mouth, nasal stuffiness, headache, fluid retention, weight gain, impotence and postural hypotension

Tizanidine : 

Tizanidine Used for spasticity treatment associted with cerebral and spinal disorders

Apraclonidine and brimonidine : 

Apraclonidine and brimonidine Alpha 2 agonists decrease introcular pressure by decreasing production of aqueous humor from the secretory epithelium

Direct acting adrenergic receptor agonists: b receptors : 

Direct acting adrenergic receptor agonists: b receptors G S (+) ATP cAMP Increase cAMP -Dependent Protein Kinase Activity Response NH 3 COOH Adenylate Cyclase

Beta agonist : 

Beta agonist Nonselective-isoprenaline Selective beta 1-prenalterol Selective beta 2-salbutamol,terbutaline,orciprenaline,salmeterol,formoterol

Salbutamol : 

Salbutamol Short acting Used in bronchial asthma Postponement of preterm labour

Salmeterol,formoterol : 

Salmeterol,formoterol Longer acting

Anorectic agents : 

Anorectic agents Inhibit feeding centre With little/no cns stimulant action Mechanism-inhibit reuptake of NA/DA or 5 HT Noradrenerica gents-appetite center Phenteramine,Phenylpropanolamine,mazindol Serotonergic agents-satiety center Fenfluramine,dexfenfluramine Noradreneric/serotoneric agents-sibutramine

sibutramine : 

sibutramine Inhibits reuptake of both NA and 5 HT Suppress appetite Stimulate thermogenesis by indirectly activating beta3 receptors Dry mouth,constipation, anxiety,insomnia Loss 3-9 kg wt but regain when discontinued

Therapeutic uses : 

Therapeutic uses Vascular Hypotensive states Anaphylatic shock-adrenaline Cardiogenic shock-dopamine/dobutamine Postural hypotension due to autonomic neuropathyephedrine,elastic stockings and fludrocortisone Neurogenic shock- ephedrine,mephenteramine Hemorrhaic shock-pressor agent along with volume replacement Septic shock-antibiotics, dopamine,volume

Slide 77: 

2. Along with local anaesthetics-adrenaline 1/200000 to 1/100000 for infiltration,nerve block,spinal anesthesia 3.Control of local bleeding from skina and mucous membrane-adr 1/10000,phenylephrine,ephedrine 4.Nasal decongestant-phenylephrine,pseudoephedrine,PPA-oral Oxymetazoline,naphazoline,xylometazoline-topical 5.Peripheral vascular disease-mainly alpha blockers--+beta agonist---isoxsuprine

Cardiac uses : 

Cardiac uses Cardiac arrest-drownin, electrocution,Stokes –Adams syndrome-Adrenaline Partial or complete AV block-Adrenaline Congestive heart failure-Dopamine/Dobutamine

Bronchial asthma : 

Bronchial asthma Salbutamol Salmeterol Terbutaline Formoterol bambuterol

Allergic disorders : 

Allergic disorders In anphylatic shock and acute hypersensitivity reaction adrenaline

In the eye : 

In the eye Phenylephrine-fundoscopy Dipivefrine,apraclonidine,brimonidine,glaucoma

Central uses : 

Central uses ADHD-amphetamine,methamphetamine Narcolepsy Obesity-phenteramine,mazindol,fenfluramine,sibutramine Other drugs-orlistat-inhibitor of gastrica nd pancreatic lipase Olestra-instaed of fat for cooking Leptin analogues rimonanbant

Slide 83: 

Nocturnal enuresis Tocolytic-isoxsuprine,ritodrine,salbutamol,terbutaline

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