Adrenergic Agonist Eliud

Question 1

What is the most common treatment of adrenergic drugs?

Answer 1

-Asthma
-Hypertension
-Common Cold Symptoms

Question 2

Which neurotransmitter is at the terminus of the sympathetic nervous system?

Answer 2

Norepinephrine

Question 3

Which neurotransmitter is synthesized mainly in the adrenal gland?

Answer 3

Epinephrine

Question 4

Describe the Biosynthesis of Norepinephrine

Answer 4

1. L-Tyrosine enters the presynaptic neurons via active transport and oxidize it though Tyrosine Hydroxylase to form L-DOPA (rate-limiting step).
2. L-Dopa decarboxilation by Dopa decarboxylase to produce Dopamine which are stored in vesicles.
3. Dopamine is oxidized by Dopamine-B-Hydroxylase to form Norepinephrine.

Question 5

Storage and Release of Norepinephrine

Answer 5

-95% is reuptake through a transporter.
-Alpha 2 inhibits NE release
-NE can be metabolized through MAO or COMT

Question 6

True or False: El metabolismo de Norepinefrina crea un metabolito inactivo bien hidrofilico para excretar.

Answer 6

True

Question 7

Alpha 1 Receptors

Answer 7

Predominantly postsynaptic found in vascular smooth muscle and the CNS

Question 8

Alpha 2 Receptors

Answer 8

Stimulation inhibits NE release

Question 9

Beta 1 Receptors

Answer 9

Found in myocardial. Stimulation increase heart rate and force of contraction.

Question 10

Beta 2 Receptors

Answer 10

Found in lungs, vascular smooth muscle, skeletal muscle, and uterus. Stimulation results in dilation or relaxation of these tissues.

Question 11

Adrenergic Receptors: Asp 113

Answer 11

La más importante ya que está con carga negativa lo que ayuda a atraer el nitrógeno positivo de NE creando un enlace ionico.

Question 12

Adrenergic Receptors: Ser204 and Ser207

Answer 12

Reconoce a los OH de anillo aromático

Question 13

Adrenergic receptors: Phe290

Answer 13

Interactúa con el grupo fenol por van der waals

Question 14

Adrenergic Receptors: Asn293

Answer 14

Puentes de hidrógeno con el OH del carbono B que tiene que está en conformación R para ser reconocido.

Question 15

What is the base structure of Phenylethylamine Adrenergic Agonist?

Answer 15

Benzenediol structure. NH2 al final luego de dos carbonos entremedio.

Question 16

R1 amine substituent (bind to NH)

Answer 16

Un grupo funcional voluminoso le dará mayor selectividad a los beta.

R1 Methyl: mayor selectividad a beta pero puede enlazarse a alpha

R1 i-propyl, t-butyl, or aralkyl: Too bulky for alpha receptor therefore high affinity for Beta. Butyl prefers B2

Question 17

R2 alpha-carbon substituent (en el carbono alpha)

Answer 17

Conformación S = acción directa
Confirmacjon R = acción indirecta

Vulnerable to MAO

R2 methyl: more selective to alpha 2 than 1

R2 ethyl: more selective to beta 2

Question 18

R3 Beta carbon substituent (en el carbono beta)

Answer 18

R3 OH: necessary for Beta receptor binding (Beta 2). A slow CNS penetration.

R3 H: Direct action decrease but indirect is maintained. Crosses BBB with no problem.

Question 19

Aromatic Substituents

Answer 19

3’ and 4’ OH: Catecol vulnerable to COMT therefore poor oral activity. Direct action to all adrenoreceptors and no cruza BBB

monophenol: OH in 3’ direct activity at alpha 1 receptors. OH in 4’ direct action at Beta receptors.

No substituents: cross BBB, direct action decrease. Mainly indirect action.

Question 20

Other patterns for aromatic substituents

Answer 20

A small H bonding in 3’ and an OH in 4’ plus t-butyl or bulky substitutes in R1 can have a Beta 2 affinity. Resistant to COMT.

An OH in 3’ and 5’ plus t-butyl or bulky substitutes in R1 can have a Beta 2 affinity. Resistant to COMT.

Question 21

Physicichemical Properties of Phenylethylamine Adrenergic Agonist

Answer 21

-Can be amphoteric (act as a base or acid)
-Different LogP
-Beta OH present and no Alpha CH3 is
more hydrophilic
-If no OH groups, more lipophilic

Question 22

Norepinephrine and Epinephrine Clinical Applications

Answer 22

-Non-Selective
-Alpha activity use for hypotension crisis
-Beta activity used for cardiac arrest
-Epinephrine is better for anaphylaxis because is a Beta 2 agonist.

Question 23

Selective Alpha 1 Adrenergic Agonist (La 1 PM)

Answer 23

Phenylphrine and Metaraminol have longer duration than NE and are vasoconstrictors for hypotensive crisis and nasal decongestant.

Question 24

Short acting Selective Beta 2 Adrenergic Agonist (TerMeLevPir)

Answer 24

Terbutaline, Metaproterenol, Levalbuterol, Pirbuterol

Bronchodilators for asthma and COPD

Question 25

Long acting Selective Beta 2 Adrenergic agonist (ay Fo Sal Ino Olo)

Answer 25

Al ser lipofilicos y tener grupo voluminosos, se ancla al receptor dándole el efecto de larga duración.

Formoterol: Faster onset than Salmeterol. Bulkiness makes both long acting
Salmeterol: treatment for severity of asthma attacks.

Indacaterol and Olodaterol are used as bronchodilators

Question 26

Arylimidazoline Adrenergic Agonist (SAR)

Answer 26

Estructura similar a phenylethanolamine pero tiene un anillo de imidazol.

En el carbono beta puede ser CH2 (selectivo alpha 2) or NH (selectivo Alpha 1)

Los grupos R voluminoso en el anillo fenol le da lipofilicidad y mayor afinidad a los receptores alpha pero si existe el grupo R3 es más selectivo a alpha 1

Question 27

Arylimidazoline Alpha 1 Agonist (carbono Beta = CH2)

Answer 27

Xylometazoline, Oxymetazoline, Tetrahydrozoline, and Naphazoline

Question 28

Clonidina

Answer 28

Arylimidazoline Alpha 2 Agonist
-Treat Antihypertensive, ADHD, Glaucoma, and Nicotine and opioid withdrawal.

-Ionizado es como se queda en la periferia y no ionizado cruza el BBB

Question 29

Arylimidazoline Alpha 2 Agonista

Answer 29

Apraclonidine: Glaucoma
Brinonidine: Glaucoma
Tizanidine: Espasmos muscular
Guanabenz (doble enlace de N) y Guanfacine (no doble enlace): Antihipertensivo
Methyldopa: prodroga antihipertensiva (metabolito no cruza BBB)