Lecture 2 Adrenotropic drugs adrenomimetics adrenoblockers Adrenergic drugs

Lecture № 2 Adrenotropic drugs (adrenomimetics, adrenoblockers) НА НА

Adrenergic drugs medical substances which act in adrenergic synapses

Adrenergic synapse Presynaptic membrane Thyrosine МА О Desamination DOPA Dopamine Thyrosine Na+ Ca 2+ Noradrenaline КОМТ О-methylation Phenilalanine Noradrenaline -, -adrenoreceptors postsynaptic membrane

Adrenergic receptor types Name α 1 α 2 β 1 β 2 β- Typical locations Postsynaptic effector cells of the smooth muscles of small vessels of the skin, mucosal membranes, kidneys, mesenterial vessels, muscle dilatator of the pupil, myometrium, sphincters of the GI tract. Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle. Especially – CNS on the brake neurons. Postsynaptic effector cells, especially heart; lipocytes. Postsynaptic effector cells, especially smooth muscles of the bronchi, myomethrium, vessels of skeletal muscles. Liver (hepatocytes), lyposytes, skeletal muscles

Main effects mediated by alpfa and beta-adrenoreceptors Alpha 1 Vasoconstriction Increased peripheral resistance Increase blood pressure Mydriasis Increased closure of internal sphincter of the bladder Alpha 2 Sedative effect on CNS, decrease BP Inhibition of the insulin release Beta 1 Increase of the all function of the heart (tachycardia increase BP, myocardium contractility, increase oxygen demands of the myocardium Beta 2 Betaspecific Broncho. Increase of dilatation the Relax methabolic myometrium processes in Relax smooth the muscles of organism sleletal (glycolysis, muscles lypolysis, Increase muscle and liver glycogenolylysis) sis Increase release of glucagonum

Classification of adrenotropic drugs І. Adrenomimetics 1. - -adrenomimetics (Adrenalini hydrochloridum) 2. -adrenomimetics (Noradrenalini hydrotartras Mesatonum, Naphtizinum) 3. -adrenomimetics (Salbutamol, Phenoterol, Dobutaminum) ІІ. Sympathomimetics (Ephedrini hydrochloridum) ІІІ. Adrenoblockers 1. -adrenoblockers (Prasosinum, Doxasosinum) 2. -adrenoblockers (Anaprilinum, Atenololum, Talinololum, Metoprololum) 3. - і -adrenoblockers (Labetalolum) ІІІ. Sympatholytics (Reserpinum, Octadinum)

Direct-acting adrenergic agonists These drugs act directly on α and β receptors, producing effects similar to those than occur following stimulation of sympathetic nerves. As a group these agents are widely used clinically.

Adrenalini hydrochloridum (Epinephrinum) is a hormone of medullar layer of adrenal glands which is used in a form of a remedy It is an adrenomimetic which stimulates 1, - 2 - and 1, - 2 -adrenoreceptors

Pharmacological effects of Adrenalinum Cardiovascular system Constriction of the small vessels and increasing the blood pressure (short effect – 5 minutes only). Cardiac output increases, increasing oxygen demands on the myocardium. Respiratory system: Bronchodilatation (β 2 receptors) Hyperglycemia: Significant hyperglycemic effect because of increased glycogenolysis in liver (β 2 effect), and the decreased release of insulinum. Thus it can be used in causes of acute hypoglycemia. Metabolic processes: Initiation lypolysis through agonist activity on the β receptors of adipose tissue, which upon stimulation, activate adenylatcyclase to increase 3, 5 cyclic AMP levels. Cyclic AMP stimulates a hormone-sensitive lipase, which hydrolyses fat. This process leads to secrete of high quantity of energy. Eye: The radial pupillary dilator muscle of the iris contains α receptors; activation by adrenaline causes mydriasis. This drug also can decrease the intraocular pressure.

Administration of adrenalinum [ Cardiac arrest, for example, during surgical narcosis, electric trauma [ sudden cardiac death (intracardial administration). [ shock and collapse conditions [ bronchial spasm [ hypoglycemic coma [ for prolongation of anesthetics action due to vasoconstriction and for reduction of regional blood flow is desirable for achieving hemostasis in surgery. [ treatment of open-angle glaucoma

Contraindications N hypertension, N severe atherosclerosis, coronarocardiosclerosis, N cardiogenic and posthemorragic shocks, diabetes mellitus, N thyreotoxicosis

Noradrenalini hydrotartras (norepinephrine) Is an adrenomimetic of direct action which stimulates preferentially -adrenoreceptors Administration in cases of acute decreasing of blood pressure shock and collapse conditions, surgeries, traumas NB! The drug is absolutely contraindicated for subcutaneous and intramuscular introductions

Dopaminum Drug of first choice for treatment of shock and collapse of different ethiology, including cardiogenic and hemorrhagic

Mesatonum (phenylephrin) Is a synthetic a 1 -adrenomimetic drug of direct action Administration z acute hypotensive conditions, z prophylaxis of decreasing of blood pressure in case of infectious diseases, poisonings, z decreasing of blood pressure during narcosis with fluorothan and cyclopropan z nose drops in case of rhinits

Naphtisin Xylometazolin are a 2 -adrenomimetics of direct action Usage for rhinitis in a form of nose drops – 1 -2 drops 2 -3 times a day NB! It is not recommended to use the drug in case of chronic cold

Dobutaminum Is a synthetic 1 -adrenomimetic Cardiotonic effects of dobutamin is 5 times stronger than action of dopamine Administration some forms of acute and chronic cardiac insufficiency intravenous transfusion with the speed of 2, 5 -10 mkg / (kg. min)

Salbutamol (ventolin) selective b 2 -adrenomimetic of direct action Administration þ inhalations during attacks of bronchial asthma and bronchial spasms of other etiology, þ premature child delivery, rapid (vigorous) child delivery

Fenoterol (berotek, partusisten) Is stimulant of mostly 2 -adreno receptors. Posses broncholytic and tokolytic activity

Sympathomimetics

Ephedrini hydrochloridum It has indirect a-, b-adrenomimetic (sympathomimetic) action Administration collapse conditions, for prophylaxis of decreasing of blood pressure before spinal anesthesia, infection diseases è treatment of rhinitis (2%, 3% solution of nasal drops) è prophylaxis and elimination of bronchial spasm (inhalations 0, 5%-1% solutions of drug) SIDE EFFECTS è agitation, excitement, tremor, inconsiderable euphoria, insomnia, seizures M drug addiction M

Classification of the adrenergic blockers I. Adrenoblockers 1) α - adrenoblockers – Prazosinum Doxazosinum 2) β – adrenoblockers Systemic (non-selective) - Anaprilinum (Propranololum) Cardioselective - Metoprololum, Atenololum 3) α and β – adrenoblockers - Labetalolum II. Sympatholytics Reserpinum Octadinum

Alfa-adrenoblockers Prazosinum, (Adversutenum, tabl. 0, 0005; 0, 005 Doxazosinum (Kardura) – tabl. 0, 001; 0, 002; 0, 004; 0, 008 Pratisolum) – 0, 001; 0, 002;

Pharmacologic effects of alfaadrenoblockers lowering of peripheral vascular resistance þ improving of microcirculation and trophics þ decrease of blood pressure, postural hypotension þ reflex tachycardia þ

Therapeutic uses of alfaadrenoblockers Complex treatment of hypertensive disease Disturbances of peripheral microcirculation Migraine headache, vertigo Prostatic hypertrophy ( 1 -antagonists block -receptors and decrease tone in the smooth muscle of the bladder neck and prostate and improves urine flow)

Adverse effects of α-adrenoblockers x ortostatic hypotension, “phenomenon of first dose”: sudden decreasing of blood pressure and even development of orthostatic collapse after first administrations of the drug Prophylaxis: administration of half-dose before sleep x tachycardia x vertigo, dizziness, x nasal congestion, x headache, x drowsiness

Beta-adrenoblockers Note! The name of all β-blockers end in “-olol”, except for labetalol, which has a component of α 1 blocking actions.

Pharmacological effects of beta-adrenoblockers Cardiovascular system - lower blood pressure. Decrease the heart rate, cardiac output Heart - decrease all functions of the heart, work and oxygen consumption of the myocardium Respiratory tract - contraction of the bronchiolar smooth muscles (bronchospasm) Uterus – stimulating of the contractility of pregnant uterus Eye - reducing intraocular pressure, due to decreasing of aqueous humor production. Metabolic and endocrine effects - decreasing of glucogenolysis and glucagons secretion. Inhibition of sympathetic nervous system’ stimulation of lipolysis

Administration of beta-adrenoblockers C C C C Ischemic heart disease Long-term prophylaxis after myocardium infarction and prevention of sudden cardiac death Hyperthyreoidism and anxiety states (decrease of heart rate) Essential hypertension Cardiac tachyarrhythmias (extrasystolies, paroxysmal tachycardia, fibrillation and scintillation of atria) Prophylaxis of migraine headache Some causes of glaucoma (timolol)

Adverse effects of beta-adrenoblockers Heart failure Bronchospasm Allergic reactions (rash, fever, purpura) Heart arrythmias (bradicardia, atrioventricular blockade) CNS disorders (sedation, fatigue, sleep disturbances, depression, sexual disfunctions) Disturbance of metabolism: hypoglycemic action Risk of premature interruption of pregnancy

Anaprilin (Propranololum) is the prorotype β-adrenergic antagonist and blocks both β 1 and β 2 receptors. Administration ischemic heart disease essential hypertension cardiac tachyarrhythmias acute myocardium infarction

Cardioselective β -adrenoblockers Metoprololum (Cоrvitol) - tab. 0, 05; 0, 1; amp. 1% - 5 ml Atenololum (Tenormin) - tab. 0, 05; 0, 1 Talinonololum (Cordanum)- dr. 0, 05; tab. 0, 1. Main speculiarities: Preferentially block the β 1 receptors without blocking of β 2 - receptors. Thus their side effects expect bronchoobstruction, hypoglycemia and premature labor

Talinololum (Cordanum) Administration disorders of cardiac rhythm (extrasystolies, paroxysmal tachycardia, fibrillation and scintillation of atria) þ stenocardia þ arterial hypetension þ

Atenolol (tenormin) cardioselelctive -adrenoblocker of long action Administration Ø ischemic heart disease Ø essential hypertension Ø cardiac arrhythmias Ø acute myocardium infarction

Labetalol -, -adrenoblocker. The drug blocks 1, 2, 1 and 2 adrenoreceptors Administration treatment of patients with essential hypertension hypertensive crisis Contraindications Atrio-ventricular blockade, cardiac insufficiency

Sympatholytics

Reserpin Is a sum of Rauvolfia (plant) alkaloids. Maximal hypotensive action develops after 5 -7 days of regular administration of the drug. After the treatment coarsed effect can still stay for two weeks. Administration treatment of different forms of essential hypertension (preparations of a second choise) (combined drugs trirezid, cristepin, adelfan, brinerdin) Side effects M manifestations of parkinsonism M fatigue, somnolence, depression, M bradycardia M increasing of motor and secretory activity of intestinal tract, M acute attacks of ulcer disease, diarrhea gastro-

Octadinum Is a sympatholytic with strong hypotensive effect. During administration of the drug decreasing of blood pressure develops gradually, after 2 -3 days. After abolition of drug administration the effect still stays for 2 weeks. Administration heavy forms of arterial hypertension Side effects v general weakness, v nausea, vomiting, v swelling of nose mucous membrane, v diarrhea, vorthostatic collapse

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