M4L3

Synthesis of the Adrenergic Transmission

Tyrosine is co-transported with Na

Synthesis of the Adrenergic Transmission

Tyrosine hydroxylase

• Tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA)

Synthesis of the Adrenergic Transmission

The synthesis is the rate-limiting step in the formation of norepinephrine

Synthesis of the Adrenergic Transmission

aromatic I-amino acid decarboxylase

• DOPA is decarboxylated to form dopamine

Tyrosine hydroxylase

Tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA)

aromatic I-amino acid decarboxylase

DOPA is decarboxylated to form dopamine

Amine transporter system

Transports dopamine for storage into the vesicle to prevent

premature degradation

Storage of the Adrenergic Transmission

Amine transporter system

• Transports dopamine for storage into the vesicle to prevent premature degradation.

Storage of the Adrenergic Transmission

Hydroxylation occurs with dopamine inside the vesicle - forming Norepinephrine

Release of the Adrenergic Transmission

The action potential causes the opening of voltage-gated calcium channels, causing an influx of Calcium ions

Release of the Adrenergic Transmission

The influx of Calcium ions triggers the release of norepinephrine from the vesicles

Binding of NE to a receptor

The neurotransmitter Norepinephrine binds to the postsynaptic receptor to elicit an effect or response

Removal of Norepinephrine

3 fates of NE

1. Diffuse out of the synaptic space and enter the systemic circulation

2. Be metabolized to inactive metabolites by catechol-O-methyltransferase (COMT) in the synaptic space followed by oxidation of monoamine oxidase (MAO)

3. Undergo reuptake back into the neuron

Adrenergic / Adrenomimetics / Sympathomimetics

Mimics the effects of endogenous cathecholamines

Adrenergic / Adrenomimetics / Sympathomimetics

Derived from B-phenylethylamine

Adrenergic / Adrenomimetics / Sympathomimetics

3 Classes (MOA)

1. Direct acting sympathomimetics

- Adrenoceptor activation: drug binding to receptor

2. Indirect-acting sympathomimetics

- drugs enhancing level of NE for binding - mechanisms

▪ Enhance exocytosis

▪ Inhibit reuptake

3. Mixed acting sympathomimetics

- Direct + Indirect (enhancing exocytosis)

Adrenergic / Adrenomimetics / Sympathomimetics

In general: for the management of hypotension except alpha 2 agonist and d1 agonist (fenoldopam)

which is used for hypertension

Adrenergic / Adrenomimetics / Sympathomimetics

Natural catecholamines do not cross the blood-brain barrier, but mixed-acting sympathomimetics does, eliciting CNS effects – increased alertness, appetite suppression, elevated mood, tremors, and potential for abuse.

Direct acting sympathomimetics

Adrenoceptor activation: drug binding to receptor

Indirect-acting sympathomimetics

drugs enhancing level of NE for binding - mechanisms

▪ Enhance exocytosis

▪ Inhibit reuptake

Mixed acting sympathomimetics

Direct + Indirect (enhancing exocytosis)

Adrenomimetics, Sympathomimetics

Other name for Adrenergic

Direct Acting

Nonselective: activate more than 1 sympathetic receptor (alpha and beta)

b. Selective: bind and activate only 1 sympathetic receptor (alpha or beta)

Nonselective

activate more than 1 sympathetic receptor (alpha and beta)

Selective

bind and activate only 1 sympathetic receptor (alpha or beta)

Nonselective direct acting

Endogenous catecholamines: Epinephrine, Norepinephrine, Dopamine

Nonselective direct acting

High potency at adrenoreceptors

Nonselective direct acting

Higher affinity in beta than alpha

- beta effect at low dose

- alpha effect at high dose

Epinephrine

B1=B2 >>> a1

• Only with activity at B2 = only bronchodilating endogenous

Norepinephrine

B1 > a1

Dopamine

D1 > B1 >> a1

- D1: enhance renal vasodilation

Polar/hydrophilic - impermeable BBB = no CNS effects

Dopamine

Extensively metabolized by MAO and COMT

- low oral bioavailability: no oral preparation

- has short duration of action

Epinephrine/Adrenaline

1st line cardiac stimulant

Epinephrine/Adrenaline

1st line agent in the treat of anaphylactic shock (hypotension - shock caused by allergy)

Epinephrine/Adrenaline

1st line agent for:

• Anaphylaxis

  • increase histamine = bronchoconstriction

  • IgE mediated

• Anaphylactoid reaction

  • increase histamine = bronchoconstriction

  • Non IgE mediated; drug induced

  • can be caused by: Morphine, Tubocurarine

Epinephrine/Adrenaline

Local vasoconstrictor - combined with lidocaine = enhanced local anesthesia of lidocaine and minimize bleeding

Epinephrine/Adrenaline

For glaucoma

• Dipivefrin: prodrug of EPI, pivalic acid ester of EPI

Anaphylaxis (Epinephrine/Adrenaline)

• increase histamine = bronchoconstriction

• IgE mediated

Anaphylactoid reaction

• increase histamine = bronchoconstriction

• Non IgE mediated; drug induced

• can be caused by: Morphine, Tubocurarine, Guanethedine

Dipivefrin

prodrug of EPI, pivalic acid ester of EPI

Norepinephrine/Noradrenaline/Levarterenol

1st line for septic shock (caused by infection)

Dopamine

Alternative for septic shock, and cardiogenic shock (caused by HF)

Dopamine

Management of acute HF with complication of oliguria and anuria (low urine output)

Selective direct acting Alpha agonist

Alpha1 agonist = constrictor drugs

• Phenylephrine, Methoxamine

• Propylhexedrine

• Tetrahydrozoline, Oxymetazoline, Nafazoline

Alpha1 agonist

• Phenylephrine, Methoxamine

• Propylhexedrine

• Tetrahydrozoline, Oxymetazoline, Nafazoline

Drixine

Oxymetazoline nasal spray

Effects of alpha 1 agonist 1 (Local)

Intranasal → Decongestant

▪ Oxymetazoline nasal spray (Drixine)

Eye drops → treatment of red eyes

▪ Tetrahydrozoline eye drops (Eye Mo Red)

Eye Mo Red

Tetrahydrozoline eye drops

Phenylephrine eye drops

mydriatic in eye examination = for full view of the retina

Mydriasis

Phenylephrine eye drops - mydriatic in eye examination = for full view of the retina

Toxic effects of alpha 1 agonist 1

a. Local

• Intranasal: Rhinitis medicamentosa = rebound congestion if used more than 3 days

b) Systemic

• increase blood pressure

• urine retention

Antiglaucoma agents

Apraclonidine, Brimonidine

Antihypertensive agents

Methyldopa, Clonidine, Guanfacine, Guanabenz

METHYLDOPA

Prodrug → amethylnorepinephrine – false NT

METHYLDOPA

Aldomet®

METHYLDOPA

For HTN emergency

METHYLDOPA

Sedation

Hepatotoxicity

(+) Coombs Test

→ (+) Hemolytic Anemia

CLONIDINE

Catapres®

CLONIDINE

Initial: increase in BP

(transient)

Final: decrease in BP

CLONIDINE

For HTN crisis

CLONIDINE

Withdrawal

Rebound HTN

Nonselective beta agonist

Ex. Isoproterenol/Isoprenaline

• alternative agent during shock

• alternative in the management of acute heart failure

Dobutamine

- Diagnosis: for pharmacologic stress test

- Treatment: 1st line treatment for the treatment of cardiogenic shock

- Used for management of acute HF

Beta2 selective agonist

Bronchodilators → for BA, COPD

Short-Acting Beta2 Agonists (SABA)

• Terbutaline – only SQ

• Albuterol (Salbutamol)

• Metaproterenol

• Pirbuterol

Long-Acting Beta 2 Agonists (LABA)

• Salmeterol - slow onset

• Formoterol - fast onset

• Indacaterol

• Bambuterol

Isoproterenol/Isoprenaline

alternative agent during shock

Isoproterenol/Isoprenaline

alternative in the management of acute heart failure

Dobutamine

Diagnosis: for pharmacologic stress test

Dobutamine

Treatment: 1st line treatment for the treatment of cardiogenic shock

Dobutamine

Used for management of acute HF

Short-Acting Beta2 Agonists (SABA)

• Terbutaline – only SQ

• Albuterol (Salbutamol)

• Metaproterenol

• Pirbuterol

Long-Acting Beta 2 Agonists (LABA)

Salmeterol - slow onset

• Formoterol - fast onset

• Indacaterol

• Bambuterol

Terbutaline

only SQ SABA

Salmeterol

slow onset LABA

Formoterol

fast onset LABA

Tocolytics

treatment of preterm labor, relax uterine smooth muscle

Tocolytics

• Isoxsuprine (Duvadilan)

• Ritodrine

• Terbutaline - off label for tocolytic

Terbutaline

off label for tocolytic

Toxic effects of Beta agonist

• Hypokalemia

• Ventricular tachycardia - due to overdose also activating Beta1

Releasers

enhance exocytosis of NE

Tyramine

has D/I with MAOI = increase NE = hypertensive crisis

Ephedrine

from Ma Huang

Amphetamine

alternative for ADHD

Modafinil

1st line agent for narcolepsy

Methamphetamine

Shabu

Methylphenidate

1st line agent for ADHD

Phenmetrazine

anorexiant

Phentermine

currently used for weight loss

Cocaine

only vasoconstrictor local anesthetic

Atomoxetine

alternative agent for ADHD

Sibutramine

used in management of obesity, discontinued in the Philippines due to unnecessary cardiovascular risks to patients

Phentermine

typically prescribed for short-term weight loss.

Orlistat (Xenical®, Alli®)

a fat absorption inhibitor that helps with weight management

Liraglutide (Saxenda®)

An injectable medication that regulates appetite and caloric intake.

Naltrexone-Bupropion (Contrave®)

A combination drug that works on the brain's hunger and

reward centers to reduce appetite.

Phenylpropanolamine

Treatment for nasal congestion

- Treatment for hypotension

- OTC appetite suppressants, but was removed from the market due to hemorrhagic stroke in

young women

Mephentermine, Metaraminol

used for hypotension

Indirect Acting Releasers

Tyramine - has D/I with MAOI = increase NE = hypertensive crisis

• Ephedrine - from Ma Huang

• Amphetamine - alternative for ADHD

• Methamphetamine - Shabu

• Modafinil - 1st line agent for narcolepsy

• Methylphenidate - 1st line agent for ADHD

• Phenmetrazine - anorexiant