Chapter 6- Adrenergic Agonists

Albuterol ( Ventolin)

Short acting B2 specific adrenergic agonist Inhaled for direct bronchodilator activity on bronchial smooth muscle Most commonly prescribed inhaled beta-2 specific agonist in the treatment of Asthma

Adrenergic agonists (sympathomimetics)

drugs that have an affinity for and have intrinsic activity at receptors that are stimulated by norepinephrine Most of these drugs ( direct acting adrenergic agonists) are administered IV in acute care & some are given by inhalation to dilate the bronchi in asthma autonomic sympathetic nervous system

Dopamine is a precursor to

norepinephrine

Epinephrine: ( alpha & beta )

pulse rate increases via action on Beta-1; Systolic BP increases via epi's effect on renal beta-1 receptors to release renin which produces angiotensin II potent vasoconstrictor + alpha-1 receptor activation PVR & Diastolic BP decrease via beta-2 receptor activation on skeletal muscles arteries

Isoproterenol: ( pure Beta)

pulse rate increases via action on cardiac Beta-1 receptor; PVR & Diastolic BP decrease via skeletal muscle beta-2 receptor activation on the smooth muscle of arteries in skeletal muscle Systolic BP may increase ( moderate) because of its cardiac stimulatory action on Beta-1 and renin release from stimulation of renal Beta-1 receptors.

Beta 1 receptors

1-In the Heart, Beta-1 Stimulation gives: + chronotropic ( heart rate) + Inotropic ( force of contraction) 2. In the Kidney: Beta-1 receptors on granular cells. when stimulated, beta-1 receptors in the kidney secrete Renin from granular cells. Renin converts Angiotensin to Angiotensin I, and Ang I Ang II, via Angiotensin Converting Enzyme ( ACE) Angiotensin II = Vasoconstriction, increase aldosterone from adrenal cortex, increased Na+/water reabsorption =BP increase

Beta 2 receptors

1-Relaxes Bronchial Smooth Muscle ( bronchial dilation) 2-Dilates Arteries to skeletal muscle Relaxes Uterine Smooth Muscle ( inhibits labor) Pupil Dilation Bladder Detrusor Muscle Relaxation (detrusor muscle remains relaxed to allow the bladder to store urine, and contracts during urination to release urine) Increased glucose metabolism /lipolysis Dilates smaller coronary arteries Dilates hepatic artery

Adernergic Receptors

ALPHA RECEPTORS: α1 and α2 receptors BETA RECEPTORS: β1 , β2, and ( new ) β3 receptors.

Effects of Adrenergic Stimulation- bladder

Bladder Smooth Detrusor Muscle relaxation ( allows bladder to store urine)

Effects of Adrenergic Stimulation- Bronchial smooth muscle

Bronchdilation

Epinephrine Injection for Allergic Reactions

Epinephrine is also a Mast Cell Stabilizer Through its action on alpha adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation that helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis. Epinephrine blocks the release of inflammatory mediators by mast cells and basophils in response to an antigenic challenge.( mast cells release histamine, heparin, prostaglandins, leukotrienes) Epinephrine also alleviates pruritus ( itching) , urticaria ( hives) , and angioedema and may be effective in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder

Effects of Adrenergic Stimulation- glucose

Glucagon Secreted ( Glucose from glycogen)

Guanfacine ( Tenex)

Guanfacine lowers both systolic and diastolic blood pressure by activating the central alpha-2 norepinephrine autoreceptors, which results in reduced peripheral sympathetic outflow and thus a reduction in peripheral sympathetic tone and a decrease in BP.

Effects of Adrenergic Stimulation- cardiac Muscle

Increased HR and force of contraction

Mirabegron( Mybetriq)

a Beta-3 adrenergic agonist Beta3-Receptors are found in the gallbladder, urinary bladder, and in adipose tissue In the urinary bladder, the Beta-3 receptor is thought to cause relaxation of the bladder and prevention of urination Indication: Myrbetriq™ is a direct beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity.

α2 agonists

inhibit adenylyl cyclase activity. (reduce brainstem vasomotor center-mediated CNS activation via a negative feedback mechanism)

Norepinephrine: (noradrenaline) (Levophed)

Another natural catecholamine Direct acting ( not dependent on endogenous NE stores) ALPHA-1 AGONIST: Very high affinity for Alpha-1 receptors ( potent vasoconstrictor on smooth muscle cells of blood vessels) Blood vessels with α1-adrenergic receptors are present in the skin, the sphincters of gastrointestinal system, kidney (renal artery)and brain. Very low affinity for beta receptors Restores BP in emergent Acute low BP episode

ALPHA-2 Adrenergic Receptors

Are located on the presynaptic nerve ending membrane, inhibit sympathetic response, and activation of this receptor is inhibitory on the sympathetic response. Stimulation of alpha-2 receptors causes an inhibition of further release of NE from the stimulated adrenergic neuron. Serves as a negative feedback mechanism when there is high sympathetic activity ( down regulates)

Effects of Adrenergic Stimulation- GI

Decreased moyility

Effects of Adrenergic Stimulation-eyes

Dilation

Dopamine ( Intropin)

Direct Acting Natural Catecholamine Occurs naturally from the CNS basal ganglia, and in the adrenal medulla ( along with epi and NE) Endogenous catecholamine, acting on both dopaminergic and adrenergic neurons.....Alpha & Beta Agonist, and ALSO a Dopamine receptor Agonist dopaminergic receptors, which are distinct from alpha and beta receptors and occur in the renal vascular bed, are stimulated.... where binding of dopamine to them produces renal vasodilation & INCREASED RENAL BLOOD FLOW IV Infusion: Low dose stimulates mainly dopaminergic receptors, producing renal and mesenteric vasodilation; higher dose stimulates both beta1-adrenergic and dopaminergic receptors, producing cardiac stimulation and renal vasodilation; large dose stimulates alpha-adrenergic receptors

Levalbuterol ( Xopenex)

Is another short acting direct Beta-2 specific adrenergic agonist in the treatment of asthma that is an enantiomer of Albuterol The use of levalbuterol over the more traditional albuterol is controversial among health care professionals.

Alpha -1 Adrenergic receptors

Located on the post-synaptic membrane of the effector organ , mediates sympathetic response, and activation is excitatory to the sympathetic nervous system. Activation of leads to an increase of intracellular Ca+ ions, α1-receptors primarily mediate smooth muscle contraction. In smooth muscle cells of blood vessels the principal effect of activation of these receptors is vasoconstriction. Blood vessels with α1-adrenergic receptors are present in the skin, the sphincters of gastrointestinal system, kidney (renal artery)and brain. During the fight-or-flight response vasoconstriction results in decreased blood flow to these organs. This accounts for the pale appearance of the skin of an individual when frightened.

Salmeterol ( Serevent)

Long acting Direct B2 specific adrenergic agonist Inhaled for direct bronchodilation on bronchial smooth muscle in the treatment of asthma

Epinephrine (adrenaline)

Natural catecholamine secreted by Adrenal Medulla Shows highest affinity for alpha receptors compared to NE and Isoproterenol. Direct acting. ( not dependent on endogenous stores of norepinephrine) ALPHA & BETA AGONIST: For IV infusion, DOSE RELATED AFFINITY for both Alpha and Beta Receptors Epinephrine is primarily a beta receptor agonist at low doses ( beta-1 heart chronotropy and inotropy, beta 2 lung and dilation of skeletal muscle arteries) and an alpha receptor agonist at high doses (vascular smooth muscle constriction) Beta effects are seen throughout Alpha ( vasoconstriction) effects increase as dose increases..!!

Effects of Adrenergic Stimulation- skeletal muscle arteries

Relaxation of skeletal vascular smooth muscle ( Vasodilation)

termination of norepinephrine

Reuptake of NE back into presynaptic neuron is the PRIMARY mechanism for termination ONCE NOREPINEPHRINE IS TAKEN UP BY THE PRE-SYNAPTIC NEURON, IT HAS 3 FATES: 1-Can then be taken back up into a cytoplasmic storage vesicle 2-Can simply persist in cytoplasm 3-Can be oxidized by MAO ( Monoamine Oxidase)

COMT - ( Catechol-MethylTransferase)

Secondary mechanism for the removal of NE. This is the NE that has not been taken back up into the presynaptic neuron. ( the NE that persists in synaptic cleft) Is one of several enzymes that degrades the catecholamines—dopamine, epi, NE COMT is associated with the post-synaptic membrane in the synaptic space

Norepinephrine

Synthesized by a series of enzymatic steps both in the adrenal medulla and postganglionic neurons of the sympathetic nervous system from the amino acid tyrosine: 1-Tyrosine enters the cytoplasm of the neuron and is synthesized into L-DOPA , and then Dopamine. 2-Synthesized Dopamine enters into a protective neurotransmitter storage vesicle and is converted into Norepinephrine 3-A neuron action potential / accompanied by an influx of calcium, causes the storage vesicle to "dock" at neuron cell membrane and release norepinephrine into synaptic space 4-Norepinephrine crosses the synaptic space and then binds to a postsynaptic adrenergic receptor ( alpha or beta) 5-Norepinephrine's effect is terminated primarily by reuptake back into presynaptic neuron, and also by COMT.

Isoproternol (Isuprel)

Synthetic catecholamine Direct acting( not dependent on endogenous NE stores) BETA AGONIST: PURE BETA RECEPTOR AGONIST with NO alpha effects Unselective for B1 or B2 Increases HR & FOC ( B1) Bronchodilation ( B2) Skeletal muscle arterial smooth muscle relaxation ( B2) used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma.

Norepinephrine: ( alpha)

Systolic BP , Diastolic BP, PVR all increase via NE's intense vasoconstriction effect on alpha-1 vascular receptors. Pulse rate decreases via reflex bradycardia.

Clonidine (Catapres)

a central acting Alpha-2 adrenergic agonist which inhibits the sympathetic response, decreases peripheral vascular resistance, and lowers blood pressure It has specificity towards the presynaptic α2-receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels, thus inhibiting the release of norepinephrine (NE). The net effect is a decrease in sympathetic tone or influence and a decrease in BP

Tizanidine ( Zanaflex)

a drug that is used as a muscle relaxant. It is a centrally acting α2 adrenergic agonist. a potent, central-acting myotonolytic agent that principally affects the spinal polysynaptic reflexes vs. the vasomotor center