Sympathetic transmission and Adrenergic Receptor (Drugs)

Beleh Slides

Describe the Adrenergic System

1. Neurotransmitter

   • Difference in chemical structure

2. Receptor Subtypes

3. Termination

4. Metabolism

1. Norepinephrine and Epinephrine from adrenaline medulla

   • CH3 in Epi and H in NE

2. Alpha receptor: alpha 1 and 2 ; Beta receptor: beta 1,2,3

3. Reuptake back into the nerve terminal —> different from ACh

4. Metabolism by Monoamine oxidase (MAO) and cathechol-O-methyl transferase (COMT)

Describe the steps of adrenergic transmission:

1. uptake of tyrosine—> precursor for catecholamines in nerve terminals

2. biosynthesis of NE:

   • L-Tyrosine—(tyrosine hydroxylase)—> DOPA ——(DOPA carboxylase)→ Dopamine—(Dopamine B-hydroxylase)—> NE

     • Dopamine to NE happens within the storage vesicle

3. Release of NE from vesicles via exocytosis, which is caused by Ca2+ influx after depolarization of neuron

1. NE action at post synaptic adrenergic receptors or at presynaptic adrenergic autoreceptors (alpha 2)

2. Internal: NE reuptake into presynaptic neuron via Norepinephrine Transporter —> metabolized via mitochondrial MAO

3. External: NE diffuse out to general circulation and metabolized by COMT

SAR for adrenergic agent (NE, E, Dopamine)

Basic Amine required for binding

• R1 on nitrogen: larger alkyl group increase specificity to beta receptor and smaller groups increase specificity for alpha receptor

  • Bulky: iPr>Me>H

  • Small: H>Me>iPr

• H: must be a hydrogen; tertirary amine shows decreased activity due to steric hinderance.

R2 on alpha carbon: small (H or Me) is required. A methyl substitution—> slow down MAO metabolism

• beta carbon: hydroxyl is required for maximal binding: R>S

R3 on Benzene: 3,4 di-OH> 3-OH> 4-OH

• a benzene right shows best activity

A two-atom side chain is required between the terminal amine and the aromatic ring

NE binding interactions with a1 adrenergic receptor

1. the basic amine or positively charged amine (NHR) forms a salt bridge

2. the phenyl ring forms pi-pi interactions

3. the para-catechol forms a hydrogen bond

4. the meta-catechol does not participate

5. the beta hydroxyl forms a hydrogen bond

NE binding interactions with alpha 2 & beta adrenergic receptor : different from a1

1. the basic amine or positively charged amine (NHR) forms a salt bridge

2. the phenyl ring forms pi-pi interactions

3. the meta & para-catechol forms a hydrogen bond

4. the beta hydroxyl forms a hydrogen bond

Norepinephrine

• agonist (admin route)

• agonist: alpha 1 receptor (vasoconstriction), beta 1 receptor (positive inotropic effect)

  • admin route: IV infusion to counteract acute hypotensive state: make low BP to high BP after heart transplant, shock or cardiac arrest

  • Short acting but can terminate effect quickly. 

Epinephrine

• agoinst

  • admin

• agoinst: alpha 1 receptor, beta 1 receptor (positive inotropic effect), beta 2 receptor (bronchodilation)

  • anaphylaxis (epipen and nasal spray), temporary relief in asthma (inhaler), and as adjunct with local anesthetic (injection)—> how vasoconstriction makes it local

Dopamine

• its selectivity on receptor is

• Low

• Intermediate

• High

• usage:

• Suprising fact:

• Dose dependent

• Low dose: dopaminergic receptor (vasodilation)

• Intermediate dose: elective at the B1 receptor (tachycardia)

• High dose: activate alpha receptor (vasoconstriction)

• Shock and to increase renal perfusion & Heart failure

• in epithelial cells: Has specific actions in kidney at low doses: Vasodilatation; ↑ Glomerular filtration rate, ↑ Na excretion, ↑urine 

What are the alpha 1 adrenergic agonist?

• main action & usage

Phenylephrine and Midodrine (prodrug)

• peripheral vasoconstriction

  • midorine —> orthostatic hypotension (BP downs on standing)

    • active drug after releasing the amine (H2N-C=O)

  • phenylephrine—> nasal decongestant but ineffective; Pupillary dilation and glaucoma 

• act similarly to NE and Epi

SAR of alpha 1 adrenergic agonist that is imidazolines

1. imidazoline in place of the basic amine

2. single carbon link between aromatic and imidazoline

3. Ortho substituent R1 must be lipophilic and an aromatic ring is required

4. Bulky lipophilic meta and/or para substituents (R2) improve alpha 1 selectivity and form hydrophobic interaction

What are alpha 1 adrenergic agonists that are imidazolines?

• main action

• peripheral vasoconstriction

  • Xylometazoline: nasal decongestants

  • Tetrahydrozoline: eye drops and nasal spray

SAR of alpha 2 adrenergic agonist imidazolines

1. imidazoline in place of the basic amine forms salt bridge

2. single carbon link between aromatic and imidazoline

3. Ortho substituent R1 must be lipophilic and an aromatic ring is required—> at least one or 2 ortho Cl, Br, or methyl group is essential to create a twist in the molecule then bind

4. the two rings forms pi-pi interaction

What is alpha 2 adrenergic agonists that are imidazoline

• usage

• adverse

Clonidine (Beer’s List)

• treat hypertension

• ER table—> ADHD

• epidural solution—> post operative or cancer related pain = sedation effect

Tizanidine

• muscle spasticity associated with multiple sclerosis and spinal cord injury

• DDI: CYP 1A2 inhibitor

Dexmedetomidine

• adjunct to general anesthesia and for sedation in intubated patients in ICU unites

• reduce agitation in biplor disorder and schizophrenia

Adverse Effect

• drowsiness, confusion, fatigue

• do not use with other CNS depressants

• avoid sudden withdrawal of these agenst due to the risk of developing CNS adverse effects plus a rapid rise in catocholamines levels and in blood pressure

What is alpha 2 adrenergic agonists that are phenylethanolamines 

• mechanism

α-Methyldopa (binds similary to E, NE)

• It is transported to the CNS via an aromatic amino acid transport system due to hydrophilic group (-COOH)

• Methyldopa →decarboxylated and hydroxylated to alpha methyl NE= fake NE in the brain → turns down sympathetic tone → lowers BP (pregnancy-safe)

  • fake NE —> Metabolized mainly by COMT (minimal MAO metabolism).

SAR of beta adrenergic agonist- phenylethanolamines

• bulky groups (-CH3) on amine —> specific to beta receptors

  • higher branched & bulk —> better beta 2 specificity

• Non-cathecol hydroxl group on the aromatic chain in albuterol and terbutaline improve beta 2 specificity

**specificity is relative term

what is beta 1 adrenergic agonist that is phenylethanolamine?

what is beta 2 adrenergic agonist that is phenylethanolamine?

what is beta nonselective adrenergic agonist that is phenylethanolamine?

dobutamine, albuterol, isoproterenol,

Dobutamine

• acts on specifically to

• used

• specific to heart due to

• beta 1 receptor

• in critical care by IV infusion as it suffers from first pass effect due to the formation of the 3 methoxy metabolites via enzyme COMT

• racemic mixture: the s isomer is beta 1 and alpha 1 agonist, while the r isomer is alpha 1 antagonist and beta 1 agonist —> net: beta 1 agoinst

Isoproterenol

• Receptor

• Used for

• nonselective beta agonist

• bronchospasm during anesthesia, as adjucnct therapy in cardiac arrest, heart block, and hypotension due to shock.

Albuterol

• receptor

• used for

• administration route

• short acting beta 2 adrenergic agonist

• used in acute treatment in asthma, prophylaxis, especially induced asthma

• used orally, via inhaler or nebulizer

  • inhaler fast onset but better specificity to bronchi but relative short duration of action

what is long acting beta 2 adrenergic agonist?

• used for

  • What is its nature?

  • How?

• BBW

salmeterol

• used in combination with inhaled corticosteroid (ICS) in asthma and COPD

  • lipophilic nature

  • when the receptor is activated by albuterol at first, its long chain anchors onto another pocket within the receptor via a hydrogen bond, pi-pi, hydrophobic bond.

• use of this without concomitant use of ICS increase the risk of asthma-related death

What is selective beta 3 adrenergic agonist?

Mirabegron:

• overactive bladder

• on the kid’s list

• bind in a perpendicular: salt bridge between the amine, aromatic ring—> pipi bond, beta hydroxyl group and amine form additional hydrogen

What is mixed acting antagonist?

• what are their direct and indirect effects & administration?

Ephedrine/Pseudoephedrine

• both direct and indirect effects

  • direct: agonist effect at alpha and beta; binding similar to norepinephrine and epinephrine

  • indirect: increase the release of norepinephrine from nerve terminals

• Ephedrine: CNS stimulant —> IV infusion to counteract hypotension or hypothermia associated with the use of anesthesia.

• Pseudoephedrine: very little or less CNS stimulant —> nasal decongestant effect and in allergic rhinitis.

What are indirect adrenergic agonists and their structural characteristics?

Amphetamine, Lisdexamfetamine, Phentermine

• lack the catechol and beta hydroxyl groups, lowering their receptor binding affinity

Amphetamine: centrally to reverse NET and inhibit VMAT and may affect other neurotransmitters. It is used in ADHD and narcolepsy 

Lisdexamfetamine= prodrug—> cleave (N-C=O)

Phentermine is used in obesity 

How does indirect agonists work

increase level of NE and other monoamines

What are other indirect agonists

Other indirect agonists include MAO inhibitors and COMT inhibitors, NRI and SNRI (NRI = Norepinephrine Reuptake Inhibitors), which are used in different CNS-related disorders such as ADHD, narcolepsy, Parkinson’s disease and major depressive disorders. 

This is how amphetamine mainly affects NET

reverse NET by accumulating NE in cytosol by replacing it from the vesicle

This is an advantage of using non-catechol containing agents in adrenergic agonists.

What is resistance to COMT metabolism? Or improve selectivity

•These are the two factors that affect mean arterial pressure.

What are cardiac output and peripheral resistance?

•The difference between initial effect of administering epinephrine and norepinephrine on heart rate.  Reason.

Drug	Initial HR effect	Why
Epinephrine	↑ HR	β1 ↑ HR + β2 vasodilation → no strong reflex
Norepinephrine	↓ HR	α1 ↑ BP → baroreceptor reflex bradycardia

•This is the structural change to adrenergic agents more specific to β₂-receptors.

What is substitution of a t-Bu group on the amine?

This is an additional substituent that leads to long-acting β₂ agonists.  Reason.

What is long chain on the amine? Additional binding (anchoring) —> 3 bindings

This is an advantage, beside providing a twist, that the chlorines provide in clonidine.

What is increased lipophilicity?

I am a prodrug of amphetamine primarily used to avoid dependence.

What is lisdexamfetamine?

The effect of adrenergic stimulation in uterine smooth muscles and receptor involved

What is contract and α₁ and relaxation and β₂?

The effect of adrenergic stimulation in eye radial and receptor involved.

What is contraction (causing pupil dilation and mydriasis) and α₁