SYMPATHOMIMETIC DRUGS

ALPHA ADRENERGIC AGONISTS 1-Selective Agonists Major effects due to stimulation of 1 receptors in vascular smooth muscle Increase in peripheral vascular resistance & BP Clinical utility limited – some use in hypotension and shock states

1 – Selective Agonists Phenylephrine Direct simulation of 1 receptors Methoxamine Methoxamine: Relatively selective 1-agonist; No action at  receptors. CV effects :  BP, Reflex bradycardia May be used IV in hypotensive states Phenylephrine: 1 selective,  actions at much higher doses Effects similar to methoxamine Uses: nasal decongestant, mydriatic – local instillation

1 – Selective Agonists Xylometazoline Oxymetazoline Naphazoline: Direct 1 – agonists, Used as nasal decongestants Rebound hyperaemia occurs

Used primarily for treatment of systemic hypertension. Selective actions on 2-adrenoceptors Decrease release of NE from presynaptic terminals Act at brainstem level to  central sympathetic tone 2 – Selective Agonists

2 – Selective Agonists Clonidine:– Selective action on 2 (partial agonist with high affinity) Developed as a nasal decongestant Produces hypotension, sedation, bradycardia and mild analgesia Major effects on BP IV :  in BP (peripheral  receptors on blood vessels) – short lasting Followed by prolonged hypotensive effect Mainly central (lower brainstem) +  NE release from terminals. Oral: The early hypertensive phase is not seen Additional effects: Bradycardia ( Vagal tone) Sedation Mild analgesia

Clonidine…. Well absorbed orally – 100 % bioavailability Peak effect 1-3 hours 50 % excreted unchanged ADVERSE EFFECTS : Dry mouth, sedation, sexual dysfunction Marked bradycardia in some Rebound hypertension following sudden stoppage USES: Hypertension Tt. of symptoms of narcotic withdrawal Menopausal hot flashes (lower doses) Guanfacine and Guanabenz : similar to clonidine

2 – Selective Agonists α-Methyldopa : Converted to α-MNA which acts like clonidine Prodrug Tizanidine: Has same effects like clonidine Used mainly for relieving muscle spasticity of cerebral or spinal origin Apraclonidine: Used locally to  IO pressure ? aqueous formation

BETA ADRENERGIC AGONISTS Isoproterenol ( Isoprenaline) Synthetic catecholamine Extremely potent  receptor agonist – NON SELECTIVE Little effect on  receptors +ve inotropic and chronotropic actions – palpitations, HR, arrhythmias Potent vasodilator – marked  in CO,  in diastolic and mean BP Relaxes all smooth muscles (esp. bronchial and GIT) USES: Bradycardia and heart block – has been replaced by other drugs

(also has  receptor actions) DOBUTAMINE : 1- selective agonist (also has  receptor actions) Resembles Dopamine But no action on DA receptors Major actions are  receptor mediated EFFECTS: +ve inotropic and chronotropic effects > isoprenaline  in SA node automaticity < than Isoprenaline Total peripheral resistance not affected much

DOBUTAMINE : ADVERSE EFFECTS: Excessive  in HR and BP (specially in hypertensives) Ventricular ectopics may occur  in infarct size in MI – ( in oxygen demand) Tolerance to effects may develop in some cases USES: Short term Tt. of cardiac decompensation eg. Cardiac surgery, MI Plasma t ½ of 2 minutes hence given by infusion

2- selective agonists Selectivity is relative – lost at higher doses Developed mainly for use as Bronchodilators with low CV effects Also used for Uterine Relaxant effect

2- selective agonists Terbutaline, Albuterol (salbutamol), Metaproterenol , Salmeterol Not metabolized by COMT -- Better oral bioavailability Pharmacological effects: Bronchodilatation - 2 receptors on bronchial smooth muscle May also :- Suppress release of leukotrienes and histamine Enhance mucociliary function  microvascular permeability  phospholipase A2 activity Uterine relaxant action -- 2 receptors on uterine muscle

2- selective agonists Adverse effects: Mainly due to excessive dosage loss of selectivity 1 CVS effects Adverse effects are limited when used by inhalational route in Asthma Terbutaline and Albuterol : Effective orally, sc, inhalation Rapid onset, duration 3 – 6 hrs Use: Long term Tt of COPD ; Ac bronchospasm; Tocolytic Metaproterenol : less 2 selective

2- selective agonists Salmeterol : 2 selective and long acting (12 hours) Onset of action slow Not suitable alone for Acute attack Ritodrine: Developed specially as a uterine relaxant Properties similar to other agents Rapidly absorbed after oral intake Administered IV to arrest premature labour

Receptor Affinity Alpha agonists Phenylephrine, methoxamine Clonidine, MNA α1> α2 >>>>> β α2> α1 >>>>> β Mixed α and β agonists Noradrenaline Adrenaline α1= α2 ; β1>> β2 α2= α1 ; β1= β2 Beta agonists Dobutamine Isoproterenol Terbutaline, Albuterol, Ritrodine β1> β2 >>>> α β1= β2 >>>> α β2 > β1 >>>> α Dopamine agonists Dopamine D1 = D2 >> β >> α

INDIRECTLY ACTING SYMPATHOMIMETICS By releasing catecholamines from neurones Amphetamine: Powerful CNS stimulant actions Orally effective Abused for psychic effects wakefulness, mood elevation, alertness,  self-confidence, concentration,  fatigue Performance enhanced but chances of errors ↑ Tolerance occurs Long term use followed by fatigue and exhaustion Toxicity: Acute – extension of sympathomimetic effects Chronic – Wt. Loss, psychotic reactions, dependence Uses: Narcolepsy Attention-deficit hyperactivity disorder Obesity - apetite suppression ?

INDIRECTLY ACTING SYMPATHOMIMETICS Tyramine : Not used clinically Importance – Present in several foods (cheese, beer, red wine) Interaction with MAO inhibitors : severe toxic effects – severe hypertensive crisis “Cheese Reaction” Methylphenidate : Structurally related to amphetamine Mild CNS stimulant – actions on mental > motor functions Used for Attention-deficit hyperactivity disorder Modafinil : Newer agent, Similar to amphetamine , lower side effects

INDIRECTLY ACTING SYMPATHOMIMETICS Ephedrine : (& pseudoephedrine) Mixed actions ( release + direct effects ) Stimulates  and  receptors Effective orally:  BP, HR, Bronchodilatation, CNS ↑ Duration : several hours – t1/2 3-6 hrs ; Tachyphylaxis occurs USES: Bronchodilator, decongestant ADVERSE EFFECTS :  BP, Insomnia, Urinary retention in elderly

INDIRECTLY ACTING SYMPATHOMIMETICS Mephentermine Direct & + Metaraminol Indirect (release of NE) Effects due to 1 stimulation + Indirect ( + ) HR, force of contraction, CO, systolic and diastolic BP. Uses : To prevent excessive hypotension during spinal anaesthesia, Other hypotensive states To relieve attacks of PAT Adverse effects: CNS stimulation, Excessive  BP, Arrhythmias

THERAPEUTIC USES OF SYMPATHOMIMETIC AGENTS Shock Hypotensive states Hypertension (2 –agonists) Local vascular effects Nasal decongestant (α1 agonists) Ophthalmic uses {Mydriasis (α1); Glaucoma (α2) Asthma and COPD (β2 agonists) Allergic reactions Narcolepsy Weight reduction Attention-deficit hyperactivity disorder in children Tocolytic (2 – agonists)

INDIRECTLY ACTING SYMPATHOMIMETICS B. By blocking reuptake of released transmitter Cocaine : Peripheral sympathomimetic actions, Amphetamine like CNS actions - drug of abuse.

Alpha methyl DOPA Alpha methyl DA Alpha methyl NA ( selective action on α2 )