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92 Cards in this Set

  • Front
  • Back
Autonomic Adrenergic Transmission

-Postglanglionic fibers in the SNS release
(NE) (a few release Epi), and

-some release Dopamine.
Catecholamine Synthesis part 1

L-tyrosine(from blood)
is taken up into adrenergic neurons.

This is then converted to L-Dopa by the action of tyrosine hydroxylase (TH)(the rate-limiting step in the synhesis).
Catechol synthesisL-part 2

Dopa is then converted into
(DA) by dopa decarboxylase(DD) (I-aa decarboxylase).
Catechol synthesis Part 3

This DA can then be released from
DA neurons.

In (NE) neurons, the enzyme, Dopamine B-hydrolase(DPH) is present in the vesicle
Catecholamine Synthesis part 4

β-hydroxylase (DBH) in vesicle
catalyzes the conversion of dopamine to norepinephrine
Catecholamine Synthesis part 5

In epinephrine neurons
a cytoplasmic enzyme, phenylethanolamine N-methyltransferase (PNMT) is present which can convert cytoplasmic norepinephrine to epinephrine.
Catecholamine Synthesis part 6

Dopa decarboxylase
is a fairly non-selective enzyme with broad substrate specificity
-(i.e. can also convert 5-hydroxytryptophan to 5-hydroxytryptamine [Serotonin]).
Catecholamine Synthesis part 7

Dopa decarboxylase can also convert
α-methyldopa to α-methyldopamine
which can be further converted to α-methylnorepinephrine (which are false transmitters).
Catecholamine Synthesis part 8

Cytoplasmic NE acts in feedback loop on the enzymes
TH and DD to decrease excessive production.
if there is excessive NE release,

there is less NE in the cytoplasm, thus less feedback, and more rapid synthesis.
Catecholamine Synthesis part 9

NE re-uptake is main contributor
to the NE pool (actually two pools, rapid and slow turnover pools)
Catecholamine Synthesis part 10

In the cytoplasm
NE acts to feedback on DA production.

In addition, NE in the cytoplasm of the adrenal medulla chromaffin cells is converted to EPI before packaging in vesicles
Catecholamine Synthesis part 11

In the chromaffin cells,
both EPI and NE are stored and released in the ratio of 80% EPI, 20% NE.

import due to the receptor specificity between Epi and NE.
Catecholamine Synthesis part 12

Catecholamine are stored
mainly in granular vesicles, and these vesicles may be made in the cell body and carried to the nerve terminal for filling,

or they may be made by endocytosis (pinching off) of the nerve terminal membrane.
Catecholamine Synthesis part 13

NE in the granules is in a complex
with ATP (4NE:1ATP) and other proteins (neurotransmitters and neuromodulators) as well as DBH and DA
Catecholamine Synthesis part 14

Neuropeptide Y
example proteins stored with NE

it is released with NE as a co-transmitter.
Catecholamine Synthesis part 15

Two cytoplasmic pools of NE exist
the fast and slow turnover pools
The fast turnover
pool is probably used as transmitter and is stored, or can be released directly from the cytoplasm.
The slow turnover pool
is probably a reserve pool, present in case NE levels get too low, at which time it can be utilized.
Enzyme inhibitors exist
for experimental determination of the system mechanics

include α-methyl-p-tyrosine, which inhibits TH,

α-methyldopa, which inhibits DD,

Disulfiram (Antabuse), which inhibits DBH
Adrenergics Release part 1

Impulse traveling down neuron triggers
-Ca++ inflow at the nerve terminal
-leading to the cascading reaction
-triggering exocytosis of vesicles and
-the synaptic release of the
neurotransmitter.
Adrenergics Release part 2

in adrenal chromaffin cells
-the neurotransmitter is released to blood vessels
-where it is picked up and transported throughout the body.
Adrenergics Release part 3

approximately 80% of NE released from neurons
is retrieved by re-uptake pumps back into the cytoplasmic pool

- (most important mechanism in stopping neurotransmitter action at the receptor sites).
Adrenergics Release part 4

The retrieved neurotransmitter is
then taken up against concentration gradient back into vesicles.
Adrenergics Release part 5

Both of these uptake mechanisms
are points of potential drug attack.
Adrenergics Release part 6

Some of the released neurotransmitter in the synapse
can act on presynaptic α2 autoreceptors to inhibit further release via feedback loop.
Adrenergics Release part 7

Very small amounts of neuronally released neurotransmitter
gets free to enter circulation (except obviously from the adrenal medulla)

Some is metabolized in the synapse before the re-uptake pumps can recycle it.
Adrenergics Metabolism part 1

The two principle enzymes responsible for the degradation of catacholamines
monoamine oxidase (MAO), and catechol-o-methyltransferase (COMT).
Adrenergics Metabolism part 2

MAO exists in two major forms
A and B
Adrenergics Metabolism part 3

Type A
is the most active form for metabolism of NE (DA, EPI, and 5-HT (serotonin) also).
Adrenergics Metabolism part 4

MAO
mainly on the outer surface of mitochondria in sympathetic neurons (and other body cells),
Adrenergics Metabolism part 5

COMT
located mainly in the synaptic cleft (and other spaces and locations in the body).
Adrenergics Metabolism part 6

The liver
has a lot of MAO and COMT, thus rapidly metabolizing circulating catecholamines.
Adrenergic receptors part 1

Characterized 50 years ago based on effects
of NE, EPI and Isoproterenol (ISO) (Isuprel) - as α and β.
Adrenergic receptors part 2

Receptor types further broken down as
α1 and α2, β1 and β2
Adrenergic receptors part 3

– α-agonist potency
EPI > NE > DA > ISO
Adrenergic receptors part 4

β-agonist potency
ISO > EPI > NE > DA
Adrenergic receptors part 5

Selective antagonists
-phenoxybenzamine for α,

-propranolol for β)
Adrenergic α-receptors part 1

Pre-junctional (α2)
found to be different than post-junctional (α1).
Adrenergic α-receptors part 2

Clonidine
one of first compounds shown to have more agonist potency for α2 than α1 receptors
Adrenergic α-receptors part 3

Phenylephrine (Neo-Synephrine)
more potent at α1 than at α2 receptors
Adrenergic α-receptors part 4

Selective antagonists for α1 receptors include
prazosin, and yohimbine for α2.
Adrenergic α-receptors part 5

Now known that some α2 agonists act
some post-junctional sites, showing contraction of smooth muscles, platelet aggregation, etc.
Adrenergic α-receptors part 6

α1 and α2 receptors have been further divided (3 subgroups).
α1 broken down to α1A, α1B, and α1D

α2 receptors have been broken down into 4 subgroups (so far).
Adrenergic α-receptors part 7

All α2 receptors inhibit
adenyl cyclase by G protein interaction, causing a hyperpolarization.
Adrenergic α-receptors part 8

α1 stimulation triggers
increased intracellular Ca++ release by activation of phospholipase C, which is also G protein mediated
Adrenergic α-receptors part 9

α2 receptor agonists
used in anesthesia for sedative, analgesic, and BP control in surgery on hypertensive patients.
Adrenergic β-receptors part 1

β receptors broken into β1 and β2 subclasses
-β1 mainly on cardiac tissue,

-β2 everywhere else
Adrenergic β-receptors part 2

β2 receptor potency
EPI > NE
Adrenergic β-receptors part 3

β1 receptor potency
NE > EPI
Adrenergic β-receptors part 4

Selective antagonists
-β1- atenolol and metoprolol

-β2– butoxamine
Adrenergic β-receptors part 5

Selective agonists
- β1: dobutamine

-β2: albuterol
Adrenergic β-receptors part 6

β3 receptor
in colon and adipose tissue

propranolol does not act on it to block the action of isoproterenol.
Adrenergic β-receptors part 7

β3 agonist potency
NE > EPI
Adrenergic β-receptors part 8

– All β receptors function
stimulatory G protein to stimulate adenyl cyclase.

In heart, this leads to ^ inotropy and chronotropy controlled by increasing Ca++ release
Adrenergic β-receptors part 8

– In smooth muscles, increased cAMP leads
to relaxation as membrane hyperpolarizes.
Adrenergic Receptor Distribution
See figure in text about cholinergic and adrenergic receptor distribution - Know!!

Tissue response is often a balance of several effects.
Adrenergic Agonists

Norepinephrine (Levophed) (l-isomer) part 1
Potent vasoconstrictor and inotropic agent
– L-isomer much more potent than d-isomer
–More α than β activity
–α activity produces increased peripheral vascular resistance, and increased SBP and increased CA blood flow
–Some β1 activity: in lower doses, β1 cardiac stimulatory effects are seen, but with larger doses, vasoconstrictive effects (α1) are predominate cause of increased BP.
–Like other catacholamines, NE increases cAMP in cells via β stimulation, and decreases cAMP via α stimulation.
Adrenergic Agonists

Norepinephrine (Levophed) (l-isomer) part 2
Glycogenolysis, inhibition of insulin release and lipolysis is less than seen with EPI.
–Reflexive vagal stimulation secondary to increased TPR and BP slows the heart and increases stroke volume.
–Blood flow to abdominal organs and skeletal muscle is decreased, while coronary blood flow is increased indirectly due to a stimulation.
–Does not increase myocardial O2 consumption.
–Normally given only via IV, with rapid onset and short (1 - 2 minute) duration.
–Does not cross the BBB.
–Use limited, mainly used for shock and severe hypotension.
Adrenergic Agonists

Epinephrine (Adrenalin) part 1
Administered parenterally, via inhalation, or topically to eye.
–Used as a cardiac stimulant and bronchodilator (anaphylactic shock).
–Other uses in asthmatics is limited now due to more selective compounds.
– Combined with other drugs (such as local anesthetics and topical eye preps) to prolong action by vasoconstriction, causing slower absorption and removal of the other agent from the site.
–Ophthalmic use as a diagnostic aid.
–Potent α and β agonist (non-selective adrenergic agonist).
Adrenergic β-receptors part 8

– In smooth muscles, increased cAMP leads
to relaxation as membrane hyperpolarizes.
Adrenergic Receptor Distribution
See figure in text about cholinergic and adrenergic receptor distribution - Know!!

Tissue response is often a balance of several effects.
Adrenergic Agonists

Norepinephrine (Levophed) (l-isomer) part 1
Potent vasoconstrictor and inotropic agent
– L-isomer much more potent than d-isomer
–More α than β activity
–α activity produces increased peripheral vascular resistance, and increased SBP and increased CA blood flow
–Some β1 activity: in lower doses, β1 cardiac stimulatory effects are seen, but with larger doses, vasoconstrictive effects (α1) are predominate cause of increased BP.
–Like other catacholamines, NE increases cAMP in cells via β stimulation, and decreases cAMP via α stimulation.
Adrenergic Agonists

Norepinephrine (Levophed) (l-isomer) part 2
Glycogenolysis, inhibition of insulin release and lipolysis is less than seen with EPI.
–Reflexive vagal stimulation secondary to increased TPR and BP slows the heart and increases stroke volume.
–Blood flow to abdominal organs and skeletal muscle is decreased, while coronary blood flow is increased indirectly due to a stimulation.
–Does not increase myocardial O2 consumption.
–Normally given only via IV, with rapid onset and short (1 - 2 minute) duration.
–Does not cross the BBB.
–Use limited, mainly used for shock and severe hypotension.
Adrenergic Agonists

Epinephrine (Adrenalin) part 1
Administered parenterally, via inhalation, or topically to eye.
–Used as a cardiac stimulant and bronchodilator (anaphylactic shock).
–Other uses in asthmatics is limited now due to more selective compounds.
– Combined with other drugs (such as local anesthetics and topical eye preps) to prolong action by vasoconstriction, causing slower absorption and removal of the other agent from the site.
–Ophthalmic use as a diagnostic aid.
–Potent α and β agonist (non-selective adrenergic agonist).
Adrenergic Agonists

Epinephrine (Adrenalin) part 2
α1 action leads to arteriolar vasoconstriction. α2 stimulation leads to decreased NE release from neurons.
– β1 stimulation leads to increased chronotropic and inotropic activity. β2 stimulation leads to arteriolar vasodilation, bronchial smooth muscle relaxation and increased glycogenolysis.
–Major therapeutic effects include: bronchodilation, cardiac stimulation, skeletal muscle vasodilation, and glycogenolysis.
–Smooth muscle effects are varied and depend on receptor density and hormonal effects.
–Lowers intraocular pressure (wide-angle glaucoma) and causes brief mydriasis.
–Topical or local administration constricts blood vessels (hemostasis).
Adrenergic Agonists

Epinephrine (Adrenalin) part 3
–β2 stimulation also decreases mast cell histamine release.
– Systolic pressure usually increased (due to increased inotropy) while diastolic is decreased (vasodilation).
–Increases coronary artery vasodilation and stimulates increased myocardial O2 demand which has further local effect (via NO) to increased coronary vasodilation.
–Increased risk of arrhythmias due to β1 activity.
–At normal doses, some vasoconstriction, some dilation. Mostly constriction at higher doses.
Adrenergic Agonists

Epinephrine (Adrenalin) part 4
α stimulation in liver increases gluconeogenesis and inhibits insulin release. β stimulation (β3) in adipose tissue causes catabolism and increased free fatty acids in plasma.
–β2 stimulation at skeletal muscle and liver increases glycogenolysis.
–Does not cross BBB well.
–Duration varies with administrative route: IV – few minutes; IM - 1 - 4 hours; Inhalation - 1 - 3 hours
–Uses include acute bronchospasm, anaphylaxis, asthma(??), cardiopulmonary resuscitation, glaucoma, surgical bleeding, ventricular fibrillation and asystole.
Adrenergic Agonists

Isoproterenol (Isuprel)
Potent bronchodilator and inotrope.
–Synthetic compound similar to EPI.
–Potent β agonist (non-selective).
–Not used much now due to more selective compounds.
–Very little α activity at therapeutic doses.
–Increases blood flow (vasodilation) and relaxes GI smooth muscles.
–Oral (sublingual), inhalation and IV routes.
–Sublingual onset - 30 minutes with 1 - 2 hour duration.
– IV very rapid, but less than 1 hour duration.
–Inhalational duration is 2 - 4 hours.
–Used for acute bronchospasms, bradycardia, asthma, etc
Adrenergic Agonists

Dobutamine (Dobutrex)
–Parenteral inotrope.
–Selective β1 agonist (minor β2 or α effects).
– Stimulates rate and contraction of heart, increasing CO.
–Systolic pressure is increased due to increased stroke volume, with little change in diastolic pressure.
– Increased coronary blood flow and myocardial O2 demand seen.
–Unlike DA, does not increase NE release from sympathetic nerves.
–Plasma half-life approximately 2 minutes, so needs to be administered via constant IV infusion.
–Uses include cardiac surgery, cardiogenic shock, and heart failure.
Adrenergic Agonists

Dopamine (Intropin)
Mimics action of endogenous DA, which is a precursor of EPI and NE.
– Works at DA receptors to dilate renal arterioles and increase renal blood flow and GFR.
–At low doses, causes much vasodilation in renal, mesenteric, coronary vessels.
–At moderate doses, also stimulates β1 receptors, stimulating the heart (while maintaining vasodilation).
–At high doses, α receptors also stimulated, increasing TPR.
–Does not cross BBB.
–Normally given via continuous IV infusion (half-life ~ 2 minutes).
–Used for heart failure, shock
Adrenergic Agonists

Metaproterenol (Alupent)
Synthetic compound similar in structure to isoproterenol.
–More β2 selective than isoproterenol (but less than Albuterol).
–Exclusively used as a bronchodilator.
–Use declining due to better β2 agonists.
–For COPD, asthma, chronic bronchospasms.
Adrenergic Agonists

Albuterol (Ventolin)
–Selective β2 agonist.
–Indications - bronchospasm in patients with obstructive airway disease, asthma.
–Adverse reaction - nervousness, tremor, tachycardia, palpitations.
Adrenergic Agonists

Pirbuterol (Maxair)
Relatively selective β2 agonist.
–Structurally similar to Albuterol.
– Used for asthma and bronchospasms
Adrenergic Agonists

Salmeterol (Serevent)
β2 agonist.
–Much more selective for β2 than albuterol.
–Note: many β2 receptors now known to be located on the heart. Their function is unclear at present.
–For chronic treatment of asthma (BID dosing, due to longer half-life).
–Side effects include tachycardia, palpitations, hypersensitivity, tremor, and headaches.
Adrenergic Agonists

Terbutaline (Brethane)
β2 agonist.
–Used for bronchospasms and asthma, emphysema.
–Side effects include tremor, nervousness, tachycardia, palpitations, nausea and vomiting.
Adrenergic Agonists

Ritodrine (Yutopan)
β2 agonist.
– Used mainly to maintain pregnancy in cases of spontaneous abortion.
– Not used prior to 20th week, or if prolongation of pregnancy may be hazardous to mother.
–Side effects include tachycardia (maternal), pulmonary edema, nausea and vomiting, decreased blood pressure, nervousness, chest pains
Adrenergic Agonists

Alpha-methylnorepinephrine
–α1 and α2 agonist.
–Works in CNS and periphery. In CNS, α2 receptor stimulation causes a decrease in sympathetic nervous system outflow, and an increase in parasympathetic outflow.
Adrenergic Agonists

Clonidine (Catapres)
Selective α2 agonist.
– More CNS activity than peripheral.
– α2 receptor stimulation in the CNS leads to decreased sympathetic outflow, increased parasympathetic outflow.
– Indicated for control of hypertension.
–Also used for analgesia (IV and epidural).
–Side effects include dry mouth, skin irritation.
Adrenergic Agonists

Phenylephrine (Neosynephrine)
α agonist.
– Used as vasoconstrictor to maintain blood pressure during surgery, decongestant, mydriatic (without cycloplegia).
– Contraindicated in narrow angle glaucoma, ventricular tachycardia, aneurisms.
–Side effects include bradycardia, decreased CO, arrhythmias, angina, dizziness, CNS excitation.
Adrenergic Agonists

Metaraminol (Aramine)
– A parenterally administered potent vasoconstrictor (α1).
– Used to prevent surgical (spinal anesthesia) hypotension and shock.
– Adverse reactions include anxiety, cardiac arrhythmias, and hypertension.
Adrenergic Agonists

Methyldopa (Aldomet
Forms α-methyl NE - acts as a false transmitter - less potent than NE.
– Used to treat hypertension.
– Contraindicated in patients with hepatic disease.
– Side effects include angina, congestive heart failure, orthostatic hypotension, bradycardia, many others!
Adrenergic Agonists

Cocaine
Inhibits amine re-uptake pump, thus causing increases stimulation. (Indirect effect).
– Also has local anesthetic effects - blocks Na+ channels of nerve membranes.
– Used for local (topical) anesthesia of mucous membranes in mouth, laryngeal and nasal cavities.
– Side effects include vasoconstriction, mydriasis, nervousness, respiratory failure, cardiac arrest, general CNS stimulation
Indirect Adrenergic Agonists

indirect adrenergic agonists trigger
NE release
Indirect Adrenergic Agonists

Amphetamine (Dexedrine)
Stimulates sympathetic neurons to release neurotransmitter.
–Also has direct post-synaptic effect (mixed action).
–Used for Narcolepsy, ADD, obesity.
–Contraindicated in any cardiovascular disease, hypertension, hyperthyroidism.
–Adverse reactions include: palpitations, tachycardia, increased blood pressure, psychoses, insomnia, headaches, tremor, general CNS stimulation
Indirect Adrenergic Agonists

Ephedrine
Stimulates both α and β receptors
– Peripheral actions are due partly to norepinephrine release and partly to direct effect on receptors.
– Therapeutic doses of ephedrine produce mainly relaxation of smooth muscle and, if norepinephrine stores are intact, cardiac stimulation and increased systolic and usually increased diastolic blood pressure.
– Metabolized to a small extent, with remainder excreted unchanged in urine.
– Available in oral and parenteral forms.
– Much controversy over its use.
– Fairly high abuse potential.
– Many reported cases of cardiovascular events.
Indirect Adrenergic Agonists

Pseudoephedrine (Sudafed)
Potent sympathomimetic, they possess direct α1, β1 and β2 activity in addition to triggering the release of catacholamines from the nerve terminal (mixed effects).
– Used mainly for asthma, stimulant (OTC) preps.
– Contraindicated in CV disease, hypertension.
– Side effects include: CNS excitation, tremors, insomnia, nervousness, palpitations, tachycardia, cardiac arrhythmias, headache, sweating.
Indirect Adrenergic Agonists

Tyramine (not used clinically
Taken up into nerve terminal and converted to false transmitter that has less activity, leading to decreased sympathetic tone.
– Slight direct α activity.
– Also triggers release of neurotransmitter from neuron.
– Found in some foods (Red wine, chocolate, cheese, etc.) and presents a potential interaction on patients taking monoamine oxidase inhibitors.
Indirect Adrenergic Agonists

Others
–Methamphetamine (Desoxyn)
• More potent than Amphetamine, widely abused

–Methylphenidate ( Ritalin)
• Used in Attention Deficit Hyperactivity Disorder (ADHD)

–Phenmetrazine (Preludin)
•Appetite suppressant

–Phentermine (Adipex)
•Appetite suppressant
Overview of Adrenergic Agonist Drugs and Effects

α1 agonists
NE, EPI, DA(higher doses),Phenylephrine, Metaraminol, Methoxamine
• Effects: Increased arterial tone, increased TPR, increased diastolic pressure, decreased heart rate (reflex), increased venous tone.
Overview of Adrenergic Agonist Drugs and Effects

α2 agonists
NE, EPI, Clonidine, α-methyldopa
•Effects: Increased tone in large arteries, increased TPR (Post synaptic α2), increased coronary vasodilation
Overview of Adrenergic Agonist Drugs and Effects

β1 agonists
NE, EPI, ISO, DA, Dobutamine
• Effects: Increased heart rate, increased O2 consumption, increased automaticity, conduction velocity, increased force of contraction, increased stroke volume and CO, decreased filling volume (in tachycardia), increased coronary vasodilation.
Overview of Adrenergic Agonist Drugs and Effects

β2 agonists
• Albuterol, Terbutaline, EPI, ISO
•Effects: Decreased arterial tone, decreased TPR, decreased diastolic pressure, increased heart rate (reflexive).