Direct Agonists PDF

Cholinergic System Muscarinic Agonists DIRECT AGONISTS FARM-7225 JOSÉ O. COLÓN SÁEZ PHD. Objectives • Learn the steps involved in cholinergic neurotransmission. • Recognize the organ effects of cholinomimetics and the receptors involved. • Understand for both Direct and Indirect cholinomimeti...

Cholinergic System Muscarinic Agonists DIRECT AGONISTS FARM-7225 JOSÉ O. COLÓN SÁEZ PHD. Objectives • Learn the steps involved in cholinergic neurotransmission. • Recognize the organ effects of cholinomimetics and the receptors involved. • Understand for both Direct and Indirect cholinomimetics the: ✓ Mechanism of action ✓ Pharmacodynamics ✓ Pharmacokinetics ✓ Therapeutic ✓ Adverse applications effects Cholinergic agonists Often called parasympathomimetic drugs or cholinomimetics because their action mimics the action of ACh in the ANS. ↑ las drogas q . activan los receptores modulando Ach . niveles & Cholinergic Neurotransmission Neurotransmission in cholinergic neurons  Choline Acetyltransferase involves six sequential steps: ✓ Acetyl CoA -> det Todo de cico Krebs comienza con laentrada de colina Rate Limiting Step - I la ✓ Choline entrada de -> sale Krebs (primer pasol H  Acetylcholine(ACh)  Cholinergic Receptors La Respuesta depende del tipo ✓ ✓ de receptor Muscarinic Nicotinic ->Siempre Des se libera r estimulatorio presinaptico  Acetylcholinesterase (AChE) - El serialamiento Rompe acetato . Ach encolina y Luego Ach reciclado y es utilizado ↑ hay de Ach por Parasimpatico cuando degradacion de AChE el sist - I del ciclo de Colina ↑ post sinaptico Regulation of Neurotransmitter release -Solo Myben el Parasimpatico feedback negative -envia • Autoreceptors: located on or close to the axon terminal of a neuron, the neuron's own transmitter can modify transmitter release. Disminuge seralamiento ✓ NE released from may Sister gene sympathetic neurons interact with*α2 receptors to inhibit neuronal release of NE. El SNSlibera et g postyangliapreganglic es per Celulas : AcHen a WE muchas efectoras . ACh released from parasympathetic neurons gir may interact with DM4 receptors to inhibit neuronal release of ACh. ✓ - Gi v Regulation of Neurotransmitter release • Heteroreceptors: are presynaptic receptors that respond to neurotransmitters, neuromodulators, or neuro-hormones released from adjacent cells. * ✓ ACh can influence the release of NE from sympathetic neurons by acting on M4 receptors. ✓ NE can influence the release of ACh from parasympathetic neurons by acting on α2 receptors. is - Sisteras Manera donde ambos prede afestar el serial amiento atraves del sist . se parasimp . comunican Acetylcholine ↳ en la . Imp 49 3 Jerking sinapsis cando Ach se tapido hay ↑AChE para degradar libera . Si hubiese ↑2] de Ach tendras 24 Temp El sist . completo se descuadra · ACh: naturally occurring neurotransmitter, with no systemic therapeutic applications (actions are diffuse, and its hydrolysis is rapid). *  Cholinergic synapses are foundespecifico at: * ✓ Peripheral Bien para Ach menos especifica esteres . y hidroliza ↳ . Nervous system En 19 ❖ Somatic motor nerves ❖ Autonomic Nervous System sangre . Funcion: asegurara . Ach No este en ✓ CNS Mucha contraction la : sangue Seforma . ->en el ↑ Temp ado nig  ACh administered systemically, can act on multiple sites; however, its penetration to the CNS is limited, and the amount that reaches target areas is limited due to hydrolysis by plasma butyrylcholinesterase. ↳ esta en la Sangre ; Make Sure AcH No este en la sangre - -Short long W Trong short v Muscarinic Agonists Muscarinic, based on the observation that the alkaloid muscarine acts selectively at those sites and produces the same qualitative effects as ACh. - por eso fiene electo Amanita Muscaria terapeutico .  Muscarinic agonists mimic the effects of ACh at most sites. They are longer-acting congeners of ACh or natural alkaloids, some of which stimulate nicotinic as well as muscarinic receptors. The basis for the therapeutic uses of the muscarinic receptor agonists and antagonists can be deduced from the physiological effects of ACh at the parasympathetic nervous system. Cardiovascular System (M2): excitatory ✓negative chronotropic effect. ✓negative inotropic effect. ✓Vasodilation (M3). ↳ localizado - Inhibitor Respiratory Tract (M3): ✓Bronchoconstriction. ✓Secretions. SLUD -> - SiqueremosM3 Block se Urinary Tract (M3): ✓Bladder contraction. ✓Urine formation. - GI Tract (M3): ✓Secretions. ✓GI motility. Bronco dilatacion . esfinter relagacioninterno-Lautonomical del control Esfinter externo somatico = . ↓ detiene ganas Baumenta contraction Relaja esfinter para poop de orinat Glands (M3): ✓Stimulates secretion (lacrimal, salivary, and sweat glands). receptores ↳ sist . Simpatico per Cholinergico(M3) Eye (M3): ✓Miosis ✓Increased secretion CNS effects: All five muscarinic receptor subtypes are found in the brain, and recent studies suggest that muscarinic receptor-regulated pathways may have an important role in cognitive function, motor control, appetite regulation, nociception, and other processes. ↳Sensacion del dolor Muscarinic Receptors Erupan RECEPTOR M1 M3 M5 Gq INTRACELLULAR TRANSDUCER Phospholipase C Diacyl-glycerol IP3 ELECTRICAL MECHANICAL PHYSIOLOGICAL RESPONSES • Depolarization • Smooth muscle M3 ➢ Contraction ➢ Dilation • Glandular secretion Cuando injectas Ach directamente simpatico . nicotinicos estan en advenal los al anadir atopinataide attac disminuye : dilatation VASO- 's conatropina vasodilatatio Block NO Mu pero X A Bajos Niveles Receptor IOS Nicotinico de Act nay vasoconstriction No hay Sistere - Los M3 asociado can vasos sangineus No estar el directamente ensino musculo liso ; endotelio en el . qu Se puede libera NO Muscarinic Receptors M3 mediated vasodilation por la Oxide liberacion de Nitric (NOL Mer selibera -> sekelajar Es un de la NO . efeAo indirecto de liberation ·efecto indirecto vasodilato * Muscarinic Receptors Inhibitorius n I M2 RECEPTOR Gi INTRACELLULAR TRANSDUCER M4 Go Adenylyl cyclase cAMP ELECTRICAL • Hyperpolarization MECHANICAL (heart) PHYSIOLOGICAL • Cardiac inhibition RESPONSES inhibe la liberacion de Canales y K . de calt Muscarinic Agonists Esters 3 Modificaciones dan duf efecto . Synthetic No tiene etecto Nicotinico por el CHy A featuring Resistente a degradation la de AckE Alkaloids efuctocardiac tiemefuctoentodus M4 ↓ los receptores Synthetic tiene afinidadM3 por MI y No tiene efecto cardiaco Methacholine or ⑦ - I Provocholine C3 & 0 H Nor I  Hydrolyzed by acetylcholinesterases at a relatively slow rate. Anadir Grupo un metilo SCH)  Lacks nicotinic actions. efects : en Pierde su receptores Nicotinico is 240-fold active more than R los  Insoluble to lipid cell membranes, poor absorption from the GI tract and does not cross the BBB. Mechanism of Action: Profound cardiovascular effect limit the therapeutic use. ✓ Causes both bradycardia and hypotension. Methacholine espirometria Therapeutic applications: diagnosis of bronchial hyperreactivity (asthma and COPD). Asiste diagnostico al de Asma ✓ Methacholine challenge test: a subject inhales aerosolized methacholine → bronchoconstriction (asthmatics react to sus efectos lower doses of drug). seusade manera oral por cardiovasculares Adverse effects: Other therapeutic uses are limited by its adverse cardiovascular effects. ✓ Bradycardia and hypotension, which arise from its function as a cholinomimetic. . Pariente con Asma y COPD * . En este test queremos causar S oroncoconstriction ④ mayor a Here severidad . I squeteHere gena attrtf en en [JP de metacholina; Note pasa nadar ↑ Siestoy sin : Agonista causa Bronco constriction -> Inkalada saludable ninguna Carbachol (Miostat) O It + NH2-LOXNY Structurally related to acetylcholine, in which the acetate is replaced by carbamate. ↳ less liable to hydrolysis  Not hydrolyzed by acetylcholinesterases. - - -> directamente activa M2  Has both muscarinic as well as nicotinic actions. agonistan Mechanism of Action: has profound effects on both the cardiovascular system and the gastrointestinal system because of its ganglion-stimulating activity. ✓ Can cause release of epinephrine from adrenal medulla. L cierde I ritro : fibrilacion e por eso no se da Sistemico Carbachol ↓ No Sistemico 49 mal el T pore Therapeutic applications: Because of its high potency, receptor non-selectivity, and relatively long duration of action, carbachol is rarely used therapeutically. Casino vieven estos med . ✓ Eye -> este uso con . drops are used to ↓ eye pressure (glaucoma) and constrict pupils for cataract surgery. Adverse effects: At doses used ophthalmologically, little or no side effects occur due to lack of systemic penetration. • Not administered systemically because of its relatively larger component of nicotinic action at autonomic ganglia. Bethanechol especificos (Urecholine) ↳ etectos agonista de receptors mAChRs Structurally related to acetylcholine, in which the acetate is replaced by carbamate and the choline is methylated.  Not hydrolyzed by acetylcholinesterases.  Lacks nicotinic actions. * Mucha especificidad en Muscarinico 103 Receptores Mechanism of Action: Directly stimulates muscarinic receptors in smooth musculature of the bladder and gastrointestinal tract. Gangla parasimpatica este Bethanechol Atropina en bajas Cantidades para quel paciente no se wine/poop Orinar- en operation Therapeutic applications: urologic treatment. ✓ Non-obstructive ❖ Neurogenic urinary retention. atony (poor muscular condition). ❖ Postpartum. via oral para evitar ❖ Postoperative. Ganglia del Sist parasimp. esta en . ✓ Paralytic - Crisis los organis efectores ileus Gando cholinergic tiene constipation prolongado ❖ Megacolon (dilation of the colon associated with prolonged constipation). Ien -> humanos) Seve cierta selectividad por la uninacim per activa porcualquier receptor Adverse effects: effects of generalized cholinergic stimulation (sweating, salivation, flushing, ↓HR/BP, nausea, abdominal pain, diarrhea, and bronchospasm). ADME Absorption: polarity dependent (poor for ACh, quaternary ammonium), intravenous, subcutaneous and intramuscular for local effects (ACh). Metabolism: Highly dependent on the susceptibility to acetylcholinesterase (AChE). Basic and Clinical Pharmacology, 13e> Cholinoceptor-Activation Contraindications for choline esters metacholine , carbechol y - Betamechol Contraindications: asthma, hyperthyroidism, coronary insufficiency, and acid-peptic disease. ✓ Bronchoconstrictor action could precipitate an asthmatic attack. - >actividad simpatico ✓ Hyperthyroid patients may develop atrial fibrillation. mas ↳ subreactivation del simpatico ... Ar air ✓ Hypotension induced by these agents can severely reduce coronary blood flow, especially if it is already compromised. ✓ The gastric acid secretion produced by the choline esters can aggravate the symptoms of acid-peptic disease. Causes Cholinergic Side effects (DUMBELLS), depending on administration route. Pilocarpine (Salogen or Isopto ⑪ 1 Carpine) a muscarina - I Om similar I i A naturally occurring alkaloid, obtained from the leaves of tropical South American shrubs from the genus Pilocarpus. ADME: lipid soluble, penetrates the CNS at therapeutic doses. Stable to hydrolysis by Acetylcholinesterases. -M3  It has Muscarinic actions only. # * a los nicotinics Agonista parcial *  Less potent than acetylcholine and its derivatives. Mechanism of Action: When applied locally to cornea produces rapid miosis and contraction of ciliary muscle. ✓ Vision is fixed making cannot focus for far situated objects. Pilocarpine  Most potent stimulators of secretions (secretagogue): sweat, tears, and saliva. ↳sweat griesO Therapeutic applications: used to promote glandular secretions. El tratamiento permite oral dryness : ✓ Salivation o in xerostomia from irradiation of the head and neck. ✓↑ Salivation and ↑ tears in patients with Sjgoren's syndrome. ✓ Sweat ⑪ - No determina severidad chloride test: cystic fibrosis diagnosis. ↳lung , intestine, gland . https://www.cff.org/intro-cf/sweat-test#:~:text=If%20you%20show%20symptoms%20of,reliable%20way%20to%20diagnose%20CF. Pilocarpine Drug of choice in emergency ↓ of intraocular pressure. ✓ Both narrow-angle (also called closedangle) and wide-angle (also called openangle) glaucoma. Adverse effects: can enter the brain and cause CNS disturbances. ✓ Stimulates salivation. profuse sweating and [ aumento en presion ocular Glaucoma Tris Block  Progressive eye disease classified as open angle glaucoma (most common) and close angle glaucoma. ✓ Both types of glaucoma cause an elevated eye pressures that may result in optic nerve damage and permanent blindness if not treated.  Raised intraocular pressure (above 21 mmHg or 2.8 kPa) is the most important and only modifiable risk factor for glaucoma. Effects of Glaucoma  Patients with glaucoma are asymptomatic until visual field destruction occurs. Visual field loss occurs in 8%-20% of patients despite appropriate management.  80% of patients without treatment will develop bilateral blindness. ciegi Cholinergic Crisis 33 Antidoto Atropine competitively antagonizes ACh at muscarinic receptors to reverse excessive secretions, miosis, bronchospasm, vomiting, diarrhea, diaphoresis, and urination.