adrenergic agonists and antagonists synchronous

pharm week 4 synchronous lecture

what sites of ANS use NE at NT?

Norepinephrine (NE) is primarily used as a neurotransmitter at postganglionic sympathetic neurons in the autonomic nervous system (ANS). Specifically, norepinephrine is released from postganglionic sympathetic nerve endings and acts on adrenergic receptors (alpha and beta receptors) at target organs to mediate the "fight or flight" response.

Key sites where norepinephrine acts as a neurotransmitter in the ANS:

• Postganglionic sympathetic neurons that innervate:

  • Blood vessels (causing vasoconstriction via alpha-adrenergic receptors)

  • Heart (increasing heart rate and contractility via beta-1 adrenergic receptors)

  • Bronchioles (causing bronchodilation via beta-2 adrenergic receptors)

  • Other organs like the liver, fat tissue, and gastrointestinal tract

However, it's important to note that sweat glands are an exception; although they are innervated by postganglionic sympathetic neurons, they use acetylcholine (ACh) instead of norepinephrine.

steps of adrenergic synapse

• Synthesis of Norepinephrine:

  • Tyrosine is transported into the presynaptic neuron.

  • Tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase.

  • DOPA is converted into dopamine by DOPA decarboxylase.

  • Dopamine is then transported into vesicles via the vesicular monoamine transporter (VMAT), where it is converted into norepinephrine by dopamine β-hydroxylase.

• Storage:

  • Norepinephrine is stored in synaptic vesicles within the presynaptic neuron.

• Release:

  • An action potential arrives at the presynaptic terminal, causing depolarization.

  • Voltage-gated calcium channels open, leading to an influx of calcium ions.

  • Calcium triggers the fusion of norepinephrine-filled vesicles with the presynaptic membrane, causing the release of norepinephrine into the synaptic cleft via exocytosis.

• Binding to Postsynaptic Receptors:

  • Norepinephrine binds to adrenergic receptors (alpha or beta receptors) on the postsynaptic membrane.

  • This leads to various physiological effects, such as increased heart rate, vasoconstriction, bronchodilation, etc., depending on the receptor subtype.

• Reuptake:

  • Norepinephrine is primarily removed from the synaptic cleft by reuptake into the presynaptic neuron through the norepinephrine transporter (NET).

• Metabolism:

  • Inside the presynaptic neuron, norepinephrine is either repackaged into vesicles or degraded by monoamine oxidase (MAO).

  • Norepinephrine in the synaptic cleft can also be degraded by catechol-O-methyltransferase (COMT).

• Termination of Signal:

  • Reuptake and enzymatic degradation ensure that the signal is terminated and prevent excessive stimulation of the postsynaptic cell.

Sites of Drug Action at the Adrenergic Synapse

• Synthesis Inhibition:

  • Drugs can inhibit tyrosine hydroxylase, preventing norepinephrine synthesis (e.g., Metyrosine).

• Vesicular Storage Inhibition:

  • Drugs like Reserpine block VMAT, preventing dopamine and norepinephrine from being stored in vesicles, leading to depletion.

• Release Modulation:

  • Agents like Clonidine (alpha-2 agonists) inhibit the release of norepinephrine by acting on presynaptic receptors.

  • Indirect sympathomimetics (e.g., amphetamine) increase NE release.

• Receptor Agonists/Antagonists:

  • Drugs can either stimulate adrenergic receptors (agonists) or block them (antagonists). For example:

    • Albuterol (beta-2 agonist) for bronchodilation.

    • Propranolol (beta-blocker) reduces heart rate by blocking beta-adrenergic receptors.

• Reuptake Inhibition:

  • Drugs like cocaine and some antidepressants (e.g., SNRIs) block NET, increasing norepinephrine levels in the synapse.

• Enzymatic Degradation Inhibition:

  • MAO inhibitors (MAOIs) prevent the breakdown of norepinephrine, prolonging its action.

• Autoreceptor Modulation:

  • Alpha-2 autoreceptor agonists like Clonidine inhibit norepinephrine release, while antagonists would promote it.

adrenergic receptors

alpha and beta

alpha receptors

alpha 1 and alpha 2

alpha 1

Gq (stimulatory/excitatory)

increase intracellular Ca2+

found in vascular smooth muscle throughout the whole body

can cause vasoconstriction, dilation of pupil (mydriasis), contraction of urinary sphincter (urinary retention), glycogenolysis, inhibition of renin release

alpha 1 causes

sympathetic response (Opposite of SLUDD)

alpha 2

Gi (inhibitory)

decrease intracellular cAMP

leads to inhibition of further release of norepi

can cause decrease in insulin secretion

beta receptors

beta 1, 2 and 3

beta 1

found in the heart

increase HR, cardiac contractility, AV node conduction

increase renin release→ results in increase in BP

beta 2

found in lungs

• bronchial smooth muscle

causes bronchodilation

found in vascular smooth muscle and arteries of skeletal muscles

• relaxation of BVs (vasodilation)

found in smooth muscle of GI tract and uterus

• decrease in GI motility

• inhibition of labor

found in the pancreas

• increase in insulin secretion

beta 3

found in adipose tissue

• increase lipolysis

found in urinary bladder

• relaxation of bladder

• prevention of urination

adrenal medulla is _______ epi and _____ norepi

80%; 20%

epinephrine

Epi

adrenaline

norepinephrine

NE

NorEpi

noradrenaline

inhibition by central presynaptic alpha 2 receptors

if too much norepi is present, alpha 2 will inhibit the release of norepi

alpha 2 auto receptors→ inhibitory

Gq

alpha 1

excitatory

increase contraction

Gi

alpha 2

inhibitory

reduces sympathetic activity

Gs

beta 1, 2, 3

stimulatory

mainly excitatory

B1 v. B2

B1

• found in the heart

• increase HR

• increase force of contraction

B2

• found in lungs and peripheral BVs

• vasodilation

• bronchodilation

alpha1

Gq

vascular smooth muscle

GU muscle (sphincter)

liver

vasoconstriction

increase in BP

contraction (urinary retention)

mydriasis (dilation)

glycogenesis and gluconeogenesis

alpha2

Gi

pancreatic beta cells

platelets

nerve (autoreceptor)

decrease insulin secretion

aggregation

decrease NE release, decrease BP, decrease ACh release

beta1

Gs

heart

kidney

increase HR and contractile force

renin release

beta2

Gs

smooth muscle

liver

skeletal muscle

relaxation

vasodilation

glycogenesis and gluconeogenesis

beta3

Gs

adipose

lipolysis

types of adrenergic receptors

alpha adrenoceptors

beta adrenoceptors

postsynaptic

alpha 1

presynaptic and postsynaptic

alpha2

equal affinity for Epi and Norepi

beta 1

affinity for epi>norepi

beta 2

catecholamines

epi, ne, dopamine

high potency

rapid inactivation by MAO and COMT

poor CNS penetration

amine nitrogen

noncatacholamines

phenylephrine, ephedrine, amphetamine

poor MAO substrate

not inactivated by COMT

better CNS access → increased lipid solubility

pseudoephedrine, amphetamine, methamphetamine

nasal decongestant

psychoactives

mechanism of adrenergic agonists

direct

indirect

mixed-action

direct adrenergic agonists

epi, norepi, isoproterenol, phenylephrine, albuterol, etc.

indirect adrenergic agonists

block NE reuptake (cocaine) or cause release of NE from cytoplasmic pools (amphetamine)

mixed-action adrenergic agonists

ephedrine and pseudoephedrine do both

adverse effect of adrenergic agonists

arrhythmias

headache

hyperactivity

tremors

nausea

insomnia

pseudoephedrine

alpha 1 agonist, non catecholamine

nasal decongestant

vasoconstriction

helps in relieving stuffy nose by vasoconstriction

WARNING: heart disease, high blood pressure, trouble urinating due to enlarged prostate → these conditions can act on alpha 1 and beta receptors and can cause worsening of symptoms

clonidine

alpha 2 agonist

acts in CNS

presynaptic and act as a break on NE release

leads to decrease NE release and decrease in BP and HR

an antihypertensive drug that lowers BP and HR by relaxing arteries and increase blood supply to the heart

albuterol

beta 2 agonist

use for relief of bronchospasm in pts with reversible obstructive airway disease

prevention of exercise-induced bronchospasm

can cause tachycardia bc alpha receptors are not blocked in this drug

epinephrine

alpha and beta agonist

increase mean arterial BP in adult pts with hypotension (septic shock)

treatment of acute anaphylactic shock

mydriasis (pupillary dilation) during surgery

causes increased BP

bronchodilation via beta 2

sympathetic effects on eye cause papillary dilation

WARNING: hypertension

• too much alpha 1 agonism can increase PVR and BP

• beta 1 agonism and elevate BP via increase HR and contractility

prazosin

alpha 1 antagonist (alpha blocker)

used for hypertension, CHF

decreased peripheral vascular resistance

decreased BP

WARNING: syncope bc peripheral BV vasodilation can cause syncope or postural hypotension

atenolol and propranolol

beta-1 antagonist (beta blocker)

atenolol→ use to manage hypertension

propranolol→ used to manage hypertension

atenolol→ beta 1 selective

propranolol→ non-selective (will cause bronchial smooth muscle contraction)

adrenergic antagonists

alpha blockers

beta blockers

alpha blockers

non-selective

selective alpha 1

beta blockers

propranolol (non selective)

atenolol (beta 1 selective)

non-selective alpha-adrenergic blocking agents

blockade reduces sympathetic tone

decrease peripheral vascular resistance

decrease BP

cause reflexive tachycardia

beta receptors are NOT blocked

drug targets alpha receptors

• vascular smooth muscle

• GU smooth muscle

adverse effect of non-selective alpha blockers

orthostatic hypotension

tachycardia

vertigo

sexual dysfunction

selective alpha 1 blockers

prazosin

tamulosin

no effect on alpha 2

no increase in NE, no increase in HR

CV effects: decrease in PVR, decrease in HR

treatment of hypertension

treatment of congestive heart failure

tamulosin

alpha 1 blockers

treatment of benign prostatic hypertrophy

relax smooth muscles of prostate gland and bladder neck → improve urine flow

tamulosin v. tolterodine

tamulosin→ bladder emptying

tolterodine→ increase bladder capacity, decrease bathroom trips

adverse effects of selective alpha 1 blockers

dizziness

nasal congestion

headache

drowsiness

orthostatic hypotension

lesser degree of reflex tachycardia

male sexual function is not as severely affected

beta-adrenergic blockers

-olols

lower BP in hypertension

used in tx of angina, cardiac arrhythmias, myocardial infarction, congestive heart failure, glaucoma

non-specific beta blockers

beta 1 and 2 blockers

cardio specific blockers

beta 1 blockers

beta blocker

occupy the receptor

prevent effects of catecholamines and other beta agonists

most are pure antagonists

cardiovascular effects of a beta blocker

reduce contractility

reduce HR

reduce release of renin

decrease cardiac output

decrease PVR and BP

effects of beta blockers on respiratory tract

block of B2 receptors in bronchial muscle → increase airway resistance

caution in asthma B1 specific blockers

B1 specific blockers

metoprolol

atenolol

no impact on the lungs

effects of beta blockers on the eye

decrease intraocular pressure via decrease in aqueous humor production

useful in glaucoma

effects of beta blockers on metabolism

propranolol (non-specific blocker) inhibit sympathetic stimulation of lipolysis

dangerous in type 2 diabetes pts

insulin + beta blocker

may lead to pronounced hypoglycemia

propranolol (non-selective)

CV→ decrease HR, force of contraction, cardiac output

Peripheral→ prevents B2 mediated vasodilation

Bronchoconstriction

glucose metabolism→ decrease glycogenolysis, glucagon

therapeutic uses of propranolol

hypertension

migraines

angina pectoris

MI

hyperthyroidism

performance activity

adverse effects of propranolol

bronchoconstriction

arrhythmias

metabolic disturbances

CNS effects

selective beta 1 blockers

atenolol

cardio selective beta 1

to avoid unwanted bronchoconstrictor effects (from B2)

lowers BP in hypertension