adrenergic agonist.pdf

4 1. Synthesis & Release 2. Actions & Receptors 3. Direct non selective agonist 4. Direct selective agonist 5. Indirect agonist 6. Mixed agonist Synthesis & Release Actions & Receptors  SYMPATHETIC NERVOUS SYSTEM Fight or flight response results in: 1. Increased BP 2. Increased blood...

4 1. Synthesis & Release 2. Actions & Receptors 3. Direct non selective agonist 4. Direct selective agonist 5. Indirect agonist 6. Mixed agonist Synthesis & Release Actions & Receptors  SYMPATHETIC NERVOUS SYSTEM Fight or flight response results in: 1. Increased BP 2. Increased blood flow to brain, heart and skeletal muscles 3. Increase depth and rate of respiration 4. Increased muscle glycogen for energy 5. Increased rate of coagulation 6. Pupil dilation 7. Piloerection  According chemical structure Catecholamines Non-catecholamines Contain catechol in their structure Does not contain catechol in their structure polar so it can not penetrate into CNS Are lipophilic so they pass BBB Rapidly inactivated by COMT post synoptically and by MAO in the it is not inactivated by COMT neuron Short duration of action Long t 1/2 Given parenterally Given orally High potency Less potent e.g. adrenaline,noradrenalin, dopamine, isoprenaline e.g. ephedrine, phenylephrine, amphetamine  According mode of action Direct acting agonists (Non Selective)  Adrenalin (all route except oral) - Naturally synthesized in adrenal medulla and Nerve endings. - Act on α & β - At low dose β effect (vasodilatation) - At high dose α effect (vasoconstriction) Actions: A- CVS: 1- +ve inotropic & +ve chronotropic effect So increase CO & O2 demand (β1) 2- Constriction of arterioles in skin, mm, &viscera. 3- Dilate BV in the liver and skmm (β2) 4- Increase renal blood flow & renin release, So? So *increase systolic BP and slight decrease in diastolic pressure ???? B- Respiratory - Bronchodilation - Inhibit allergy mediators release as histamine C- Metabolic effect a) Hyperglycemia: - Increase hepatic glycogenolysis - Increase glucagon release - Decrease insulin release b) lipolysis: hydrolysis of TG to FF and glycerol by cAMP which stimulates lipase enzyme.  Indications ABCDEG Anaphylaxis Bronchospasm Cardiac arrest Dental use Epistaxis Intraocular surgery (Mydriasis) Side effects:- 1- CNS:headache ,anxiety, tension,tremor 2- CVS: hypertension, dysrhythmia , angina pectoris, necrosis due to vasoconstriction 3- Respiratory: pulmonary edema 4- Hyperglycemia 5- Inhalational anesthetics, hyperthyroidism may increase the heart sensitivity to epinephrine which might lead to tachycardia.  Noradrenalin - In therapeutic dose α1,2 is most affected & β 1 but weak β2 effect. Action: - CVS : + inotropic & chronotropic - Vasoconstriction ( include kidney ) - increase peripheral resistance more than epinephrine ? …. SO Increase systolic and diastolic BP ??? - BUT bradycardia occur by stimulating vagus nerve activity due Stimulation of baro Receptor. - It is not useful in anaphylaxis and asthma??? Indications:- Just in shock? Contraindications:- 1- Periferal vascular diseases 2- Hypertension 3- Asthma Side effects:- Same as epinephrine+ sloughing and necrosis at site of injection.  Isoprenaline - Synthetic catechol - Non selective β-1 , β-2 so it not used therapeutically - Absorbed sublingually , inhalational and parenteral Actions: CVS: - +inotropic ,+chronotropic ? - Dilate BV of SK. M so, decrease periph.resist.. Respiratory: - Bronchodilation - Same SE of epi  Dopamin - Catecholamine synthesized in CNS in basal ganglia and adrenal medulla - It acts on D1-2 dopamine Receptors - D1 receptor, dilatation of renal, mesenteric bv. - D2 receptor just like α2 receptor ?? - (affect α1 at high dose and β1 in low dose). Indications:- 1- Cardiogenic & septic shock. 2- Hypotension 3- Oliguria 4- Bradycardia 5- Severe heart failure. S.E:- It is rapidly metabolized by MAO & COMT. So, hypertension, dysrhythmias are short lived.  Fenoldopam -Peripheral Dopamine agonist D1 - Rapid vasodilator so used in sever hypertension -Undergo first pass metabolism SE: -Headache, flushing, nausea, vomiting , and tachycardia (why) ??  Alpha- α1 Nor-epinephrine > Isoproterenol - α2 = G-Ptn coupled – PLC – IP3+DAG - Ca++ (α1) G-Ptn coupled – AC - Camp (α2) Beta - β1 Epinephrine = Nor-epinephrine - β2 Epinephrine > Nor-epinephrine - β3 Epinephrine > Nor-epinephrine The 3 receptors are G-Ptn coupled–PLC–IP3+DAG Dopamine—subsets D1- D5……..Later on..! Direct acting agonists (Selective)  Dobutamin - Synthetic catecholamine , β1 agonist - So, + inotropic & chronotropic effects. Indications : Used to increase CO in acute HF & after cardiac surgery (inotropic support) - It does not elevate O2 demand of myocardium - Used with caution in atrial fibrillation (as it increase av conductance)  SABA Albuterol, metaproterenol & terbutaline - β2 agonist - Short acting (3 hr) & rapid onset - bronchodilator(inhaler) - Terbutaline injection relax uterus so Used in premature labor SE: Tremor, restlessness, and anxiety. tachycardia if given orally (activate β1)  LABA - Salmeterol, indacaterol & formoterol (LABAs) - selective β2 agonist - Long acting(12hr) & Salmeterol slow onset Indications:- asthma and COPD. - Combined with other asthma medication as inhaled corticosteroids.  Oxymetazoline - α 1 & α2 agonist -Act as ophthalmic & nasal decongestant as nasal spray, ophthalmic drops. SE: - Irritation & sneezing in nasal administration, in systemic once, headaches and sleep disturbances ** rebound congestion & dependence if it is used greater than 3 days.  Phenylephrine - Selective α1 agonist, long t1/2 (why) ?? - Vasoconstrictor ( systolic &diastolic BP) Uses: - Hypotension in patient with rapid H rate - Paroxysmal supraventricular tachycardia ??? - Topically as nasal or oral decongestant - Ophthalmic solution for mydriasis SEs: - Large dose cause hypertensive headache and cardiac irregularities.  Clonidin - Selective α2 agonist -Used to in hypertension by inhibiting sympathetic vasomotor center then decrease sympathetic out flow -Used to control withdrawal symptoms from opiates, benzodiazepines and tobacco. - Guanfacine and clonidine used in ADHD**. SE: lethargy, sedation, xerostomia Indirect acting agonists  They potentiate the endogenous nor epinephrine and epinephrine by:- 1- Increase release of epi & nor epi (amphetamine and tyramine). 2- Inhibit re-uptake of epi & nor epi (cocaine). 3- Inhibit degradation of epi & nor epi (MAO & COMT inhibitors). Mixed action They induce release of nor epinephrine. and activate adrenergic receptors. Ephedrine & pseudoephedrine - An alkaloid, long t1/2 ?? - Have α1 , β effect - Act slowly but less potent than epinephrine. - They penetrate CNS - Ephedrine used in hypotension. - Ephedrine has slow onset bronchodilator effect - Pseudoephedrine used in nasal and sinus congestion but with precautions ??? ADRENERGIC AGONISTS ADVERSE EFFECTS Arrhythmias Hyperactivity Insomnia Tremors Tachycardia Headache Nausea DESENSITIZATION OF ADRENERGIC RECEPTORS Causes:- 1- Sequestration of the receptors so that they are unavailable for interaction with the ligand. 2- Down-regulation, that is, a disappearance of the recep_x0002_tors either by destruction or by decreased synthesis. 3- An inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side. Time for MCQs  Quiz. 1- Which of the following classes of adrenergic agents has utility in the management of hypertension? A. α1 Agonist B. α2 Agonist C. β1 Agonist D. β3 Agonist 2- Which of the following is correct regarding responses mediated by adrenergic receptors? A. Stimulation of α1 receptors increases blood pressure. B. Stimulation of sympathetic presynaptic α2 receptors increases norepinephrine release. C. Stimulation of β2 receptors increases heart rate (tachycardia). D. Stimulation of β2 receptors causes bronchoconstriction. 3- An asthma patient was given a nonselective β agonist to relieve bronchoconstriction. Which adverse effect would you expect in this patient? A. Bradycardia B. Tachycardia C. Hypotension (reduction in blood pressure) D. Worsening bronchoconstriction