Adrenergic drugs 2022_2023.pdf

Drugs that affect ANS Adrenergic agents Adrenopositive (sin. adrenomimetic sin. sympathomimetic) agents Selective Selective central Nonselective Selective α1 adrenoreceptor...

Drugs that affect ANS Adrenergic agents Adrenopositive (sin. adrenomimetic sin. sympathomimetic) agents Selective Selective central Nonselective Selective α1 adrenoreceptor α2 adrenoreceptor β adrenoreceptor β2 adrenoreceptor agonist agonist agonist agonist Isoprenaline Salbutamol Phenylephrine Clonidine (Isoproterenol) Nonselective Nonselective α, α, β adrenoreceptor agonist selective β1 adrenoreceptor agonist Epinephrine Norepinephrine Adrenonegative (sin. adrenoblocking sin. sympatholytic) agents Selective Nonselective Selective α1 adrenoreceptor β adrenoreceptor ANTAgonist β1 adrenoreceptor Propranolol ANTAgonist ANTAgonists Metoprolol Doxazosin Selective α1, nonselective β adrenoreceptor ANTAgonist Carvedilol RSU Department of Pharmacology 1 2022/2023  Pharmacology of the Adrenergic Receptors α adrenoreceptors Receptor Target structure Effect α1 Eyes m. Dilatator pupillae Contraction - mydriasis *barrorecptor reflex is sitmulated Arterioles Contraction - ↑diastol.pressure, α1 Blood vessels ↑heart afterload (skin, visceral) Venules Contraction - ↑heart preload α1 Urinary bladder Sphincters ↑ Muscular tone α2 Nerve ends Presynaptic pole ↓ NE release adn synthesis (autoreceptor) α2 Pancreas Beta cells ↓ Secretion of insulin α2 Eyes Cilliary epithelium ↓ Secretion of intraocular fluid (IOF) *vasoconstriction leads to bradycardia RSU Department of Pharmacology 2 2022/2023  Pharmacology of the Adrenergic Receptors β adrenoreceptors *pancreatic side effects Receptor Target structure Effect ß1 Eyes Ciliary epithelium ↑ Secretion of intraocular fluid SA node ↑ Heart rate: «+» chronotropic effect ß1>ß2 AV node ↑ Conduction velocity: «+» dromotropic e.; Heart ↑Automatism Atria/ventricules ↑Contractility: «+» inotropic effect His-Purkinje fibers ↑Automatism ß2 Blood vessels Arterioles Relaxation- ↓diastol.pressure (skeletal mm.), (except skin, mucosa, ↓heart afterload cerebral b/v) Venules ↓heart preload ß2 Lungs Bronchioles ↓ Muscle tone α1,ß2 Liver ↑glycogenolysis ↑glyconeogenesis ß2 Beta cells ↑ Secretion of insulin check glucose level Pancreas release in glucaogon controlled by b2 receptors - relased during hypoglycemia diabetic patient at risk ß2, ß3 Urinary m.Detrusor ↓Muscle tone bladder ß1 Kidney ↑Release of renin ß2 Uterus Myometrium ↓ Muscle tone ß2 Skeletal ↑ Muscle tone muscles ↑ glycogenolysis, ↑K+ uptake in cells RSU Department of Pharmacology can lead to hypokalaemia 3 - drug indcued side effect 2022/2023 Pharmacology of the Adrenergic Receptors MAO COMT Processes in adrenal glands COMT and MAO are primarily designed to inactivate norepinephrine, which is not bound back into the presynaptic neuron. Both enzymes are found in many tissues, including the liver and intestine. MAOs also localize in neuronal mitochondria and degrade in the cytoplasm existing norepinephrine, not accumulated in vesicles RSU Department of Pharmacology 4 2022/2023 Pharmacology of the Adrenergic Receptors VMAT – vesicular monoamine transport system NET – norepinephrine transport system RSU Department of Pharmacology 5 2022/2023  Adrenopositive agents Epinephrine q Phosphorilation of myosin Vasomotor, cardiotropic and metabolic effect of catecholamines RSU Department of Pharmacology 6 2022/2023  Adrenopostive agents In cardiomyocytes, beta-adrenoreceptor stimulation is completed by contraction, whereas in vasculature it is completed by vasodilation Vasculature Cardiomyocyte Gq - alpha 1 receptors, Beta 1 stimulation provides cardiotonic Gi - alpha 2 receptors effect. The primary cardiotonic effects are Gs - beta1, beta 2 «+» inotropy and «+» chronotropy adrenoreceptors RSU Department of Pharmacology 7 2022/2023  Adrenopositive agents Affinity of adrenopositive agents Subtype of adrenoreceptors α1 α2 β1 β2 Norepinephrine +++ +++ ++ + Epinephrine ++ ++ +++ +++ Isoprenaline - - +++ +++ Clonidine - +++ - - Salbutamol - - + +++ Norepinephrine, Epinephrine, Isoprenaline: Biogenic amines - Catecholamines: Fast and short acting, parenteral only (low oral bioavailability), Does not cross BBB. Clonidine and Salbutamol - non-catecholamines: prolonged action, enteral use is possible RSU Department of Pharmacology 8 2022/2023  Nonselective alpha, beta adrenoreceptor agonists non selective drug affects all receptors, dose dep, medication!! low conc more affects b2 receptors, high dose - alpha 1 receptors. due to receptor affinity - beta 2 more sensitive to epinephrin. alpha 1 is resistant and requires high dose. Epinephrine (adrenaline) i / m, i / v, pre-filled pen-like syringe Vasoconstrictive / vasodilatory (dose- depending) , cardiotonic («+» inotropic effect), «+» Chrontropic, «+» dromotropic effect, bronchodilatory, mydriatic action Receptors - α1, α2, β1, β2 Low dose β1, β2, high α1, β1 (β2) + β2 – relaxation of smooth metabolic effects (glycogenolysis) with muscles of blood risk of hyperglycaemia Local vessels, BP ↓ haemostatic effect Clinical use: Anaphylactic shock Asystolia Topically - in combination with local anesthetics adrnaline iduced vasoconstriction - reduces side effects of anathesia - cannot go to systemic circulation. used when local never used orally!! unstable in GI tract RSU Department of Pharmacology aneastheisa drugs may cause vasodilation 9 2022/2023  three diff receptors. not beta 2. Nonselective alpha, selective beta 1 adrenoreceptor agonists better affinity for alpha 1- better vasoconstriction Norepinephrine (noradrenaline) never for asthma or anaphalaxis - doenst cause bronchodilation Vasoconstrictive, cardiotonic («+» inotropic effect), mydriatic effect Reflector bradycardia reflex Receptors - α1, α2, β1 Both epinephrine and norepinephrine ↑ myocardial oxygen demand Norepinephrine, unlike epinephrine, does not cause bronchodilation Clinical use: Acute hypotension - collapse SBP < 70 mm Hg necrosis or damage of tissue may occur due to intense vasoconstriction RSU Department of Pharmacology 2022/2023 10  Adrenomimetc agents and their effect on CVS The vascular effects of norepinephrine are mainly caused by α1-adrenoceptor activation. Vasoconstriction occurs and peripheral resistance increases, which in turn increases SBP and DBP. If BP increases significantly, NE may cause reflector bradycardia barrorecoptor reflex - SBP Isoprenaline - Mean BP β1=β2 - DBP Epinephrine increases SBP in a dose-dependent manner, but DBP can be increased or decreased. In contrast, isoprenaline always reduces DBP. Increased heart rate increases SBP. The effect on DBP is dependent on the stimulation of the α1- and β2-adrenoceptors, which promote vasoconstriction or vasodilation. Low doses of E lead to more pronounced stimulation of β2 receptors than α1 receptors, particularly in skeletal muscle blood vessels, thereby causing vasodilation and reducing DBP. Higher doses of E cause generalized vasoconstriction throughout the body and can increase both DBP and SBP. RSU Department of Pharmacology 11 2022/2023 Selective alpha 1 adrenoreceptor agonists canbe oral or nasal etc more stable drug α1 adrenomimetic agents Local action vasoconstrictors - *nasal decongestants: causes vasoconstriction in nasal mucosa Phenylephrine Systemic vasoconstrictive effect → hypertensive effect (↑ BP), Causes reflector (indirect effect) «-» chronotropic effect Mydriatic effect Clinical use: Acute rhinitis*, nose bleeding Acute hypotension Paroxysmal ventricular tahycardia to stimulate reflex bradycardia *Recommended therapy duration not more than 5-7 days can be vasoconstriction outside of nasal mucosa leads to atrophy of nasal mucosa body can get dependent - physiological - rebound effect dryness bleeding etc can lead to rhinitis medicamentosa replace w hormonal nasal spray RSU Department of Pharmacology 12 2022/2023  Selective alpha 2 adrenoreceptor agonists α2 adrenomimetic agents via cns - sedation etc. no alcohol. used before sleep. Clonidine 1. hypotensive effects (vasomotor center) of central action Stimulation of central presynaptic α2 receptor → → ↓SANS impulsation → peripheral vasodilatation In vasculature peripheral presynaptic autoreceptor and postsynaptic α2 stimulation Bradycardizing effect very fast acting - used in first aid Hypertension, hypertensive crisis Rebound effect - BP↑ 2. Regulates brain subcortical activity. ↓ pain impulse transmission in brain periphral post synaptic alpha 2 receptors may be activated and Coanalgesia cause vasoconstrciton - if used in high conc for long time RSU Department of Pharmacology 13 2022/2023 Alpha 2 selective agonists http://tmedweb.tulane.edu/pharmwiki/doku.php/clonidine RSU Farmakoloģijas katedra 14 2022/2023  Selective beta 2 adrenoreceptor agonists β2 adrenomimetic agents - bronchodilatators used for asthma via inhalation - first used for doping pass elimination Salbutamol and prevention of abortion β2 adrenoreceptor excitation: 1. ↓ intracellular calcium concentration, Relaxation of nrochial smooth muscle → bronchodilation Clinical use: Bronchial asthma attack 2. Tocolytic effect (inhibition of uterus contractions) IV therapy β2 reduction of receptor amount Clinical use: Tocolysis Down-regulation – dose dependant , drug tolerance in long term impaired bronchodilator efficacy Side Effects: tremor, tachycardia (β2 in the heart) Interactions: reduces effects of vasoconstrictive agents RSU Department of Pharmacology 15 can affect b1 receptors in long run 2022/2023  Selective alpha 1 adrenoreceptor antagonists α1 selective blockers Doxazosin 1. Vasodilatation of peripheral blood vessels, vein and artery ↓peripheral resistance (reduces afterload), increases capacity of veins (reduces preload) and ↓ BP, hypotensive effect used for male patients Clinical use: with prostate galnd sisues Hypertension Side Effects: first-dose orthostatic hypotension and 2. ↓ urethral tone and syncope, reflector tachycardia relaxes prostate muscle → orthostatic hypotension - head rush ↓ urination disorders Clinical use: Symptomatic therapy of prostate adenoma RSU Department of Pharmacology 16 2022/2023  Beta adrenoblockers (BAB) Cardiac depressant, antianginal, anti-arrhythmia, hypotensive effects «-» ino-, chrono-, dromotropic effects Kidneys: ↓renin release Stroke volume – systolic blood volume RSU Department of Pharmacology 17 2022/2023 Nonselective beta adrenoreceptor antagonists 1. generation Nonselective β1, β2 adrenoblockers Propranolol Clinical use: Coronary artery disease Tachycardia, thyrotoxicosis, prevention of migraine attacks Atrial fibrilation (Class II antiarrhythmics) NB! Prolonged BAB therapy causes an adrenoreceptor Up-regulation effect, so suddenly stopping BAB therapy – Rebound effect! Recurrence of angina pectoris Nonselective BAB may mask initial symptoms of insulin overdose: tachycardia, tremor, anxiety In case of DM cardioselective BAB are safer SE: bradycardia, AV block, risk of bronchial obstruction, sexual dysfunction, Raynaud syndrome Interactions: Due to non-selective action, P may affect the effects of adrenopositive agents RSU Department of Pharmacology 2022/2023 17 Nonselective beta adrenoreceptor antagonists Nonselective β1, β2 adrenoblockers Timolol eye drops ↓ intraocular fluid secretion in the ciliary body → reduces intraocular pressure Clinical use: Glaucoma Does not affect drainage of fluid from the eye PANS / SANS target structures in eye: three muscles (pupil dilator, pupil constrictor muscle, ciliary muscle) and ciliary body epithelium RSU Department of Pharmacology 19 2022/2023  Selective beta 1 adrenoreceptor antagonists 2. generation Cardioselective β1 adrenoblockers Metoprolol Bisoprolol highly selective β1 BAB have rebound effect if suddenly stopped ! Clinical use: Coronary Artery Disease (CAD) Hypertension cardiodepressive ionochrono effect on heart - not first line Atrial fibrilation (Class II antiarrhythmics) CHF (chronic heart failure) Prophylaxis of migraine attacks lipophilic BAB cause vasoconstriction Cardioslectivity β1→ - less impact on b / v smooth muscle, bronchi, uterus and - electrolyte balance (risk of hyperkalemia is lower) - safer for patients with asthma, Diabetes mellitus* and Raynaud syndrome. * β2 blockade reduces insulin secretion and glycogenolysis RSU Department of Pharmacology 20 2022/2023  Selective alpha 1, nonselective beta adrenoreceptor antagonists with addtional actions eg - vasodilation! ; alpha 1 3. generation α1, β1, β2 adrenoblockers Carvedilol Cardiodepressant + reduces peripheral vascular resistance + antioxidant properties (cardioprotection, inhibits lipid peroxidation) Clinical use: Chronic heart failure CAD BAB effect on renin not so clinically Hypertension important as it will ocmpensate BAB watch for hypoglycemia as it block Lekciju ilustratīvais materiāls: gycogenolysis - imp for diabtic patients Lulman H. Color Atlas of Pharmacology 2nd Ed 2000 Thieme Katzung Basic and Clinical Pharmacology 13ed BAB masks systems of hypoglycemoa - Katzung & Trevor's Pharmacology: Examination & Board Review, 11ed tachycardia tremor anxiety RSU Department of Pharmacology 21 2022/2023  Beta adrenoreceptor antagonists Raynaud syndrome - peripheral circulatory disorders characterized by episodic stenosis of limb arteries and arterioles. Usually provoked by cold or stress. Manifested as sudden paleness or cyanosis of the fingers and toes, including the earlobe and nose 3-4% β2 blockage - BAB causes peripheral vasoconstriction! Limb freezing! RSU Department of Pharmacology 22 2022/2023  BB toxicology Mechanism of toxicity All beta blockers antagonize beta1 adrenoreceptors, decreasing heart rate and cardiac contractility. Some nonselective beta blockers also antagonize beta2 receptors, which can result in bronchoconstriction, hypoglycemia, and hyperkalemia. Propranolol with membrane depressant effects further depress myocardial contractility and conduction and may be associated with ventricular tachyarrhythmias. Propranolol is also lipid soluble, which enhances brain penetration and can cause seizures and coma. Carvedilol have combined nonselective beta and alpha adrenergic– blocking actions, and nebivolol is a selective beta1 antagonist with vasodilating properties not mediated by alpha blockade. With these drugs, direct vasodilation can contribute to hypotension in overdose. RSU Farmakoloģijas katedra 23 2022/2023  BB toxicology Clinical presentation A. Cardiac disturbances, including first degree heart block, hypotension, and bradycardia, are the most common manifestations of poisoning. Highdegree atrioventricular block, intraventricular conduction disturbances, cardiogenic shock, and asystole may occur with severe overdose, especially with membranedepressant drugs such as propranolol. The ECG usually shows a normal QRS duration with increased PR intervals, but QRS widening can occur with membrane depressant beta blocker intoxication. B. Central nervous system toxicity, including convulsions, coma, and respiratory arrest, is commonly seen with propranolol and other membranedepressant and lipidsoluble drugs. C. Bronchospasm is most common in patients ingesting nonselective beta blockers and with preexisting asthma or chronic bronchospastic disease. D. Hypoglycemia and hyperkalemia may sometimes occur. RSU Farmakoloģijas katedra 24 2022/2023  BB toxicology Treatment Emergency and supportive measures 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, hyperkalemia, and hypoglycemia if they occur. 3. Atropine, IV, may be ineffective as beta blocker–associated bradycardia is not due to increased vagal tone. Cardiac pacing may also be tried. 4. Treat bronchospasm with nebulized bronchodilators. 5. Continuously monitor the vital signs and ECG RSU Farmakoloģijas katedra 25 2022/2023  BB toxicology Treatment Specific drugs and antidotes 1. Give glucagon IV over 1–2 minutes for bradycardia resistant to basic supportive measures and repeat as needed. 2. Administer calcium chloride IV, or calcium gluconate IV, and repeat as needed. Calcium may reverse beta blocker–associated depression of cardiac contractility but does not affect sinus node depression or peripheral vasodilation, and has variable effects on AV nodal conduction. 3. Highdose insulin euglycemic therapy (HIET) 4. Give sodium bicarbonate, for wide complex QRS conduction delay and associated hypotension caused by membrane depressant beta blocker poisoning (eg, propranolol). 5. Vasopressors are often needed to manage shock from beta blocker overdose. Extraordinarily high doses may be required for refractory shock; however, ischemia (eg, limb or bowel) is a potential complication. Epinephrine (IV infusion) may be useful. RSU Farmakoloģijas katedra 26 2022/2023