Lesson 7 - Adrenergic Transmission (Agonists) PDF

Lesson 7 Adrenergic Transmission Adrenergic Agonists 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 Summary 1.Catecholamines synthesis. 2.Adrenergic receptors. 3.Adrenoceptor agonists. 4.Summary 2 ...

Lesson 7 Adrenergic Transmission Adrenergic Agonists 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 Summary 1.Catecholamines synthesis. 2.Adrenergic receptors. 3.Adrenoceptor agonists. 4.Summary 2  Peripheral Nervous System Sympathetic Parasympathetic Somatic Preganglionic neuron Ach Ach Ganglion Postganglionic neuron Nicotinic Receptor Nicotinic Receptor N.A. Ach Ach Adrenergic Receptor Muscarinic Receptor Nicotinic Receptor (Skeletal muscle) Effector organs  Catecholamines Catecholamines are compounds containing a catechol moiety (a benzene ring with two adjacent hydroxyl groups) and an amine side chain. Substances that are released in the adrenergic postganglionic nerve fiber at the level of the effector organ, producing the cellular response. CATECOLAMINES: ADRENALINE (A) NORADRENALINE (NA) DOPAMINE (DA) Adrenaline Noradrenaline Dopamine 1. CATECHOLAMINES SYNTHESIS – Dopamine, the metabolic precursor of noradrenaline and adrenaline, also a transmitter in the CNS – Noradrenaline (Norepinephrine), a transmitter released by sympathetic nerve terminals – Adrenaline (Epinephrine), a hormone secreted by the adrenal medulla – Isoprenaline (Isoproterenol), a synthetic derivative of NA, not present in the body. 4 1. CATECHOLAMINES SYNTHESIS 1) Catecholamine synthesis 2) Catecholamine storage and release They are stored in granules that are concentrated in vesicles along axons. Once the transmission of the electrical impulse occurs, by ↑ Intracellular Ca+2 favors the release of the neurotransmitter into the synaptic space by exocytosis.  1. CATECHOLAMINES SYNTHESIS 3) Reuptake and inactivation of catecholamines Reuptake: ─ Neuronal: catecholamines can be reuptaken by the same nerve terminal via specialised transporters called catecholamine reuptake transporters (NETs). ─ NA, by acting on presynaptic α2 receptors, can regulate its own release, autoinhibitory feedback mechanism. ─ Extraneuronal: catecholamines can be reuptaken by adjacent cells. In this case, catecholamines are removed from the synaptic space and taken back into the cells for storage or degradation. This process contributes to the regulation of catecholamine concentrations in the synaptic space and prevents overexcitation of postsynaptic cells. 8  1. CATECHOLAMINES SYNTESIS 4) Metabolism Mono Amine Oxidase (MAO) – MAO inhibitors are used as antidepressants MAO a (NA, Serotonine) MAO b (DOPA) Catechol-o-methyl-transferas (COMT) Mechanisms of action of some psychotropic drugs include blocking the metabolism of catecholamines by MAO and COMT, which increase the concentration of these substances at the neuronal synapse, thereby enhancing the transmission of nerve signals and affecting mood and other physiological processes. Summary 1.Catecholamines synthesis. 2.Adrenergic receptors. 3.Adrenoceptor agonists. 4.Summary 1 0 Adrenergic System Neurotransmitter: Adrenaline/Noradrenaline Adrenergic receptors: α and β  2. ADRENERGIC RECEPTORS They are all G protein-coupled receptors They are divided into: a1: Smooth muscle of blood vessels, bronchi, a gastrointestinal tract, uterus and bladder. a2: Presynaptic. b1: Heart, intestinal sphincter. b b2: Blood vessel smooth muscle, bronchial smooth muscle. b3: Adipose tissue in terms of agonist potencies: a: noradrenaline > adrenaline > isoprenaline β: isoprenaline > adrenaline > noradrenaline 2. ADRENERGIC RECEPTORS Effect of NA on adrenergic receptors: 15  2. ADRENERGIC RECEPTORS The main effect of NA on adrenergic receptors are: a1 : vasoconstriction, relaxacion of g.i. smoot muscle, salivary secretion and hepatic glycogenolysis. a2: inhibition of NA release, promote platelet aggregation, vascular smoot muscle contraction, insuline release. b1: increased cardiac rate and force b2: bronchodilatation, vasodilatation; relaxation of visceral smoot muscle, hepatic glycogenolysis, muscle tremor b3: lipolysis and thermogenesis, bladder detrusor muscle relaxation 18 Summary 1.Catecholamines synthesis. 2.Adrenergic receptors. 3.Adrenoceptor agonists. 4.Summary 1 9 Sympathomimetic drugs Drugs adrenergic receptor AGONISTS. They are divided into: CATECHOLAMINES α-AGONISTS β- AGONISTS MIXED-ACTION AGONISTS 3.ADRENERGIC AGONISTS DRUGS 1. Direct acting: drugs directly act on the adrenergic receptors 2. Indirect acting: drugs that act on the metabolism or on the reuptake of NA. 3. Mixed acting: drugs acts both directly and indirectly 21  Sympathomimetic drugs 1- CATECHOLAMINES: Adrenaline or Epinephrine Noradrenaline Dopamine Isoprenaline o Isoproterenol 2- a AGONISTS: a1 Phenylephrine,Nafazoline… a2 Clonidine 3- b AGONISTS: b1 Dobutamide b2 Salbutamol,Salmeterol, Terbutaline 4- MIXED-ACTION AGONISTS.Ephedrine and derivatives Amphetamines: amphetamine  ADME and Catecholamines All Catecholamines are ineffective orally Absorbed slowly from SC tissue Faster from IM site Inhalation is locally effective Not usually given IV Rapidly inactivated in liver by MAO and COMT  Sympathomimetic Drugs 1- CATECHOLAMINES Potent stimulant Non-selective action in Adrenaline (Epinephrine) α or β Pharmacokinetics: Low oral bioavailability It is administered via IV, SC, IM and inhalation. Does not cross the BBB Very short half-life (rapid inactivation) It is quickly eliminated in the urine. Pharmacological effects: At low doses: predominance of stimulation b At high doses: predominance of stimulation a  Sympathomimetic Drugs 1- CATECHOLAMINES Adrenaline (Epinephrine) Pharmacological effects: ► Cardiocirculatory system: (b1) ­ ­Heart rate. ­Contraction force. ­ sistolic voume Vasoconstriction ­ Blood pressure Low-dose vasodilation ► Smoot muscle(b2) ¯ Broncodilatación Effect on uterine contractions (pregnant relaxes but non-pregnant – contracts) Gastrointestinal relaxation(a y b). ► Metabolism:(b2) Hyperglycemic (glycogenolysis, insulin secretion). Lipolysis ► CNS Headaches, tremor, restlessness.....  Sympathomimetic Drugs 1- CATECHOLAMINES Adrenaline (Epinephrine) ADRs CNS: Panic, anxiety, tremors (acts on the emotions). Others: It can lead to cerebrovascular conditions due to vasoconstriction, and even cardiac arrhythmias due to the effects on the heart. Therapeutic applications: ► Treatment of cardiac arrest (intracardiac route). ► Heart block (cardiac conduction disorder). ► Shock, to compensate for the fall in AP. ► Superficial hemorrhages of skin and mucous membranes (vasoconstrictor, topical). ► Nasal decongestants, (topical). ► To prolong local anesthesia (slow down the absorption of the anesthetic).  Sympathomimetic Drugs 1- CATECHOLAMINES Noradrenaline (Norepinephrine) Pharmacokinetics: It is poorly absorbed orally and subcutaneously due to vasoconstriction can cause necrosis. It is administered IV or IM. It is quickly eliminated in urine. It does not cross the BBB. Pharmacological effects: Although NA is a receptor agonist a and b has greater selectivity for the a Generalized vasoconstriction Increased blood pressure (about 4 times more than adrenaline) Increased rate and force of contraction of the myocardium. Decreases intestinal motility.  Sympathomimetic Drugs 1- CATECHOLAMINES Noradrenaline (Norepinephrine) ADRs: Tachycardias and arrhythmias Exaggerated hypertension that can lead to vascular necrosis and bleeding Therapeutic applications: They are rare because they cause great vasoconstriction To control local bleeding. In states of severe hypotension (with loss of consciousness) due to spinal anesthesia. Anaphylactic shock. Topical nasal decongestant  Sympathomimetic Drugs 1- CATECHOLAMINES Dopamine Pharmacological effects: In small doses stimulates D1-receptors in renal, mesenteric and coronary vessels leading to vasodilatation. Moderate dose: stimulates β1-receptors in heart producing positive inotropic and chronotropic actions. High dose: stimulates vascular α1-receptors (NA release) – vasoconstriction and decreased renal blood flow  Sympathomimetic Drugs 2- α1 AGONISTS Nasal Decongestants Naphazolin, Pseudoephedrine,Pheninpropanolamine… They produce vasoconstriction and are used as nasal decongestants Naphazolin only topically. Rebound effect due to vasodilation. Pseudoephedrine is a poor bronchodilator, given in combination with antihistaminics, antitussives and NSAIDs in common cold and, allergic rhinitis Pheninpropanolamine, Xylometazoline, Oxymetazoline: decongestants in many cold and cough preparations.  Sympathomimetic Drugs 2- α1 AGONISTS Phenylephrine Selective, synthetic and direct α1 agonist Pharmacokinetics: Long duration of action – Resistant to MAO and COMT – no CNS effects Administered parenteraly & topically Pharmacological effects Peripheral vasoconstriction leads to rise in BP but Reflex bradycardia Produces mydriasis and nasal decongestion Therapeutic applications: – hypovolaemic shock as pressor agent – Sinusitis & Rhinitis as nasal decongestant (common in oral preparations) – Mydriatic in the form of eye drops and lowers intraocular pressure ADRs: Photosensitivity, conjunctival hyperemia and hypersensitivity  Sympathomimetic Drugs 3- α2 AGONISTS Clonidine Agonist to presynaptic α2 adrenoceptors in brain Centrally acting: – Decrease in BP and cardiac output Therapeutical application: treatment of opioids withdrawal and Alcohol withdrawal. Peripherally action: High dose: negative feedback suppression of NA release  Sympathomimetic Drugs 4- β2 AGONISTS Salbutamol, Terbutaline, Salmeterol b2 selective Its mechanism of action is to activate adrenergic receptors b2, located in the bronchial muscle, which causes relaxation of the muscle and therefore bronchodilation. – Onset of action within 1 to 5 minutes – Bronchodilatation lasts for 2 to 6 hours Therapeutic application: Ø Treatment of bronchial asthma. Ø Salbutamol: asthma attack (inhalation) –long acting  Sympathomimetic Drugs 4- β2 AGONISTS Ritodrine Uterine Relaxant: Dose 50 µg/min, increase by 50 µg/min every 10 minutes until contractions stop or maternal heart rate is 140 beats/minute. – Continue for 12-48 hours after contractions stop  Sympathomimetic Drugs 5- MIXED-ACTION ADRENERGICS Ephedrine and derivatives Mechanism of action: Dual mechanism of action: they can act directly on the receiptors or on the cycle of neurotransmitters (inhibiting reuptake, which produces an increase in the amount of circulating neurotransmitters). Pharmacokinetics: Well absorbed orally They are not metabolized by MAO and COMT (have long-lasting effect) Cross the the BBB. They are eliminated in urine. Ephedra distachya  Sympathomimetic Drugs 5- MIXED-ACTION ADRENERGICS Ephedrine and derivatives Pharmacological effects: The effects are similar to those of adrenaline but of longer duration. a Increased blood pressure. CNS (respiratory center) stimulant. Vasoconstriction of the mucous membranes b Increased frequency and force of contraction of the myocardium. Bronchodilation  Sympathomimetic Drugs 5- MIXED-ACTION ADRENERGICS Ephedrine and derivatives ADRs: Tachycardia,hypertension. Mydriasis. CNS stimulation. Therapeutic applications: ► In allergic rhinitis administered orally. ► As a topical nasal decongestant ► Oral, associated with "anti-flu".  Sympathomimetic Drugs 5- MIXED-ACTION ADRENERGICS Amphetamine Mechanism of action and Pharmacokinetics: similar to ephedrine and derivatives CNS stimulant action: psychoactive drug. Banned drug Pharmacological action: – alertness, euphoria, talkativeness and increased work capacity – – increased physical performance without fatigue – short lasting (Banned drug and included in the list of drugs of “Dope Test)” ADRs: Dependence, tolerance and anorexia. Therapeutic applications: Attention-Deficit/Hyperactivity Disorder (ADHD), Narcolepsy, Epilepsy and Parkinsonism Summary 1.Catecholamines synthesis. 2.Adrenergic receptors. 3.Adrenoceptor agonists. 4.Summary 4 4  SUMMARY. ADRENOCEPTOR AGONISTS. Clinical uses of adrenoceptor agonists. Cardiovascular system: – cardiac arrest: adrenaline – cardiogenic shock: dobutamine (β1 agonist). – Anaphylaxis (acute hypersensitivity): adrenaline. Respiratory system: – asthma : selective β2-receptor agonists (salbutamol, terbutaline,salmeterol, formoterol) – nasal decongestion: drops containing xylometazoline or ephedrine for short- term use.(alfa agonists) Miscellaneous indications: – adrenaline: with local anaesthetics to prolong their action – premature labour (salbutamol) – α2 agonists (e.g. clonidine): to lower blood pressure and intraocular pressure; as an adjunct during drug withdrawal in addicts ; to reduce meopausal flushing, especially when oestrogenis contraindicated as in patients with breast cancer; and to reduce frequency of migraine attacks. – A β3 agonist, mirabegron: (overactive bladder symptoms). 54 56 57 Questions?????