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Sympathomimetic Agents
SYMPATHETIC SYSTEM Sympathomimetic Agents
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SYMPATHETIC SYSTEM Mostly activated during stressful situations
Actions can be identified by reactions during “fright, fight, flight” Neurotransmitter at most post-ganglionic terminals is Noradrenaline Others: Adrenaline (Brain, adrenal) Adrenaline from adrenal medulla augments function during sympathetic activation Dopamine : Basal ganglia, other parts of brain, ? Periphery
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Synthesis Storage and Release and degradation of NA, DA, Adr
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Storage and release of Catecholamines
Storage in vesicles along with ATP and other substances Released by exocytosis Release is modified by presynaptic autoreceptors & heteroreceptors α2 ↓ β2 ↑
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Termination of action of Catecholamines
Re-Uptake Enzymatic degradation Diffusion Extra synaptic uptake
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Receptors are located PRE and POST-synaptically
Pre-synaptic receptors modify release from the terminal
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Transduction mechanisms and actions of adrenergic receptor subtypes
Agonist Alpha 1 1A 1B 1C 1D Alpha 2 2A 2B 2C 2D Beta 1 2 3 DA ( 1,2,4,5) IP3 ; DAG (common) + Ca influx ? Ca influx cAMP (common) + K , Ca channels Ca channels cAMP (common) (D1,5), cAMP (D2,3,4) Epi > NE >> Iso ( Phenylephrine, Methoxamine) ( Clonidine ) Iso > Epi > NE Dobutamine Terbutaline Iso = NE > Epi DA,
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Organ system effects of sympathetic activation
EYE Radial muscle Ciliary muscle I.O. Pressure Lacrymal glands CVS HEART SA node; Atria AV node Purkinje Ventricles Blood Vessels 1 2 1; 2 (& 1) (1 & 2) D1 Mydriasis Relaxation & accomodation Aquous outflow Increase aquous formation Secretion + HR; contractility & CV automaticity, idioventricular pacemakers +++ constriction (Skin, spalnchnic ) relaxation (Skeletal muscle) relaxation (Renal, coronary, cerebral)
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Organ system effects of sympathetic activation
BRONCHI (SmM) GIT GENITOURINARY Uterus Bladder trigone, sphincter detrussor Male sexual organs 2 1 relaxation relaxation ( ACh release) relaxation (direct - smooth muscle) contraction of sphincters contraction (pregnant) relaxation (Preg. & Non-preg) contraction ejaculation
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Organ system effects of sympathetic activation
METABOLIC Fat cells Liver Pancreas J-G cells 2 (& ) 1 Lipolysis; Inhibit lipolysis Glycogenolysis Insulin secretion Insulin secretion Renin rsecretion Renin secretion
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Targets for Pharmacological Interference
Tyrosine hyhroxylase MPT NA DOPA decarboxylase Methyldopa Pseudotransmitter* Dopamine hydroxylase Disulfiram Release of NA Tyramine Sympathomimetic Amphetamine Release of NA Guanethidine Sympatholytic Bretylium Reuptake Cocaine, effect of NT Imipramine indirect mimetics Reuptake into granules Reserpine Release Depletion
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Targets for Pharmacological Interference
Presynaptic 2 Catecholamines release Presynaptic 2 Catecholamines release Presynaptic M ACh release MAO Several metabolism Extrasynaptic uptake PBZ, Steroids Effect COMT Pyrogallol Talcapone Entacapone
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Sympathomimetic drugs
Directly acting Mixed Indirectly acting Ephedrine Tyramine Amphetamine Catecholamines Non-Catecholamines α1 agonists α2 agonists β2 agonists Clonidine Methyldopa* Apraclonidine Guanfacine Guanabenz Endogenous Methoxamine Phenylephrine Terbutaline Albuterol Fenoterol Pirbuterol Long Acting Procaterol Salmeterol DA, NA, Adr Synthetic Isoprenaline (β1 & β2) Dobutamine (β1) Isoetharine Prenalterol Oxymetazoline Xylometazoline Naphazoline
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ENDOGENOUS CATECHOLAMINES
Adrenaline Noradrenaline Dopamine
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ENDOGENOUS CATECHOLAMINES
ADRENALINE (Epinephrine): Mainly from adrenal medulla (Also some neurons in brain) Receptor actions : Both and ; Potency for > All effects of stimulation of and receptors; but some are more evident. Heart: rate, force, arrhythmias (high dose, rapid administration)
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Blood Pressure: Adrenaline is one of the most potent vasoconstrictors Pharmacological dose: ↑Force and rate of ventricular contraction (β1) ↑Vascular resistance (skin, mucosa, kidney) (α) + ↑Marked venoconstriction Lower dose: B.P. ( 2 more sensitive) Cutaneous blood flow ; Skeletal muscle blood flow Nett effect: C.O. & B.P. (systolic ; diastolic ±)
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Dale’s Reversal Phenomenon
Mean arterial blood pressure PBZ Adr
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Respiratory system: Bronchodilatation ( specially when constriction +nt) CNS: Not marked ( poor BBB penetration) Large doses: Restlessness, apprehension, headache, tremor Metabolic: Blood glucose ( insulin (2); glucose uptake; glycogenolysis) (glucagon secretion - ) Mast cells : Stabilized
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Absorption fate and excretion
Orally ineffective (hydrolyzed by liver and gut) Absorption I.M > S.C. ; Given I.V. in emergencies ; Inhalation (nebulized) Toxicity : due to and stimulation Mainly CVS: BP, vasoconstriction, tachycardia, arrhythmia Therapeutic uses: Anaphylaxis ( I.M / I.V.) ( 0.3 – 0.5 ml of 1:1000) Cardiac arrest (May have to be given intra-cardiac ) With local anaesthetics ( 1: ) Topical haemostatic :bleeding from mouth, peptic ulcer, nose Bronchial asthma – s.c. or inhalation (nebulized)
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2.NORADRENALINE (Norepinephrine)
Released from post-ganglionic sympathetic nerves 10-20% of content of adrenal medullary secretion Receptor action: α 1 , α 2 & β1 > No effect on β2
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Comparison of effects of Epinephrine and NE
Receptor action 1 α2 1 2 Heart HR CO Arrhythmias Coronary flow Blood Pressure Systolic Mean Diastolic Muscle flow Cutaneous flow Epinephrine ++ + +++ ++++ +,0,- – Norepinephrine ++ (slightly less) 0, – 0,+
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Other effects: Similar to Epinephrine Metabolic effects seen with larger doses Toxicity: Similar to Epinephrine but greater in BP Greater vasoconstriction : sloughing and necrosis can occur at site of administration Uses : Hardly used now except sometimes in peripheral vascular failure (eg. Septic shock).
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DOPAMINE Immediate precursor of NE
Neurotransmitter in CNS (? Periphery) CVS effects: Low conc. : D Renal, mesenteric and coronary vasodilatation glomerular filteration renal blood flow, Na excretion Moderate Conc. : Positive inotropic effect on heart in systolic BP and pulse pressure, ± on diastolic pressure High Conc. : Generalized vasoconstriction
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Other effects : Not significant. Therapeutic Uses:-
Severe CHF (sp. with oliguria) Cardiogenic and septic shock Major Actions of DA are within the CNS Five receptor subtypes (D1 to D5) D1 – excitatory D2 – inhibitory Involved in behavioural functions, endocrine regulation
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Sympathomimetic Catecholamines
DRUG α1 α2 β1 β2 DA Adrenaline +++ ++ Noradrenaline Dopamine + Dobutamine +/- Isoprenaline
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