Westminster Sympathomimetics

acetylcholine

norepinephrine

acetylcholine

cholinergic

adrenergic

acetylcholine

all ganglionsall parasympathetic targets

parasym

sym---nicotinic

Alpha-1 contraction of radial muscle (Mydriasis, pupil dilation)
Beta Cilliary muscle relaxation (far vision)

Alpha – 1 increase secretion
Beta-2

Beta-1 increase heart rate, conduction velocity, contractility

Alpha-1 bronchoconstriction
Beta-2 bronchodilation

Alpha-1 decrease insulin secretion
Beta-2 increase insulin secretion

Alpha-1 Sphincter contraction
Beta-2 decreased tone and motility

Liver
Alpha-1/Beta-2 Glycogenolysis and gluconeogenesis
Beta-3 unknown

Gallbladder
Beta -3 unknown

Abdominal Blood Vessels
Alpha-1 constriction
Beta-2 Dilation

Bladder
Alpha-1 Sphincter Contraction
Beta-2 Detrusor Relaxation

Alpha-2 pre and post synaptic nerve endings

which adrenergic receptor subtype is agonized.

increased contractility

increased HR, inotropy

relaxation/dilation

aggregation

vasoconstriction

renin release

inhibition of tubular Na reabsorption (lose sodium)

inhibition lypolysis

lypolysis

xxxxxx

xxxxxx

xxxxx

Epinephrine/Norepinephrine/Dopamine

Isoproterenol (isoprenaline)/Dobutamine

Ephedrine/mephentermine/amphetamines/ metaraminol (clonidine(alpha-2))
Direct acting
Phenylephrine(alpha)/methoxamine

epi, nor-epi, dopamine

Beta-phenylethylamine in structure.
Catecholamine – phenyl with two hydroxyl groups then a a chain and then an amine

isoproterenol

dobutamine

ephedrine
phenylephrine
methoxamine
amphetamine
metaraminol
mephentermine

CH3

xxxx

xxxxxxx

xxxxx

xxxxx

benzene ring w/ 2 carbons, and then an amine (alpha-1st carbon, beta-2nd carbon)

OH

albuterol/Salbutamol-short actine
metaproterenol (alupent)
terbutaline-short acting
isoetharine
formeterol-long acting
bitolterol (tornalate)-long acting
salmeterol-long acting

Often known as a “reliever” as opposed to a “symptom controller”Usually given by inhaler. Also for hyperkalemia (especially patiens with renal failure) Also used as tocolytic to relax uterine smooth muscle to delay premature labor (better than atosiban and ritodrine but replaced by calcium-channel blocker nifedipine). Can be used as agent that helps with burning fat. Does have adverse effects. Tremor, palpitations, headache, tachycardia, muscle cramps, agitation, hypokalemia, hyperactivity, imsomnia

Levalbuterol is the R enantiomer (Xopenex) – claimed to have fewer side effects.

fast acting and short term. Onset in 15 minutes and 6 hour duration (IV ofor preterm labo….and ritrodine)

moderately selective beta-2 agonist stimulates smooth muscle in lungs, uterus and vasculature supplying skeletal muscle.

rapid onset 2-5 minutes and duration 6-8 hours

long and for severe persistent asthma with 12 hour duration

long acting about 4-6 hours. Which is more of a “symptom controller” bronchodilation due to relaxation of smooth muscle Faster onset then salmeterol because less lipohphylic so moves to receptor site faster (not secluded within lung cell membranes) Also more potent than salmeterol. Formoterol and salmeterol are often formulated with cortico steriods.

Anticholinergics – ipratropium/tiotropium
Corticosterioids – beclometasone, budesonide, ciclesonide, fluticasone
Leukotriene antagonist – montelukast, pranlukast, zafirlukast
Xanthines – aminophylline, theobromine, theophylline

Clonidine
(Catapress, Dixarit)

Lofexidine

Xylazine

MDMA (extacy)
MDA

is a centrally-acting alpha-2 agonist. It selectively stimulates receptors in the brain that monitor catecholamine levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (epinephrine, also known as adrenaline, and norepinephrine) in the adrenal medulla. By fooling the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure, with side effects of dry mouth and fatigue. If clonidine is suddenly withdrawn the sympathetic nervous system will revert to producing high levels of epinephrine and norepinephrine, higher even than before treatment, causing rebound hypertension. Rebound hypertension can be avoided by slowly withdrawing treatment.

short acting alpha 1 also. Probably same mechanism because listed as anti-hypertensive. Often used to alliviate symptoms of withdrawal from heroin or opioids. More used in UK than US

nor for humans but animal sedation and anesthesia. Analogue of Clonidine and is an A2 agonist. Side effects include bradycardia, conduction disturbances, myocardial depression. Yohimbine used for reversal

Maximal activity/efficacy when 3,4-dihydroxy on phenyl group
Increased selectivity for _1 if remove 4-hydroxy
Addition of alkyl groups at nitrogen increases selectivity for _ receptor
Presence of 3,5 di-hydroxy on phenyl with longer chain give _2 specificity
Presence of hydroxyl groups limits CNS activity
Makes more hydrophillic
Levorotatory forms are more active

Most potent when have the catecholamine structural component

But removal of 4 hydroxy makes drug less potent though more selective for a1 (phenylphrine)

Nitrogen substitution, Norepinephrine little to no activity at B2 but epinephrine has activity

Hydroxyl groups limit CNS stimulation. Probably because the OH groups decrease the lipid solubility character and do not cross BBB as well

Non-catecholamines do not have the 3/4 dihydroxy

The levorotatory form of isoproterenol is 1000 times more active than dextrorotatory

ephedrine, amphetamine

Mescaline

MDMA(ecstasy), MDA

Phentermine, Fenfluramine (fen-fen), Amphetamine

Salbutamol, ephedrine

Buproprion, Phenelzine (MAOI), Tranylcypromine (MAOI)

norepi

Agonize the various receptor subtypes

always synthetic

Indirect agonists
Stimulate the release of endogenous neurotransmitter (norepinephrine) from postganglionic nerve endings

it inhibits norepi uptake.

(MAO degrades nor-epi)

alpha -2

I have also seen this compound to be listed as an antiadrenergic. It binds to adrenergic receptor but its mechanism involves then limiting the amount of catecholamine released. So agonist activity but end result being antiadrenergic

alpha 2

Mostly used to relieve symptoms of heroin or opiate withdrawal. Used more in UK than US

Norepinephrine>
Epinephrine>
dopamine>>
Isoproterenol

Epinephrine>
Norepinephrine>
dopamine>>
Isoproterenol

Isoproterenol >
Norepinephrine=
Epinephrine=
dopamine

Isoproterenol >
Epinephrine>
Dopamine>>
Norepinephrine

Isoproterenol >
Norepinephrine=
Epinephrine

Smooth muscle
(GI tract, blood vessels in skin, skeletal blood vessels, eye, lung, uterus, genitourinary)

Pre*- and postsynaptic nerve terminals, Vascular smooth muscle, CNS

Heart and cerebral cortex

Lung, smooth muscle, cerebellum, skeletal blood vessels, gland cells

Adipose Tissue, gallbladder, brain

Phenoxybenzamine
Phentolamine
Prazoxin
Tasulosin
Terazosin

Yohimbine

Metoprolol
Atenolol

Butoxamine
Propranolol

Hormone binding activates Gq protein, which is linked to phospholipase C (PLC). PLC produces IP3, which causes a rise in intracellular calcium levels, and diacylglycerol. Elevated calcium and diacylglycerol activate protein kinase C, which causes other down stream effects
In blood vessels of the skin, and skeletal muscles the principal effect is vasoconstriction which decreases blood flow. This accounts for an individual's skin appearing pale when frightened.
In the GI tract, the effect is relaxation.

Each subtype is linked to a Gi protein, which works in opposition to Gs proteins, suppressing adenylate cyclase activity with a consequent decrease in intracellular cAMP levels and decrease of entry of calcium into nuerons. This limits release (exocytosis) of norepinephrine Mediates synaptic transmission.
In smooth muscle vasculature have vasoconstrictin
In CNS causes sedation and reduces sympathetic effects (can lead to vasodilation and lower BP)

adenylate cyclase active, cAMP increase
In heart, cAMP activates kinases which phosphaorylate various substratestwhich causes influx of calcium through channel. Increased calcium enhances intensity of actin and myosin interaction which gives more forceful myocardial contractility (known as beta 1 effect). The agonists enhance myocardial contractility and increase heart rate.

adenylate cyclase active, cAMP increase. Increase in cAMP results in hyperpolarization of cell membranes and decreased influx of calcium.
In lung, agonists cause smooth muscle relaxation which results in bronchodilation.. Agonists can be useful in treating asthma.
Also inhibits activation of T cells and release of cytokines away from airway smooth muscle cells
In skeletal muscle, causes vasodilatation which can become overridden by vasoconstriction of alpha-1 stimulation
Can also cause muscle tremors
In uterus causes relaxation (tocolysis)
Glycogenolysis, lipolysis, gluconeogenesis, insulin release stimulated
Sodium/potassium pump is activated causing internalization of potassium which induces hypokalemia which can cause cardiac dysrhythmias

Adenylate cylcase active, cAMP increase
Agonist enhances lipolysis???

tyrosine-
DOPA
dopamine
noradrenalin
adrenalin

very complicated

Agonist binds to the myocardial beta1-adrenergic receptor. This receptor is a typical G-protein coupled receptor.
In the unstimulated state the G-protein is complexed with GDP (refer to p. 18 of The Receptors handout).
The receptor promotes exchange of GTP for GDP and release of G"/GTP.
The G"/GTP complex activates adenylate cyclase.
Intracellular cAMP increases and activates cAMP dependent protein kinase (PKA).
PKA phosphorylates the Ca2+ channel promoting Ca2+ influx.
Intracellular Ca2+ increases activating the contractile proteins.
PKA phosphorylates the sarcoplasmic reticulum leading to an increase in Ca2+ uptake and release.
PKA phosphorylates troponin changing its calcium binding kinetics
G" directly activates the Ca2+ channel.
Prolonged stimulation can lead to receptor down regulation via PKA and other protein kinases which phosphorylate the receptor. The other protein kinases which are involved in phosphorylation are referred to as G-protein coupled receptor kinases or GRKS. These phosphorylation steps lead to internalization of the receptor (refer to p. 20 of The Receptors handout).

http://www.mun.ca/biology/desmid/brian/BIOL2060/BIOL2060-14/1424.jpg

Kinases phosphyrolate

Phosphyrolases remove phosphjate groups

Glucose 1-phos to Glucose-6 to glucose

The action of noradrenaline at the synapse is terminated by its re-uptake across the pre-synaptic membrane. This is an energy dependent process. Sodium/potassium ATPases use energy from ATP hydrolysis to create a concentration gradient of ions across the pre-synaptic membrane that drives the opening of the transporter and co-transport of sodium and chloride ions and noradrenaline from the synaptic cleft. Potassium ions binding to the transporter enable it to return to the outward position. Release of the potassium ions into the synaptic cleft equilibrates the ionic gradient across the pre-synaptic membrane. The noradrenaline re-uptake transporter is then available to bind another noradrenaline molecule for re-uptake.

Reuptake is a receptor mediated response

Not Oral especially for catecholamines
Metabolism
SC/IV

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amphet cross fast

catechol cross poorly

SC administration can be slow due to induced vasoconstriction with alpha-1 agonists

Monoamine Oxidase (MAO)
Liver, kidneys, GI tract
Oxidative deamination
Catechol-O-methyltransferase (COMT)
Methylated hydroxyl metabolite conjugated with glucoronic acid

Monoamine Oxidase (low activity)
Slow or not at all if have alpha-methyl
Acidify urine for faster removal

MAO and COMT not one or the other but both. Norepinephrine and epinephrine after combination of two pathways give vanillylmandelic acid.
Patient with MAOIs may exhibit prolonged effect especially if using a non-catcholamine

Alpha methyl of ephedrine or ampetamine limits its enzymatic degradation by MAO.
pKas usually around 9 so to eliminate non-catecholamines which are poor substrates for the enzyme, may need to acidify the urine

Duration limited by uptake into nerve endings (primary determinant)
Metabolism in minor…

Uptake not parallel metabolism – parallels “re” uptake into nerve endings. When block reuptake, see potentiation so the uptake is important for duration

Re-uptake
Metabolism
Clearance by lunge
Norepinephrine (25%)>Dopamine (20%)>>Epinerphrine (~0%)

Lungs have been shown with the other drug classes as well to be responsible for removal of amines
With inhaled anesthetics, less of the drug is cleared by the lungs. Maybe inhibit amine transfer mechanisms of pulmonary cells

Inverse relationship between concentration of neurotransmitter and receptor density.

(the higher the concentration of drug, the lower the dendity of receptors)

Most potent alpha but also beta-1/2
Oral poor due to quick metabolism
SC slow due to vasoconstriction
Poorly lipid soluble so no distribution across BBB
Used for addition to local anesthetic for vasoconstriction/ treatment of life threatening allergic reactions/cardiopulmon

An _2 adrenergic receptor antagonist prevents the activation of the _2 adrenergic receptor. The _2 receptor is coupled to inhibitory G-proteins, which dissociate from the receptor following agonist binding, and inhibit both secondary messenger signaling mechanisms and cell depolarisation. Antagonist binding to the _2 adrenergic receptor prevents secondary messenger inhibition and allows cell depolarisation to occur.

Amphetamine
Hyperkinetic Attention Deficit Disorder
Narcolepsy
Decrease Appetite
Epinephrine
Anaphylactic Shock
_-2
Acute Asthmatic brochospsam (inhaled)
Supress pre-term labot (ritodrine, terbutaline)
_
occasionally to increase heart rate (isoproternol)
_
decrease blood flow (reduce bleeding, reduce congestion [phenylephrine], prolong local anesthesia [epinephrine]
reduce urinary incontinence (long acting indirect such as ephedrine)
_-2
Decrease blood pressure (Clonidine)
Inhibits substance P release (epidural/subarachnoid space) and lowers pain transmission
Dopamine
Maintain renal blood flow in shock
Midodrine
Treat idiopathic orthostatic hypotension

Endogenous neurotransmitter
Known as mixed agonist since stimulates A-1, A-2 and B-1 (little B-2, unlike epi in this regard)
Alpha stimulation gives intense vasoconstriction (arterial and venous) due to increased systemic vasuclar resistance and decreased venous return (tends to lower CO)
Can be used to treat hypotension
Effects terminated by reuptake which can be blocked by cocaine so cocaine can be listed as indirect agonist.

Known as mixed agonist since effective at all subtypes however, B receptors more sensitive than A so at low dose, see more B effect. At higher doses see primarily alpha stimulation
Because of B stimulation at low dose, see positive ionotrope, chronotrope and dromotrope effects. At higher doses to see vasoconstriction that overcomes the B effects.
Effective for increasing blood pressure but also venoconstriction, increased venous return, arterial constriction, increased SVR, increased HR increased myocardial contractility
Increases blood flow to skeletal muscles
Systolic BP increase due to B-1 increase in cardiac output and Diastolic BP decrease due to B-2 vasodilatation. MAP nearly the same
Oral poor due to quick metabolism
SC slow due to vasoconstriction
Poorly lipid soluble so no distribution across BBB
Used for addition to local anesthetic for vasoconstriction/ treatment of life threatening allergic reactions/cardiopulmonary resusitation
Could be used as bronchodilator
Has the most significant effects on metabolism causing glycogenolysis and inhibition of insulin secretion
Can cause arrythmogenic effects (like isoproternol less likely with dobutamine)

Precursor to NE and is also a neurotransmitter
Low doses stimulate dopaminergic receptors, intermediate doses additionally stimulate B-1, high doses additionally stimulate vascular A-1 (B-2/A-2 only weak)
At low doses dilates renal vasculature (vasopressor) giving increased GFR, renal blood flow and Na+ excretion
intermediate doses give tachycardia and increased CO (minimal change in HR, BP, vascular resistance)
High doses give vasoconstriction
Used clinically primarily to increase CO for patients with low BP, increase arterial filling, increase urine output
unique in that it can do many things at these low/intermediate doses
Combined with dobutamine to add dobutamine effects
Interpheres with ventilatory response to arterial hypoxemia.

Predominant beta-1 with some beta-2 agonism
results in more increase in contractility (positive inotropic effect) with minimal increase in HR or BP
Less tendency to have arrythymogenegic side effects as compared to other B-agonists isoproternol and norepinephrine