Published on February 20, 2014
Adrenergic receptor and mechanism of action
AUTONOMIC NERVOUS SYSTEM • Central Nervous System (CNS) - Brain and spinal cord • Peripheral Nervous System (PNS) - Located outside the brain & spinal cord * Autonomic Nervous System (ANS) & the somatic • The PNS receives stimuli from the CNS & initiates responses to the stimuli after it’s interpreted by the brain
AUTONOMIC NERVOUS SYSTEM • ANS acts on smooth muscles & glands • - Controls & regulation of the heart, respiratory. system, GI tract, bladder, eyes & glands - Involuntary - person has little or no control Somatic - voluntary - person has control (skeletal muscle)
ANS • ANS has 2 sets of neurons: 1. Afferent (sensory) - sends impulses to the CNS for interpretation 2. Efferent - receives impulses (info.) from the brain & transmits from the spinal cord to the effector organ cells - 2 branches - sympathetic & parasympathetic nervous system
FIGURE 20-2. SYMPATHETIC AND PARASYMPATHETIC EFFECTS ON BODY TISSUES
ANS - SYMPATHETIC NERVOUS SYSTEM (ADRENERGIC) • Sympathetic Nervous System (adrenergic) Norepinephrine = neurotransmitter - Drugs that mimic = adrenergic drugs, sympathomimetics, or adrenomemetics * Adrenergic agonists - Drugs initiate a response - Drugs that block = adrenergic blockers, sympatholytics or adrenolytics * Adrenergic antagonists - prevent a response
ANS • 4 types of adrenergic receptor organ cells: 1. Alpha-1 = vasoconstriction of blood vessels inc. blood return to heart, inc. circulation, inc. BP 2. Alpha-2 = inhibits release of norepinephrine dec. in vasoconstriction, dec. BP 3. Beta-1 = inc. in heart rate & force on contraction 4. Beta-2 = relaxation of smooth muscle in bronchi, uterus, peripheral blood vessels Dopaminergic = dilate vessels, inc. in blood flow - only dopamine activates this receptor
ANS - PARASYMPATHETIC NERVOUS SYSTEM (CHOLINERGIC) • Parasympathetic or Cholinergic Nervous System Acetylcholine = neurotransmitter - Drugs that mimic = cholinergic drugs, parasympathomimetics Cholinergic agonists - initiates a response - Drugs that block = anticholinergic, parasympatholytics Cholinergic antagonists - prevents a response
ANS • Sympathomimetic pathway Norepinephrine From adrenergic fiber Inc. heart rate Pupil dilation Adrenergic (sympathomimetic) agents Fight or Flight • Parasymathomimetic pathway Acetylcholine From cholinergic fibers Dec. heart rate pupil constriction Cholinergic (parasympathomimetic agents)
ADRENERGICS AND ADRENERGIC BLOCKERS • Drugs that Stimulate the sympathetic Nervous System (adrenergics, adrenergic agonists, sypathomimetics, or adrenomimetics) • Mimic the sympathetic neruotransmitters norepinephrine and epinephrine • Act on one or more adrenergic receptor sites located on the cells of smooth muscles - heart, bronchioles, GI tract, bladder, eye • 4 main receptors (alpha-1, alpha-2, beta-1, beta-2)
MECHANISM OF ADRENERGIC RECEPTORS There are two main groups of adrenergic receptors, α and β, with several subtypes. •α receptors have the subtypes α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor). Phenylephrine is a selective agonist of the α receptor. •β receptors have the subtypes β1, β2 and β3. All three are linked to Gs proteins (although β2 also couples to Gi), which in turn are linked to adenylate cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP. Downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), which mediates some of the intracellular events following hormone binding. Isoprenaline is a non-selective agonist.
Adrenaline or noradrenaline are receptor ligands to either α 1, α 2 or β adrenergic receptors. α 1 couples to Gq, which results in increased intracellular Ca2+ and subsequent smooth muscle contraction. α 2, on the other hand, couples to Gi, which causes a decrease of cAMP activity and a resulting smooth muscle relaxation. β receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis .
MOLECULAR MECHANICS OF ADRENRGIC RECPTOR Beta adrenergic receptor kinase (βARK) is a serine/threonine intracellular kinase. It is activated by PKA and its target is the beta adrenergic receptor. βARK Activation : 1.Upon stimulation of the Beta adrenergic receptor by epinephrine, Gs will be activated. 2.Gs alpha will then stimulate adenyl cyclase to make cAMP. 3.cAMP will then activate cAMP-dependent kinase (PKA), which, among other proteins that it acts on, will phosphorylate serine and threonine residues on β AR K. 4.β ARK, itself a serine/ threonine kinase, will then phosphorylate serine and threonine resides on the β -adrenergic receptor itself. 5.This will facilitate Beta-arrestin's binding to the receptor. Additional stimulation by epinephrine will now be unable to activate Gs due to arrestin. Therefore, β AR is a negative feedback enzyme that will prevent overstimulation of the β K adrenergic receptor.
SYMPATHOMIMETICS/ ADRENOMIMETICS • Stimulate adrenergic receptors: 3 categories 1. Direct-acting = directly stimulates receptors (epinephrine or norepinephrine) 2. Indirect-acting = stimulates release of norep. from terminal nerve endings (amphetamine) 3. Mixed-acting (indirect & direct) = stimulates receptor sites & release of norep. from nerve endings (Ephedrine)
SYMPATHOMIMETIC AGENTS/ ADRENERGICS • Action - Many of the adrenergic drugs stimulate more than one of the adrenergic receptor sites (alpha & Beta) • Response = Inc. BP, pupil dilation, inc. HR, & bronchodilation • Use = Cardiac stimulation, bronchodilator, decongestant • Side effects = Hyperness in body
SYMPATHOMIMETICS/ADRENER GICS • Albuterol - Beta-2 agonist (bronchodilation) Use - bronchospasm, asthma, bronchitis SE - nervousness, restlessness CI - severe cardiac disease, HTN • Epinephrine - stimulates alpha & beta Use - allergic reaction, cardiac arrest SE - nervousness, agitation CI - cardiac dysrhythmias
ADRENERGIC AGENTS • Dopamine - alpha-1 & beta-1 stimulation Use - Hypotension, shock, inc. cardiac output, improve perfusion to vital organs SE - N & V, headache CI - V. Tach
ADRENERGIC BLOCKERS (ANTAGONISTS/SYMPATHOLYTI CS) • Block alpha & beta receptor sites (nonselective) • direct or indirect acting on the release of norepinephrine and epinephrine • Use - Cardiac arrthymias (HR), HTN ( cardiac output), angina (O2 demand) • SE - CHF, bronchospasm, bradycardia, wheezing
NONSELECTIVE VS SELECTIVE BETA BLOCKERS • Nonselective have an equal inhibitory effect on B1 & B2 receptors - - Drugs have lots of interactions due to lots of alpha/beta receptor sites throughout body - use with caution on clients with cardiac failure or asthma • Selective B1 helpful in asthma clients
ADRENERGIC BLOCKING AGENTS • • • Inderal (Propranolol) - Nonselective Use - angina, dysrhythmias, HTN, migraines SE - Many d/t nonselective CI - asthma, heart block > 1st degree Minipress (Prazosin) - A blocker Use - mild to mod. HTN SE - orthostatic hypotension Tenormin (Atenolol), Lopressor (Metoprolol) B1 (cardio) selective Use - mild to mod HTN, angina
CHOLINERGICS AND ANTICHOLINERGICS parasympathetic • Cholinergics stimulate the nervous system • Mimic the neurotransmitter acetylcholine • 2 types of cholinergic receptors 1. muscarinic - stimulates smooth muscle & slows HR 2. nicotinic - affect skeletal muscle • Many = nonselective & affect both receptors • Some affect only the muscarinic receptors and not the nicotinic receptors
CHOLINERGIC AGENTS • Direct acting - act on the receptors to activate a tissue response • Indirect acting - inhibit the action of the enzyme cholinesterase (acetylcholinesterase - ACH) • Major uses = Stimulate bladder & GI tone, constrict pupils (miosis), neuro- muscular transmission
DIRECT-ACTING PARASYMPATHOMIMETIC (CHOLINERGIC DRUGS)
CHOLINERGIC AGENT (PARASYMPATHOMIMETICS) • Bethanechol (Urecholine) selective to muscarinic receptors, mimic action of acetylcholine Use - For urinary retention * Take on an empty stomach d/t inc. peristalsis * Alert- Never give IM or IV – circulatory collapse, hypotension, shock & cardiac arrest poss. • Pilocarpine (Pilocar) - Ophthalmic - direct acting
CHOLINERGIC BLOCKING AGENTS ANTICHOLINERGICS/PARASYMP ATHOLYTICS • Drugs that inhibit action of acetylcholine (ACH) receptors • Affects the heart, resp. tract, GI tract, bladder, eye, & exocrine glands. • Allows the sympathetic nervous system to dominate • Anticholinergic & cholinergic drugs have opposite effects • Major responses = dec. in GI motility, dec. in salivation, dilation of pupil (mydriasis), inc. pulse rate
ANTICHOLINERGICS • Uses: Pre-op meds,bradycardia, GI/urinary antispasmodic • SE: Dry mouth/mucus membranes blocks vagal • Atropine Sulfate - Inhibits ACH effects on SA & AV nodes inc. HR inc. conduction & Use = Bradycardia, pre-up to dec. secretions, peptic ulcer disease SE = Many. Most frequent = dry mouth,
ANTICHOLINERGICS • Bentyl (Dicyclomine) - Inhibits ACH on muscarinic receptors & dec. GI motility Use - Irritable bowel syndrome SE - constipation, urinary retention, dry mouth • Robinul (Glycopyrrolate) - Similar to above Use - pre-op to dec. secretions, GI disorders SE - Similar to above
ANTICHOLINERGICS • Anticholinergics effect the CNS & benefit people prone to motion sickness • Scopolamine Patch - Classified as an antihistamine for motion sickness - Topical skin patch behind the ear x3 days Use = cruising on water, flying, car sickness Other drugs = Dramamine, Bonine SE = Dry mouth, visual disturbances d/t pupil dilation
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