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