L6 Autonomic pharmacology：Adrenergic and Anti-adrenergic Drugs

Objectives

To understand the pharmacological effects
The mechanisms of drug action
Therapeutic applications of alpha and beta adrenergic agonists

Sympathetic nervous system

Fight or flight response results in:

Increased BP
Increased blood flow to brain, heart and skeletal muscles
Increased muscle glycogenolysis for energy
Pupil dilation

Sympathetic and Parasympathetic Effects on Body Tissues

Noradrenaline (NA)

Noradrenaline(NA) or norepinephrine(NE)

most postganglionic sympathetic fibers (Adrenergic fibers)

1. Noradrenaline VS Adrenaline

Noradrenaline is the main neurotransmitter of the sympathetic nerves in the cardiovascular system.

Adrenaline is the main hormone secreted by the adrenal medulla.

The sympathetic noradrenergic system plays major roles in tonic and reflexive changes in cardiovascular tone.

Adrenaline is a major determinant of responses to metabolic or global challenges to homeostasis.

Adrenaline responses to stressors are more closely linked to responses of the hypothalamic‐pituitary‐adrenocortical system than of the sympathetic nervous system.

The sympathetic noradrenergic system is active even when the individual is at rest and maintains tonic levels of cardiovascular performance.

2. Synthesis of Adrenaline and Noradrenaline

A catecholamine: an organic compound that has a catechol (benzene with two hydroxyl side groups at carbons 1 and 2) and a side-chain amine

3. NA synapse: synthesis, storage, release and regulation

4. Norepinephrine degradation

COMT is found in the gut and liver, so catecholamines are not active orally

5. Metabolism of NA

Norepinephrine transporter targeted by amphetamine and cocaine

amphetamine is a competitive antagonist,competitively binds the receptor
cocaine is noncompetitive antagonist,inhibit the receptor

Adrenoceptors

Adrenoceptors in the membranes of effector cells determine the physiological and metabolic effects of catecholamines.

Beta‐adrenoceptors mediate stimulatory effects of catecholamines on the rate and force of the heartbeat;

stimulation of vascular alpha‐adrenoceptors produces vasoconstriction and increases blood pressure, and stimulation of vascular beta‐adrenoceptors – especially beta‐2 adrenoceptors in skeletal muscle – produces vasodilation.

Catecholamines affect cardiovascular functions by actions at adrenoceptors on cardiovascular cells, in the nervous system,and in the kidneys

1. Signaling pathway of α1 receptor activation

α receptor: α1, α2
β receptor: β1,β2,β3

2. Signaling pathway of β and α2 receptor

3. Adrenoceptors: signaling

Sympathetic Responses

Stimulation

1. Effects of stimulation of α1 adrenergic receptors

2. Effects of stimulation of α2 adrenergic receptors

3. Effects of stimulation of β–adrenergic receptors

4. Different role of cAMP in Smooth and Cardiac Muscles

Review of functions of sympathetic nervous system receptors

Alpha 1—smooth muscle contraction

Alpha 2-negative feedback causes less norepinephrine to be released so BP is

reduced

Beta 1—increased heart rate

Beta 2—bronchodilation

Beta 3—actual site for lipolysis

1. Adrenoceptor Activating Drugs And Other Sympathomimetics

Sympathomimetics are drugs that partially or completely mimic the action of Epinephrine (E) Or Norepinephrine (NE)

Directly – acts on adrenergic receptor
Indirectly – stimulates the release Catecholamines (CA) from nerve ending

Classifications: the endogenous biogenic amines (NE, E, DA, ISO)

ephedrine and other vasocontractors
bronchodilators
CNS stimulants

Their effects can be predicted from the knowledge of:

The type of adrenergic receptor
Property for penetration into CNS
Receptor selectivity

Pharmacological responses of α and β–R agonists

1. Cardiovascular system

2. Eye

Mydriasis (radial pupillary dilator muscle of iris contains → receptors, → stimulation → muscle contraction → pupil dilation)

3. Respiratory tract

Bronchial smooth muscle: ß2 receptor → relaxation → bronchodilation

Upper respiratory tract mucosa: → receptors; → stimulants → decongestion

4. Gastrointestinal tract

Both α and ß stimulants induce the relaxation of GIT smooth muscle

ß receptor activation (smooth muscle cells) → hyperpolarization → relaxation

α stimulants act indirectly; reduce presynaptically the release of acetylcholine

5. Genitourinary tract

Human uterus (α and ß receptors). ß2 receptor stimulation → relaxation

Bladder base and urethral sphincter: α receptor → contraction → continence

Bladder wall: ß2 receptors → relaxation

Ejaculation is dependent upon normal α receptor activity

6. Exocrine glands

Salivary gland: increased secretion (mucinous rich saliva,)

Apocrine sweat gland (eg. palms of hands): α stimulants → sweat production ↑

7. Metabolic effects

Fat cells: ß3 receptor activation → increased lipolysis

Lipocytes: α receptor activation → inhibited lipolysis

Liver: ß2 & α1 receptor activation → glycogenolysis → blood glucose ↑

Skeletal muscle: ß1 receptor activation → glycogenolysis → lactate ↑

8. Endocrine function

Insulin secretion is stimulated by ß1 and inhibited by α2 stimulation

Renin secretion is stimulated by ß1 and inhibited by α2 receptors

Endogenous catecholamines: - norepinephrine, epinephrine, dopamine

Synthetic catecholamines: - isoproterenol

Substitutions:

On the amino group

Increasing the size of the alkyl group → increased ß and decreased α activity

On the benzene ring

Maximal α and ß activity is found with CAs (R1 and R2 = OH)
Absence of one or two -OH increases bioavailability
Absence of -OH groups increases lipid solubility (potential CNS effects)

On the α carbon

Substitution blocks the oxydation by MAO and prolongs the action

On the β carbon

Mostly hydroxyl except Dopamine; facilitates receptor activation and for storage in neural vesicles

Specific Sympathomimetic Drugs

Catecholamines Epinephrine (E, Adrenaline)

Acts on both α and ß receptors(low concentration -ß effects, high dose - α effect dominated

1. Effects on blood pressure

Low doses of E: BP ↓ (ß2 receptor stimulation → Vasodilatation, cAMP effect on endothelium)

Large doses of E: BP ↑ (α receptor stimulation → Vasoconstriction, Ca2+ effect on muscle)

Norepinephrine (NE, Noradrenaline)

NE is almost equipotent with E on ß1and α receptors but with little effect on ß2 receptors

1. Pharmacokinetics of Epinephrine and Norepinephrine

Poor absorption following oral administration (rapid conjugation and oxydation)

Slow absorption following subcutaneous administration → local vasoconstriction

Inhaled solutions are used in the disease of respiratory tract

They can be given intravenously

Metabolism in the liver (COMT and MAO); excretion in the urine

2. Chemistry and pharmacokinetics

Catecholamines:

Noncatecholamines:

Ephedrine: from TCM, 麻黄

Non-Catecholamines

1. Phenylephrine

Pure α receptor agonist, with long duration of action (not inactivated by COMT)

Direct acting sympathomimetic, its effects are similar to those of NE but less potent
Vasoconstriction, BP ↑, reflex bradycardia occurs after parenteral administration