Exam 1 Lecture 3 adrenergic agonists

Adrenergic drugs affect receptors stimulated by…

Epi and NE

What are sympathomimetics

Drugs that activate receptors

How do direct acting sympathomimetic drugs work?

They directly activate receptors

How do indirect acting sympathomimetic agents function?

Activate receptors via enhancing the release of or blocking release of norepinephrine

How do direct acting adrenergic agonists work?

Act directly on alpha or beta receptors

Effects similar to those produced by endogenous release of epi from the adrenal medulla

How do indirect acting adrenergic agonists work

Agonists that block norepi reuptake or cause norepi release from cytoplasmic pools or vesicles

How do mixed action adrenergic agonists work

Directly stimulate adrenoceptors and release norepi from adrenergic neurons

What is a sympatholytic drug?

Drugs that block the activation of receptors

Albuterol (class)

Direct acting adrenergic agent

Clonidine (class)

Direct acting adrenergic agonists

Alpha 2 agonist

Mechanism of action of clonidine

Inhibition of sympathetic vasomotor centers in CNS, decreasing sympathetic outflow to the periphery

Therapeutic uses of clonidine

HTN

symptom minimization during withdrawal of opioids, tobacco, and BZDs

ADHD

Adverse effects of clonidine

Lethargy, sedation, constipation, xerostomia

Abrupt discontinuation results in rebound HTN

*Epinephrine (class)

Direct acting adrenergic agonists

Effects of epinephrine

Direct acting agonist, catecholamine

Naturally occurring NT released by the adrenal medulla into systemic circulation

Interacts with alpha and beta receptors

-low doses: b effects predominate (vasoconstriction)

-high doses a effects dominate (vasoconstriction)

Acts on cardiovascular and respiratory systems, causing hyperglycemia and lipolysis

Cardiovascular effects of epi

Increased systolic blood pressure, slight decrease in DBP, vasodilation of skeletal muscle vascular bed

B1 - vasoconstriction in heart and kidneys (release renin)

B2 - vasodilation in liver and skeletal muscles

Alpha - constricts arterioles in viscera, skin, and mucous membranes

Effects of epi on respiratory systems

Bronchodilation via B2 and inhibits release of allergy mediators (ex: histamines)

Epi effects on hyperglycemia

B2 effect on liver causes increased glycogenolysis coupled with increased release of glucagon and decreased insulin release via A2

Epi effects on lipolysis

Agonist activity at B receptors in adipose tissue

Therapeutic uses of epi

Bronchospasm (acute asthma/anaphylaxis)

Cardiac arrest

Local anesthesia

-used with local anesthetic to produce vasoconstriction and increase duration of action of local anesthesia

Topically to control oozing of capillary blood

Pharmacokinetics of Epi

Rapid onset and brief duration of action due to degradation via MAO and COMT

-metabolites are excreted in urine

Can be given IM, IV, subq, inhalation or ET tube

Adverse effects of epi administration

CNS effects (HA, anxiety), cardiac arrhythmia, tachycardia, increased BP, pulmonary edema, hyperglycemia

Fenoldopam(class)

Corlopam

Direct acting adrenergic agonists at peripheral D1 dopaminergic receptors

Actions of fenoldopam

Rapid vasodilation of coronary arteries, kidney arterioles, mesenteric arteries

Therapeutic use of fenoldopam

Severe HTN in hospitalized patients

Pharmacokinetics of fenoldopam

Extensive first pass metabolism

Given via IV infusion

Elimination half life 10 minutes

Adverse effects of fenoldopam

HA, flushing, dizziness, N/V, tachycardia (due to vasodilation)

*Isoproterenol (class)

Direct acting adrenergic agonists

Synthetic catecholamine with beta 1 and 2 receptor (insignificant effect on alpha)

Mechanism of action of Isoproterenol

Intense stimulation of heart (B1)

-increased HR, contractility, cardiac output, systolic BP

Dilates skeletal muscle arterioles (B2)

-decreased peripheral resistance, reduced MAP and diastolic BP

Bronchodilator (B2)

Therapeutic uses of Isoproterenol

Rarely used therapeutically due to receptor nonselectivity

May be useful in treating AV block

Similar adverse effects to epi

Midodrine (class)

Direct acting adrenergic agonists

Selective for alpha 1

Mechanism of action of midodrine

Prodrug metabolized to active form

Desglymidodrine -pharmacologically active

Causes increased arterial and venous tone

Therapeutic use of midodrine

Orthostatic hypotension

-Dosed TID at 3-4 hr intervals

-Avoid dose within 4 hours of sleep to avoid supine hypertension

*Norepinephrine (trade/class)

Levophed

Direct acting adrenergic agonists

What receptor does NE primarily effect

Alpha

How does NE affect the cardiovascular system?

Vasoconstriction: increased peripheral resistance, SBP, DBP

Baroreceptor reflex: increased BP stimulates vagan activity and reflex bradycardia

Therapeutic uses of norepi

Shock

-increases vascular resistance and leads to increased BP

Pharmacokinetics of NE

Rapidly metabolized by CMOT and MAO

Administered IV for rapid onset of action (“never” in peripheral vein)

Duration of action is 1-2 minutes following end of infusion

Adverse effects of norepi

Blanching/sloughing of skin due to vasoconstriction, tissue necrosis due to extravasation

Oxymetazoline

Afrin, visine

Direct acting adrenergic agonists

synthetic adrenergic agonist at alpha 1 and 2

Actions of oxymetazoline

Vasoconstriction of blood vessels that supply nasal mucosa and conjunctiva

Therapeutic use of oxymetazoline

Found in OTC nasal spray decongestants and eye drops for redness relief due to swimming, colds, or contact lenses

Pharmacokinetics of oxymetazoline

Reaches systemic circulation despite local administration

Adverse effects of oxymetazoline

Nervousness, Zaharia, Difficulty sleeping, local irritation

Rhinitis medicamentosa- rebound congestion, dependence (limit to 3 days therapy)

Phenylephrine (trade/class)

Neo-synephrine, Sudafed PE

direct acting adrenergic agonists

Synthetic drug that binds alpha 1

Actions of Phenylephrine

Vasoconstriction, increased SBP and DBP

reflex bradycardia after IV admin

Therapeutic use of Phenylephrine

IV: hypotension in hospitalized and post surgical pts

-particularly in pts with high HR

topical or oral: decongestant

Ophthalmic: mydriasis

Adverse effects of Phenylephrine

Hypertensive headache and cardiac irregularities with high doses

Amphetamine (trade/class)

Adderall

Indirect acting adrenergic agonists

Cocaine

Indirect acting adrenergic agonists

Ephedrine (class)

Akovaz

Mixed action adrenergic agonists

Ephedrine effects and tx uses

Causes vasoconstriction, cardiac stimulation, Bronchodilation, and mild CNS stimulation

Used to treat hypotension, fatigue, increased alertness, improved athletic performance

Pseudoephedrine (trade/class)

Sudafed

Mixed action adrenergic agonist

Uses of pseudoephedrine

Used to treat nasal and sinus congestion

Used to make meth

What is the primary NT released from adrenergic neurons?

Norepinephrine

Where are adrenergic neurons located?

central nervous and sympathetic nervous system.

Neurons serve as links between ganglia and effector organs.

How do adrenergic drugs act on adrenergic receptors?

Presynaptically on the neuron or post synaptic ally on effector organ.

What are the steps of neurotransmission at adrenergic neurons?

1. Synthesis

2. Storage

3. Release

4. Binding of NE

5. REMOVAL OF THE NT from the synaptic gap

Describe the synthesis step of neurotransmission at adrenergic neurons

• Tyrosine is transported into the adrenergic neuron via a carrier

• Tyrosine is hydroxlyated to DOPA by tyrosine hydroxylase (rate limiting step)

• DOPA is decarboxylated by the enzyme aromatic 1- amino acid decarboxylase to form dopamine in the presynaptic neuron

• Describe the storage step of neurotransmission at adrenergic neurons

Storage of ne in vesicles

an amine transporter allows dopamine to be transported into synaptic vesicles

-carrier system is blocked by reserpine (anti hypertensive and antiphyschotic)

Dopamine is hydroxylated to form norepinephrine by the enzyme dopamine b-hydroxylase

Describe the release step of neurotransmission at adrenergic neurons

AP arrives at nerve junction and triggers movement of calcium ions from ecf to cytoplasm of a neuron.

Increased calcium in the cytoplasm causes fusion of synaptic vesicles to the cell membrane.

Exocytosis occurs and contents stored in synaptic vesicles are released into the synapse

-Guanethidine can block this release (anti hypertensive)

Describe the binding step of neurotransmission at adrenergic neurons

NE released from vesicles to bind postsynaptic receptors on effector organs or to presynaptic receptors on nerve endings.

Cascade of events (second messenger formation -cAMP)

Norepinephrine binding to presynaptic receptors modulates release of NTs

Describe the removal step of neurotransmission at adrenergic neurons

Diffusion from synapse to systemic circulation

Metabolized to inactive metabolites by COMT in synaptic space

Reuptake back into neuron

-primary method

-blocked by TCAs and SNRIS(antidepressants - imipramine and duloxetine)

What are the two main families of adrenoceptors in the sympathetic nervous system

Alpha and beta receptors

How are adrenergic receptors classified?

Classified based on their responses to adrenergic agonists (epi, norepinephrine, isoproterenol)

Rank order of potency and affinity of alpha receptors

Epi =norepi »isoproterenol

Alpha 1 receptors

EFFECTS: vasoconstriction, increased TPR, increased BP

Alpha1A, alpha1B, alpha1C, alpha1D

present on postsynaptic membranes of effector organs.

-responsible for mediation of “classic effects” (smooth muscle CONSTRICTION)

GPCR to create second messengers IP3 and DAG

-IP3 triggers release of calcium from ER

-DAG turns on cell proteins

Example of A1a: tamulosin - an A1a antagonist binds to receptors located primarily in urinary tract and prostate (treats enlarged prostate)

Alpha 2 receptors

A2a, A2b, A2c

Located primarily on presynaptic sympathetic nerve endings where they control NE release

-feedback inhibition and decreased NE release —> inhibitory autoreceptor

-local mechanism for modulating norepinephrine output in situations of high sympathetic activity.

Also exists at presynaptic parasympathetic neurons

-inhibits ACh release (inhibitory heteroreceptor)

Rank order of potency and affinity for beta receptors

Isoproterenol > epi > norepinephrine

Which beta receptor has equal affinities for epi and norepinephrine

B1

Which beta receptor has a higher affinity for epi than norepi

B2

What are the effects of b1

Cardiac stimulation

-increased HR and contractility

-increased lipolysis

-increased release of renin

Effects of B2 receptors

Vasodilation

Decreased peripheral resistance

Bronchodilation

Increased muscle and liver glycogenolysis

Increased release of glucagon

Relaxed uterine smooth muscle

What are the catecholamines

Epi, NE, Isoproterenol, dopamine

What are the properties of catecholamines

High potency

Rapid inactivation via COMT and MAO

-inactive/ineffective if given orally

-brief duration of action if given parenterally

Poor CNS penetration

-some action possible (anxiety, tremor, headache)

What are the non catecholamines

Phenylephrine, ephedrine, amphetamine

What are the properties of non catecholamines

Longer half lives and duration of action

-not activated by COMT

-poor MAO substrates

Greater CNS penetration

-increased lipid solubility

Dopamine class

Direct acting adrenergic agonist

Naturally occurring NT in CNS basal ganglia and adrenal medulla

-immediate metabolic precursor to norepi

Dopamine mechanism of action

Activated alpha and beta adrenergic receptors and dopaminergic receptors

-high doses: stimulates alpha 1 —> vasoconstriction and increased peripheral resistance

-low doses: stimulates B1 cardiac receptors —> positive inotropic and chronotropic effects increase cardiac output

-dopamine 1 and 2 receptors—> vasodilation of renal and splanvhniv arterioles enhances perfusion

Therapeutic uses of dopamine

Cardiogenic shock, septic shock, hypotension, heart failure

-continuous IV infusion

-rapidly metabolized, short duration of action

Adverse effects of dopamine

Nausea, hypertension, arrhythmia

Dobutamine (class)

Synthetic catecholamine and B1 receptor agonist

Direct acting adrenergic agonists

Minor B2 and A1 effects

Actions of dobutamine

Increased cardiac rate and output

-few effects on oxygen demand and vasculature

Therapeutic effects of dobutamine

Heart failure and post cardiac surgery

-increases cardiac output in patients with HF

-provides inotropic support after surgery

Side effects/caution with dobutamine

Adverse effects similar to epi

Use cautiously in pts with afib (increased AV conduction)

Tolerance may develop with prolonged use

What are the SABAS

Albuterol and terbutaline

What are the LABAS

Formoterol, arformoterol, salmeterol, indacaterol

What is the class and action of SABA (Albuterol/terbutaline)

Short, direct acting B2 adrenergic agonists

Duration of action <3 hours

Bronchodilation

Therapeutic use of sabas

Treatment of acute asthma exacerbations

Albuterol -rescue therapy

Terbutaline - IV used off label as uterine relaxant, suppresses pre term labor

Pharmacokinetics of sabas

Administered primarily via MDIs

Adverse effects of SABAs

Inhalation: tremor, restlessness, apprehension, anxiety

-tolerance may develop to tremor with time

Oral admin: tachycardia and arrhythmia

-MAOIs increase risk of these effects and concomitant use should be avoided

Class/action of LABAS

Long acting (direct) B2 agonists

Duration of action >12 hours

Bronchodilation

Pharmacokinetics of LABAS

Administered primarily via metered dose inhalers

Therapeutic use of LABAS

Agents of choice in treatment of nocturnal asthma

-maintenance therapy for asthma/COPD

-used in combo with inhaled corticosteroids

-**monotherapy associated with increased asthma related deaths

Mirabegron (class/action)

B3 direct acting adrenergic agonist

relaxation of detrusor smooth muscle and increased bladder capacity

Therapeutic use of Mirabegron

Overactive bladder

Pharmacokinetics of Mirabegron

Increases digoxin levels

CYP2D6 inhibition

Adverse effects of Mirabegron

May increase BP

-avoid use in pts with uncontrolled hypertension

What are indirect acting adrenergic agonists

Drugs that cause release of, inhibit reuptake of, or inhibit degradation of epi or norepi.

Potentials effects of epi and norepi produced by the body but do not directly effect post synaptic receptors.

What are the indirect acting adrenergic agonists

Amphetamine, tyramine, and cocaine