Sympathomimetics: Adrenergic Receptor Activators

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Sympathomimetics:

substances that mimic the effects of sympathetic transmitters (drugs that ACTIVATE peripheral adrenergic (Epi, NorEpi) receptors
ex. catecholamines, mimic epinephrine

Catecholamines (6)

Epinephrine
Norepinephrine
Dopamine
Fenoldopam
Isoproterenol
Dobutamine

Other Sympathomimetics (5)

Phenylephrine
Midodrine
Pseudophedrine
Theophylline
Clonidine

-do we need to add the non-Bolded ones in???

Special sympathetic agents (6)

Cocaine
Tyramine
Ephedrine
Amphetamine
Methamphetamine
Mehtylphenidate
(all act indirectly)

Receptor Specificity
Epinephrine

none

Epinephrine
Use?
Tox?

Epinephrine
Use- glaucoma (increase outflow), anaphylaxis, Hypotension, Heart Failure, Severe asthma
Tox- SYMPATHETIC EXCESS; arrythmia, HYPERtension, cerebral hemorrhage, tachycardia, anxiety

Receptor Specificity
Norepinephrine

a1=a2, b1>>b2

Norepinheprine
Use?
Tox?

Norepinephrine
Use- Hypotension, Heart Failure
Tox- Same as EPI
PLUS- reflex bradycardia, risk cardiac ischemia

Receptor Specificity
Isoproterenol

b1=b2, >>>>>>>>a

Isoproterenol
Use?
Tox?

Isoproterenol
"IS bien" = is Beta
Use- bradycardia (Atropine resistant), or heart block
Tox- Palpitations/Arrythmias, tachycardia, headache flushing, cardiac ischemia

Receptor Specificity
Dobutamine

b1>b2>>>>>>>>a

Dobutamine
Use?
Tox?

Dobutamine
Use- Heart Failure
Tox-Palpitations/Arrythmias, tachycardia, headache flushing, cardiac ischemia, with more pressor effects

Receptor Specificity
Dopamine

D1=D2>>b>>a

Dopamine
Use?
Tox?

Dopamine
Use-Hypotension, Heartfailure, Cardiogenic/HyPOvoluemic shock (d/t low cardiac output and renal function)
Tox- same as EPI

** Dopamine has a three level response:
low- decreases vascular resistance, increase flow to renal vasculature
medium- decreases vascular resistance, INCreases heart rate
high- Increases vascular resistance, increases heart rate

Receptor Specificity
Fenoldopaam

D1>>D2

Fenoldopam
Use?
Tox?

Fenoldopam
Use- Hypertension
Tox- HYPOtension, tachycardia, nausea/vomiting, Nasal congestion, constipation

Receptor Specificity
Phenylephrine
Midodrine
Psuedophedrine

a1>a2>>>>>>B

Alpha 1 drugs
-effect
-response?

Alpha 1 drugs (Phenylephrine, Midodrine)
-effect smooth AND cardiac muscle
(Gq= IP3 and Ca++) ---> SM contraction
Responses; vasoconstriction, increase sphincter tone, mydriasis

Alpha 1's:
Phenylephrine
Pseudoepherine
Use?
Toxicity?

Phenylephrine
Use- shock, hypotension, decongestant, fundus exam
Tox- hypertension

Pseudoepherine
Use- nasal decongestant, stress incontinence
Toxicity- hypertension

Alpha 1's:
Methoxamine
Midodrie
Use?
Toxicity?

Alpha 1's:
Methoxamine
Midodrie
Use- Hypotension, Orthostatic Hypotension
Toxicity -Hypertension

Alpha 1's:
Xylometazoline
Oxymetzoline
Use?
Toxicity?

Alpha 1's:
Xylometazoline
Oxymetzoline
Use- Nasal Decongestant
Toxicity - hypotension

Clonidine

a2>a1>>>>>>B

Alpha 2 drugs
-effect
-response?

Alpha 2 drugs (clonidine)
-effect presynaptic noradrenergic neurons
(Gi= decrease cAMP --> norepi release)
Responses; decrease NT release, decrease CNS effects, decreases BP, decreases Ach release in peripheral GI
-increase platelet aggregation

Alpha 2's
Clonidine
Methyldopa
Use?
Tox?

Alpha 2's
Clonidine
Methyldopa
Use-ANTI-Hypertensive, diarrhea, narcotic/alcohol withdrawls, ADHD, Hot flashes
Tox-Sedation, Constipation, drymouth, impotence
MUST TITRATE with Clonidine!!!
-will cause severe hypertension without down titration

Alpha 2's
Apraclonidine
Brimonidine
Use?
Tox?

Alpha 2's
Apraclonidine
Brimonidine
Use- Glaucoma
Tox - Sedation, Constipation, drymouth, impotence

Alpha 2's
Dexmedetomidine
Use?
Tox?

Alpha 2's
Dexmedetomidine
Use-Sedation
Tox-Sedation, Constipation, drymouth, impotence

NorEpi synthesis
Describe basic steps and enzymes involved
1)

1)Tyrosine -----> DOPA
-via Tyrosine hydroxylase

NorEpi synthesis
Describe basic steps and enzymes involved
2)

2) DOPA ----> Dopamine
-via Dopa Decarboxylase

NorEpi synthesis
Describe basic steps and enzymes involved
3)

3) Dopamine ---> Norepinephrine
-via Dopamine Beta Hydroxylase

Catecholamines:

Most commonly;
-epinephrine (adrenaline)
-norepinephrine (noradrenaline)
-dopamine
All of which are produced from phenylalanine and tyrosine.

What can be used to measure Catecholamines in your body?

VMA (Homovanillic acid)

Made from
Monoamine Oxidase --> and oxidized metabolite

Catechol-O-methyltransferase --> Methylated metabolite

-Metabolites can be MEASURED

Neuronal Signaling Steps
1)

1) Tyrosine taken up in nerve terminals

2)
-this step can be inhibited by ______

2) Tyrosine Hydroxlyase turns Tyrosine into Dopa
-can be inhibited by Metyrosine

3)
-this step can be inhibited by ______

Dopa --> dopamine, goes into vesicles
-Reserpine can inhibit this step

4)

Dopamine --> NorEpi

Adrenergic Receptor Subclasses & Interaction with Drugs

Alpha-
Beta-

Adrenergic Receptor Subclasses & Interaction with Drugs

Alpha - drugs interact with Alpha 1 & 2, but NOT their subclasses

Beta- drugs interact with Beta 1 & 2, but NOT Beta 3 or 4

Adrenergic Receptor Subclasses & Interaction with Drugs
-most drugs __________

MOST drugs have MIXED effects on Alpha AND Beta receptors, but have a preference for one or the other

OPEN is BIEN =

alpha PEN is Beta ien =
Alpha receptors
Phenylephrine A1>A2
Epinephrine A1=A2
Norepinephrine A1=A2

Beta Receptors
Isoproterenol B1=B2
Epinephrine B1= B2
Norepinehprine B1>>B2
-has very weak affinity for B2, usually, clinically, won't even see Beta 2 effects

Clinical Use
Systemic Control of Blood Presssure
Hypotension
Short term;
-direct acting alpha agonists:
Long term;

Clinical Use
Systemic Control of Blood Presssure
Hypotension
Short term;
-direct acting alpha agonists: norepi, phenylphrine, methoxamine, dopamine
Long term;
-ephedrine, midodrine

Clinical Use
Local Reduction of Blood Flow
-surgical
-nasal

Clinical Use
Local Reduction of Blood Flow
-surgical; Epi
-nasal;
short acting- pseudoephedrine
long acting- xylometazoline & oxymetazoline

Specific Beta Adrenergic Agonists
B1 Drug?
Response?
Use?

Dobutamine
- Increases heart rate and Force
-Increases Renin Release
-Used for HTN, angina, palpitations

Specific Beta Adrenergic Agonists
B2 Drugs (6)?
Effects?
Use?

Specific Beta Adrenergic Agonists
B2 Drugs (6)
Pirbuterol
Metaproterenol
Formoterol
Albuterol
Salmeterol
Terbutaline

Effects: Bronchodilation, Uterine Relaxation, Vasodilation, Decreaes GU/GI wall tone, glucagon release, increase glycogenolysis

Use- asthma, COPD, Hyperkalemia

Beta's remember _____________

1 heart (Beta 1 on heart)
2 Lungs (Beta 2 lungs)

INdirect acting Sympathomimetics
-cross BB barrier
-catecholamines had fever CNS actions (epi, NorEpi, Isoproterenol)

ok

Clinical Use of Adrenergic Agonists
Narcolepsy (4)

Narcolepsy
-Modafinil
-Amphetamine
-Pemoline
-Methylphenidate

Clinical Use of Adrenergic Agonists
Obesity (1)

Obesity
Dextramphetamine

Clinical Use of Adrenergic Agonists
ADD (5)

ADD
METHYlphenidate (ritalin)
Amphetamine (adderall)
Pemoline
Dextroamphetamine
Clonidine (an alpha 2 agonist) -ADHD especially with tics

Clinical Use of Adrenergic Agonists
Cocaine
MOA:
Use:
TOX:

Cocaine
MOA: decreases re-uptake of NE and dopamine
Use: local reduction of blood flow
TOX: same as amphetamines

Clinical Use of Adrenergic Agonists
Tyramine
MOA:
Use:
TOX:

Tyramine
MOA: Increases release of NorEPI
Use: NONE
TOX: Catecholamine excess especially wen taken with MAO inhibitors

Clinical Use of Adrenergic Agonists
Ephedrine
MOA:
Use:
TOX:

Ephedrine
MOA: Increases release of NorEPI
Use: Nasal decongestant, asthma, chronic hypotension
TOX: anorexia, insomia, HTN, arrhythmias

Clinical Use of Adrenergic Agonists
Amphetamine
MOA:
Use:
TOX:

Amphetamine
MOA: Increases release of NorEPI
Use: ADHD, narcolepsy, anorexiant
TOX: restlessness, dizzyness, tremor, hyperactive reflexes, anxiety, libio changes, psych: paranoia, hallucinations, panic, suicidal tendencies

Clinical Use of Adrenergic Agonists
Methylphenidate
MOA:
Use:
TOX:

MOA: Increases release of NorEPI
Use: narcolepsy, anorexiant
TOX: restlessness, dizzyness, tremor, hyperactive reflexes, anxiety, libio changes, psych: paranoia, hallucinations, panic, suicidal tendencies

Clinical Use of Adrenergic Agonists
Methamphetamine
MOA:
Use:
TOX:

MOA: Increases release of NorEPI
Use: narcolepsy, anorexiant
TOX: restlessness, dizzyness, tremor, hyperactive reflexes, anxiety, libio changes, psych: paranoia, hallucinations, panic, suicidal tendencies

Adverse Effects of Adrenergic Agonists:

B1 = HT, ANgina, MI, Arrythmias
B2 = restless ness, anxiety, tremor
Insomnia
Dry mouth
Rteinal damage

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