Adrenergic Agonists and Antagonists - Antihypertensive I PDF

Adrenergic agonists and antagonists – Antihypertensive I Dr. Alemayehu Toma, B.Pharm, MSc, PhD Ass. Professor in Pharmacology 1  Alpha adrenergic receptors Alpha1-Adrenergic Receptors Located on postsynaptic effector cel...

Adrenergic agonists and antagonists – Antihypertensive I Dr. Alemayehu Toma, B.Pharm, MSc, PhD Ass. Professor in Pharmacology 1  Alpha adrenergic receptors Alpha1-Adrenergic Receptors Located on postsynaptic effector cells (the cell, muscle, or organ that the nerve stimulates) The predominant α1-adrenergic agonist responses are: Vasoconstriction and CNS stimulation Alpha2-Adrenergic Receptors Located on presynaptic nerve terminals (the nerve that stimulates the effector cells) Control the release of neurotransmitters  Beta adrenergic receptors All are located on postsynaptic effector cells β1-adrenergic receptors—located primarily in the heart and kidney β2-adrenergic receptors—located in smooth muscle of the bronchioles, arterioles and visceral organs ❖Beta-adrenergic agonist response results in: Bronchial, GI and uterine smooth muscle relaxation Glycogenolysis Cardiac stimulation 3  Class work: Mention adrenergic effects on different organ systems Organs Effects CVS CNS Respiratory GIT Eye Salivary gland Liver 4  Drugs acting on the sympathetic nervous system Sympathomimetics or Sympatholytics adrenergic drugs: /sympathoplegics: ▪ Drugs that mimic the ▪ Drugs that inhibit the effects of sympathetic activity of sympathetic nerve stimulation nerve or that of sympathomimetics 5 Sympathomimetics 1. Direct Acting: directly stimulates receptors (NE, Epi, Isoproterenol) 2. Indirect Acting: ✓ displace stored NE from nerve endings ✓ inhibit re-uptake of released NE (Amphetamine, Tyramine, Cocaine, Imipramine (TCA)) 3. Mixed (indirect & direct): stimulates receptor sites & release of norep. from nerve endings (Dopamine, Ephedrine) 6 Direct acting drugs Agonist (non-selective) potency rank: For alpha receptors: Epinephrine ≥ Norepinephrine >> Isoproterenol For beta Receptors- β1, 2, 3: Isoproteronol > E > NE CATECHOLAMINES High potency in activating receptors Rapid inactivation Poor penetration into the CNS Nevertheless, most of these drugs have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS. 7  Epinephrine Ineffective when given orally and should be given intramuscularly or subcutaneous one of the commonly used in therapy Epinephrine is synthesized in the adrenal medulla stimulates all the adrenergic receptors α effects: vasoconstriction, mydriasis, increase in blood glucose ß1 effects: increased contractility and rate of heart 8  Epinephrine Indications 1. Acute bronchial asthma and anaphylactic shock 2. Local haemostatic to stop bleeding 3. With local anesthesia to prolong the action 4. Cardiac arrest Adverse effects: anxiety, fear, tension, headache, and tremor 9  Selective Adrenergic agonists Direct alpha 1 agonists Direct  receptors agonists Phenylephrine Non-selective Methoxamine ✓ Isoproterenol Oxymetazoline  1-selective Direct 2 agonists: ✓ Dobutamine Clonidine ✓Dopamine  2-selective Methyldopa ✓ Terbutaline Guanabenz ✓Metaproterenol Guanfacine ✓Albuterol Tizanidine ✓Salmeterol ✓Ritodrine  -selective - Mirabegron 10 Beta1- Selective Agonists Dopamine Increase renal blood flow (renal dopamine receptors) Moderate dose: Increase in contractility and heart rate, increase in C.O. High dose: Increase in T.P.R. (effect at α-ARs) Dobutamine Increase in contractility, heart rate and Cardiac output. High dose: Increase in T.P.R. (effect at α-ARs) No effect on renal dopamine receptors 11  - Selective Agonists In the bronchial smooth muscle β2 stimulation causes relaxation of smooth muscle (bronchodilatation) In the smooth muscle of blood vessels supplying the skeletal muscle. β2 stimulation causes relaxation of smooth muscle (Vasodilatation) Albuterol, salbutamol Relaxation of airway smooth muscle →used as aerosol in asthmatics Ritodrine Relaxation of uterine smooth muscle (delay or prevent premature parturition) 12  case A 33-year-old female with a known peanut allergy presented with sudden difficulty breathing, hives, and swelling after accidental peanut ingestion. She was hypotensive and in respiratory distress. Intramuscular epinephrine (0.3 mg) was administered immediately, rapidly improving her symptoms, stabilizing her vitals, and preventing anaphylactic shock. I. Class of the drug II. Mechanism of actions III. Effects on different organ system IV. Clinical uses V. Adverse effects VI. Contraindications 13  Sympatholytics Alpha-adrenergic receptor antagonists Non-selective α-AR antagonists Phentolamine, Phenoxybenzamine - for pheochromocytoma α1- Alpha-Adrenergic Receptor selective ✓Prazosin ✓Terazosin ✓ Alfuzosin ✓Tamsulosin Alpha-2 Adrenergic Receptor selective ✓Yohimbine, Mertazapine 14  Prazosin effective drug for the management of hypertension has high affinity for alpha1 receptor and relatively low affinity for alpha2 receptor Prazosin leads to relaxation of both arterial and venous smooth muscles Thus it: ✓ lowers blood pressure ✓ reduces venous return and cardiac output ✓reduces the tone of internal sphincter of urinary bladder 15 Beta-adrenergic receptor antagonists Non-selective β-AR antagonists ✓Propranolol ✓Nadolol ✓Pindolol ✓Timolol β1-AR selective antagonists ✓Metoprolol ✓Atenolol ✓Esmolol β2-AR selective antagonists ✓Butoxamine 16  Propranolol Actions Pharmacokinetics ✓Bradycardia almost completely absorbed from oral administration ✓ Reduces force of contraction of the heart but 1/3 rd of the dose to reach the systemic circulations ✓ Reduces blood pressure bound to plasma to the extent of 90-95% ✓ Bronchoconstriction excreted in the urine ✓ Hypoglycemia ✓ Anti-anxiety action ✓Decrease the rate of Aqueous humor production ✓ Decrease renin secretion 17  Indications: ✓Cardiac arrhythmias ✓Hypertension ✓Prophylaxis against angina ✓Myocardial infarction ✓Thyrotoxicosis ✓ Anxiety states ✓Prophylaxis against migraine attacks ✓ Glaucoma 18 Non Selective Adrenergic Receptor Antagonists Labetalol Non-selective beta receptor antagonist Alpha 1 receptor antagonist beta-blocking activity prevents reflex tachycardia normally associated with alpha1 receptor antagonists Administered: Oral, parenteral Uses: Hypertension, hypertensive crisis Doesn’t cross Placenta - used in pregnancy 19  Carvedilol Non-selective beta receptor antagonist Alpha 1 receptor antagonist Beta -blocking activity prevents reflex tachycardia normally associated with alpha1 receptor antagonists Administered: Oral Uses: Hypertension, congestive heart failure 20  Case A 45-year-old male with a history of hypertension and anxiety presented with palpitations and tremors. He was diagnosed with essential tremor and elevated heart rate. Propranolol was prescribed at 40 mg daily. Within two weeks, his symptoms improved significantly. I. Class of the drug II. Mechanism of actions III. Effects on different organ system IV. Clinical uses V. Adverse effects VI. Contraindications 21  Hypertension Hypertension is defined as either a sustained systolic blood pressure of greater than 140 mm Hg or a sustained diastolic blood pressure of greater than 90 mm Hg. Classification of hypertension 22 Blood pressure regulation BP = CO x TPR ↓CO and thus heart rate and of TPR by vasodilatation is target for HTN treatment The baroreceptor reflex are involved in day to day regulation of BP while the humeral [renin angiotensin- aldostrone ] is involved in long term BP regulation In hypertension there is an abnormal increase in TPR and an abnormal activation of the RAS Drug therapy of hypertension is therefore target to this abnormally increased and activated system. 23  Non pharmacologic intervention- hypertension ◆Involve both life style modification and drug therapy ◆life style modification includes: (First line therapy) ✓Dietary sodium restriction ✓Weigh control ✓Aerobic physical activity ✓Limiting alcohol consumption ✓Fruit reach and vegetables (K) ✓Low dairy products (decreased saturated fat) ✓Food with fiber 24  Pharmacologic intervention for hypertension 1. Diuretics 2. Sympatholytics 1. Beta blockers 2. α2 agonist 3. α1 blockers 3. Renin angiotensin system [RAS] inhibitors 1.ACE Inhibitors 2.Angiotensin receptor antagonists 3.Direct renin inhibitors 4. Calcium channel Blockers 5. Vasodilators 25  Calcium Channel Blockers (CCB) Verapamil: More selective on cardiac muscle Diltiazem: Acts equally on both cardiac & smooth muscles Nifedipine: More selective on blood vessels Mechanism of action (-) SAN → ↓Heart rate (-) AVN → ↓ Conductivity (-) Cardiac contractility Vasodilatation ; T.P.R 26  CCB: Adverse effects ◆Flushing ◆Headache, ◆Dizziness ◆Ankle edema, ◆bradycardia, ◆Atrioventricular node block 27 Class work Describe mechanism of action, clinical use and adverse effects of the following drugs, Propranolol Carvedilol Verapamil Prazosin Atenolol 28 Thank you! 29