Sympathomimetics

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Drugs which mimic the action / effects of stimulation of the adrenergic nerve terminal are called sympathomimetics.

Phenylethylamine can be considered as the parent compound from which sympathomimetic drugs are derived. It consists of a benzene ring with an ethylamine side chain. Addition of OH- at the carbon 3 & 4 position converts it into Catechol that is Catecholamine.

 

Catecholamines—compounds that contain Catechol ring. Natural Catecholamines are adrenaline and nor-adrenaline. Catecholamines cannot be given by mouth. Adrenaline, Nor-adrenaline, Dopamin, Isoprenaline etc

 

Non-catecholamine—can be given by mouth. Dobutamine, Amphetamine, Salbutamol, Ephedrine, Tyramine.

 

*** Catecholamines cannot be given orally because 2 enzymes are responsible for destruction of these—COMT (Catechol-ortho methyl transferase) and MAO (mono-amine oxidase).

COMT is present in the GIT, which causes degradation of the Catechol ring.

*** Catecholamines cannot cross the BBB

 

Classification of the sympathomimetic drugs—

Directly acting drugs—

Non-selective—

o  Adrenaline (α, β1, β2)

o  Nor-adrenaline (α, β1)

o  Isoprenaline (β1, β2)

o  Dopamine (α, β1, D1, D2)

 

Selective—

o  α1—Phenylephrine

o  α2—Methoxamine

o  β1—Dobutamine

o  β2—Salbutamol

Indirectly acting—

Amphetamine

Tyramine

Metaraminol

 

Mixed acting—

Ephedrine

(directly acts on the β2 receptor of the bronchial smooth muscle and also releases nor-adrenaline from nerve endings)

 

 

Adrenaline—

 

Pharmacological effects of the Adrenaline—

On the CVS—

On heart—

Heart mainly contains β1 receptors, activation of the β1 receptor causes—

↑ Heart rate ( with the stimulation of the β1 of SA node)

↑ AV conduction (with the stimulation of the β1 of the AV node)

↑ The force of contraction and ↑ CO (with the stimulation of the β1 of the blood vessels)

On blood vessels—

 

 

Blood vessels contains α1 and β2 receptors—

α1 stimulation causes vasoconstriction and ↑ BP

β2 stimulation causes vasodilatation and ↓ BP

(so whether the PR will ↑ or ↓ depends upon the number of receptors of each type present in the vessels. In splanchnic nerves PR ↑ as the α1 are more and in skeletal muscle vessels the β2 is more and PR ↓. So as α1 are more in total body ultimately the PR ↑)

§    Cerebral blood vessels are not affected by adrenaline

§    Pulmonary blood vessels may develop slight vaso-constriction as true arterioles are absent.

§    Coronary blood vessels contain α1 and also β2 receptors. Adrenaline indeed causes direct vaso-constriction but it also causes ↑ myocardial contractility, ↑ HR and thus ↑ O2 demand, producing a local hypoxia which, in turn dilates coronary arteries. (via AMP)

On blood pressure—

↑ Chiefly systolic pressure, diastolic pressure is not sharply altered { because diastolic pressure which is due to ↑ PR is subjected to two opposing factors—1.general arteriolar constriction of peripheral vasculature (α1), 2. dilatation of the skeletal muscle arterioles due to vascular smooth muscle relaxation (β2)}

 

*** Adrenaline is a very potent vasoconstrictor and cardiac stimulant.

*** Adrenaline can act on α, β1 and β2 receptors.

*** Nor-adrenaline mainly acts on α1 but also β1.

*** Isoprenaline is an extremely potent β-receptor (β1 and β2) agonist.

 

On smooth muscle—

1. smooth muscle of the arterioles relaxes / β2

2. smooth muscle of the GIT relaxes / β2

3. Smooth muscle of the bronchial tree relaxes / β2

4. Detrusor muscle of the bladder relaxes / β2

5. Smooth muscle of the sphincter of the bladder constricts / α1

6. Uterine smooth muscle relaxes in the late pregnancy

 

On eye—

α1 receptor agonist drugs activates radial pupillary dilator muscle and causes mydriasis, they are also believed to ↑ the outflow of the aqueous humor. β1 stimulation leads to rise in aqueous humor production.

 

On Respiratory tract—bronchial smooth muscle contains β2 receptors. Sympathomimetics stimulate the β receptors and causes bronchodilatation. (Adrenaline, Isoprenaline, Ephedrine)

 

On Metabolism—

§    Sympathomimetics activate the β3 receptors in fat cells and causes lipolysis.

§    They activate β2 receptors in the liver and enhance glycolysis.

§    They activate the β2 receptors and promote the uptake of K+ into the cells.

 

Adrenaline administration produces hyperglycemia by several mechanism—

a. Adrenaline causes glycogenolysis in both liver and muscle, end product in liver is glucose and in muscle is lactic acid. Adrenaline stimulates the enzyme phosphorylase.

b. It ↓ insulin secretion by stimulating the α1 receptors of the β cell, it also ↑ the insulin secretion a little bit by stimulating the β2 receptor but α1 stimulation is stronger.

c.  It ↑ the secretion of glucagon by stimulating the β receptors of the α cells of islets of langerhans.

d.Glucose uptake by the peripheral tissue is inhibited.

 

On genitor-urinary tract—the human uterus contains α and β2 receptors. β2 receptor activation causes uterus relaxation. The bladder base, urethral sphincter contain α receptor, the activation of which promote urinary continence.

It also stimulates the β1 receptor of the myoepithelial cells of the juxtra-glomerular apparatus and thus ↑ the production of Renin. As a result the rennin-angiotensinogen pathway is activated and ↑ BP.

 

Selective β2 agonist—Salbutamol (Albuterol), Terbutalin, Salmeterol.

 

Nor-adrenaline—

§    They are not used therapeutically.

§    Nor-adrenaline is secreted from the—

a. Postganglionic sympathetic nerve endings

b. From some nor-adrenergic nerves of the brain.

c.  From the supra-renal medulla.

*** normally the ratio between adrenaline and nor-adrenaline secretion is 4:1

 

Dopamin—it is a catecholamine. Dopaminergic nerves are present in the brain, where they are concerned with certain psychiatric disorders. Beside this in the ANS dopamine may be a neurotransmitter, where it behaves somewhat funnily—

1. in low dose dopamine binds with the dopamin receptors and acts as a agonist of the dopamin receptors.

2. in moderate dose dopamin acts as a agonist of the β1 receptors.

3. in higher doses dopamin acts as a agonist of the α1 receptors.

Dopamin has several receptors but dopamin A1 and A2 are well known. DA1 is present in the blood vessels, particularly in the renal, mesenteric and coronary arteries. Stimulation causes vasodilatation.

§    In low doses DA1 stimulation leads to renal vasodilatation thus improve renal blood flow and ↑ GFR. So dopamin is popularly used in cardio-vascular shock.

§    In moderate dose it stimulates the β1 receptors of heart muscle leading to ↑ HR, ↑ contraction, ↑ CO and ↑ systolic BP.

§    In higher doses stimulation of the α1 receptor of the peripheral smooth muscle arterioles and ↑ diastolic BP.

 

Clinical use of sympathomimetics / Catecholamines—

Adrenaline—

1.  Bronchial asthma—adrenaline working on the β2 receptors of the smooth muscle of the bronchus activates C-AMP which ↓ the Calcium level→ dilatation of the bronchus (effective in status asthmaticus)

2.  Nasal congestion

3.  Local haemostasis

4.  Combination with the local anesthetics to prolong the action

5.  Anaphylactic shock—in serious type-1 allergic reaction, Adrenaline is used. (penicillin may cause the allergy)

6.  Sudden cardiac shock

7.  Hypovolumic shock (Dopamin and Dobutamine are more effective)

8.  Hypoglycemic shock—diabetic patients who intake too much insulin. Adrenaline ↑ the  glycogenolysis in liver.

 

Nor-adrenaline—not popular as therapeutic agent.

 

Dopamin—in some varieties of hypo-volumic shock, especially those with oligurea. Besides some cardiogenic and septic shock.

 

Adverse effects—sharp rise of hypertension, after IV injection. Cardiac arrhythmia.

 

Name of some drugs—

α1 agonist—Phenylephrin, Methoxamine.

α2 agonist—Clonidine, Guanfacidine, Guanabenz, Methyldopa.

Non selective β agonist—Isoprenaline.

β1 agonist—Dobutamine

β2 agonist—Salbutamol, Terbutalin, Iso-Etharine, Ritodrine.

Miscellaneous—Amphetamine, Ephedrine.