Adrenergic receptor and mechanism of actionAdrenergic 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. BP2. Alpha-2 = inhibits release of norepinephrine dec. in vasoconstriction, dec. BP3. Beta-1 = inc. in heart rate & force on contraction4. Beta-2 = relaxation of smooth muscle in bronchi,
uterus, peripheral blood vesselsDopaminergic = 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)
SYMPATHETIC RESPONSES
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),[2] 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 α1, α2 or
β-adrenergic receptors.
α1 couples to Gq, which results in
increased intracellular Ca2+ and subsequent smooth muscle
contraction. α2, 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
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 βARK.
4.βARK, 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, βARK is a negative feedback enzyme that will prevent overstimulation of the β-adrenergic receptor.
Beta adrenergic receptor kinase (βARK) is a serine/threonine intracellular kinase. It is activated by PKA and its target is the beta 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/ADRENERGICS
• 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/SYMPATHOLYTICS)• 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
• Cholinergics stimulate the parasympathetic 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
PARASYMPATHETIC RESPONSES
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 AGENTSANTICHOLINERGICS/PARASYMPATHOLYTICS
• 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
• Atropine Sulfate - Inhibits ACH blocks vagal effects on SA & AV nodes inc. conduction & inc. HR
Use = Bradycardia, pre-up to dec. secretions,
peptic ulcer disease
SE = Many. Most frequent = dry mouth, blurred vision, urine retention, constipation
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