Sympathomimetic Agents SYMPATHETIC SYSTEM Sympathomimetic Agents

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

Synthesis Storage and Release and degradation of NA, DA, Adr

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 ↑

Termination of action of Catecholamines Re-Uptake Enzymatic degradation Diffusion Extra synaptic uptake

Receptors are located PRE and POST-synaptically Pre-synaptic receptors modify release from the terminal

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,

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)

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

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

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

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

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

ENDOGENOUS CATECHOLAMINES Adrenaline Noradrenaline Dopamine

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)

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 ±)

Dale’s Reversal Phenomenon Mean arterial blood pressure PBZ Adr

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

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: 200000) Topical haemostatic :bleeding from mouth, peptic ulcer, nose Bronchial asthma – s.c. or inhalation (nebulized)

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

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,+

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).

DOPAMINE Immediate precursor of NE Neurotransmitter in CNS (? Periphery) CVS effects: Low conc. : D1 - Renal, mesenteric and coronary vasodilatation  glomerular filteration renal blood flow, Na excretion Moderate Conc. : 1 - Positive inotropic effect on heart  in systolic BP and pulse pressure, ± on diastolic pressure High Conc. : 1 - Generalized vasoconstriction

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

Sympathomimetic Catecholamines DRUG α1 α2 β1 β2 DA Adrenaline +++ ++ Noradrenaline Dopamine + Dobutamine +/- Isoprenaline