Systemic Pharmacology

Drugs act on Sympathetic NS (adrenergic system)

Adrenergic Drugs (Sympathomimetics), adrenergic

agonists, or alpha- and beta-adrenergic agonists

Antiadrenergic Drugs (Sympatholytics), adrenergic

antagonists, or alpha- and beta-adrenergic blocking drugs

• Many therapeutic agents that alter Sympathetic NS function are used primarily for effects on the CVS and lungs. Drugs that alter CVS function are used to treat

hypertension, heart failure, angina pectoris, & other

disorder. Drugs affecting the lungs are used primarily for

asthma.

Dr. Utoor

Lecture 7: Neuropharmacology

16/12/2018

• The Sympathetic NS helps the body cope with external stimuli and functions during stress.

• The system has 3 main functions: Regulating the CVS Regulating body temperature Implementing fight-or-flight response.

• When we are faced with adversity – stressful situations, (such as danger, trauma, fear, hypoglycemia, cold, exercise, intense emotion, or severe illness). Sympathetic NS prepares the body for immediate reaction to a stressful conditions by

the following responses: • Increasing cardiac function – heart rate & BP • Diverting blood to skeletal muscles by shunting blood away from

the skin & viscera

• Increasing respiratory function by dilating the bronchi to improve oxygenation

• Dilating the pupils (perhaps to enhance visual acuity) • Increasing metabolism by mobilizing stored energy, thereby

providing glucose for brain and fatty acid for muscle. Dr. Utoor 16/12/2018

• Neurotransmitters for sympathetic NS are

Norepinephrine (NE) released by all postganglionic neurons

of the sympathetic nervous system.

Epinephrine (Epi) released by the adrenal medulla

Dopamine is very important transmitter in CNS & there is

evidences that it release by some peripheral sympathetic fibers.

• Receptors for sympathetic NS are Adrenergic receptors

Alpha-receptors

Beta-receptors

Dopamine receptors

Dr. Utoor 16/12/2018

There are three types of adrenergic receptors:

Alpha-receptors ( ) – alpha1 and alpha2 receptors.

Beta-receptors ( ) – beta1 and beta2 receptors.

Dopamine receptors

• Epinephrine can activate all alpha-receptors & beta-receptors but not

dopamine receptors.

• Norepinephrine can activate alpha1 & alpha2 & beta1 receptors but not

beta2 or dopamine receptors.

• Dopamine can activate alpha1, beta1 & dopamine receptors.

Dr. Utoor 16/12/2018

Adrenergic drugs or adrenergic agonists

• Drugs that stimulated sympathetic or adrenergic receptors and produce adrenergic effects similar to those produced by stimulation of the sympathetic NS (Sympathomimetics).

• Chemical characteristics of adrenergic agonists:

• Adrenergic agonists fall into two chemical classes

Catecholamines contain a catechol group & an amine group – ethylamine

Non-catecholamines contain ethylamine but no catechol group.

• (catechol group = benzene ring that has hydroxyl groups on two adjacent carbons – polar in nature)

• These compounds differ from each other in three important respects:Duration of action Oral usability & Ability to act in the CNS

Dr. Utoor 16/12/2018

Classification of adrenergic drugs based on adrenergic

receptor specificity:

Alpha1 adrenergic agonists

Alpha2 adrenergic agonists

Beta1 adrenergic agonists

Beta2 adrenergic agonists

Dr. Utoor 16/12/2018

Drugs Receptors

Ephedrine Epinephrine or Adrenaline alpha1, alpha2, beta1, beta2

Norepinephrine or Noradrenaline alpha1, alpha2, beta1

Phenylephrine - selective alpha1

Isoproterenol - less selective beta1, beta2

Dobutamine - selective beta1

Terbutaline - selective beta2

Dopamine alpha1, beta1, dopamine

Selectivity of adrenergic drugs Effect produced by an adrenergic drug depends on the type of receptor

activated. Some adrenergic drugs are nonselective, e.g., Epi., NE.,

dopamine. Other adrenergic drugs are less selective, acting on beta1

& beta2 receptors e.g., Isoproterenol. Some adrenergic drugs are

highly selective, acting on one receptors only e.g., Phenylephrine,

Dobutamine, Terbutaline.

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• Alpha1 adrenoceptors agonists: • E.g., Adrenaline , Noradrenaline, Phenylephrine, Ephedrine,

Dopamine.

• Activation of alpha1 adrenergic receptors elicits two responses that can

be of therapeutic use: Vasoconstriction and Mydriasis. Vasoconstriction is the response for which alpha1 agonists most often

employed.

Therapeutic application of alpha1 agonists include: 1. Hemostasis:

2. Nasal decongestion:

3. Adjunct to local anesthesia:

4. Elevation of blood pressure

5. Mydriasis:

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Adverse effects of alpha1 activation: • All of the adverse effects caused by alpha1 activation

result directly or indirectly from vasoconstriction.

Hypertension

Necrosis:

Bradycardia:

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Alpha2 adrenoceptors agonists:

• Alpha 2 receptors is presynaptic auto receptors. Their function

is to regulate transmitter release, NE binds to receptors causing suppression of further NE release.

• Peripheral alpha 2 receptors: there are no therapeutic applications related to activation of peripheral alpha 2 receptors. Furthermore, activation of these receptors rarely causes adverse effects of any consequence.

• Central alpha 2 receptors (CNS) are of great clinical significance. These drugs also called indirect acting antiadrenergic drugs.

• By activating central alpha 2 receptors, we can produce two useful effects: (1) reduction of sympathetic outflow to the heart and blood vessels – inhibit the release of NE and (2) relief of severe pain.

Dr. Utoor 16/12/2018

Beta1 adrenoceptors agonists: • All of the clinically relevant responses to activation of beta1

receptors result from activation of cardiac beta1

receptors. Activation of renal beta1 receptors is not

associated with either beneficial or adverse effects.

• E.g., Adrenaline ,Noradrenaline, Isoproterenol, Dopamine, Dobutamine, Ephedrine

Therapeutic application of beta1 adrenergic include: 1. Cardiac arrest:

2. Heart failure:

3. Shock:

4. Atrioventricular (AV)heart block: Dr. Utoor 16/12/2018

Adverse effects of beta1 adrenoceptors activation:

• All the adverse effects result from activation of cardiac

beta1 receptors

1. Overstimulation of cardiac beta1 receptors can produce

tachycardia (excessive heart rate) & dysrhythmias

(irregular heart beat).

2. Angina pectoris: Anginal pain occurs when oxygen supply

(blood flow) to the heart is reduced or insufficient to meet

the heart's oxygen needs.

Dr. Utoor 16/12/2018

Beta2 adrenoceptors agonists: • Therapeutic applications of beta2 agonists are limited to the

lung & uterus, including: Adrenaline, Isoproterenol, Terbutaline, salbutamol

1. Asthma: a chronic condition characterized by

inflammation & bronchoconstriction occurring in response

to a variety of stimuli.

2. Delay of preterm labor: activation of beta2 receptors in

uterus relaxes uterine smooth muscle.

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Adverse effects of beta2 adrenoceptors activation

1. Hyperglycemia (elevation of blood glucose): beta2

agonists can cause hyperglycemia by acting on the liver &

skeletal muscles to promote breakdown of glycogen into

glucose.

2. Tremor: is the most common side effect of beta2 agonists.

•

Dr. Utoor 16/12/2018

Dopamine adrenoceptors agonist

• Activation of peripheral dopamine receptors causes

dilation of the vasculature of the kidney.

• This effect exploited in the treatment of shock: by

dilating renal blood vessels, we can improve renal

perfusion and can thereby reduce the risk of renal

failure.

• Dopamine is the only drug available that can

activate dopamine receptors.

• Dopamine also enhances cardiac performance by

activating cardiac beta1 receptors, when given to

treat shock.

Dr. Utoor 16/12/2018

• Nursing consideration: • Epinephrine (adrenaline) - Prototype of adrenergic drugs • Preadministration Assessment Assess the patient’s condition in relation to disorders in which

Epinephrine are used. Epinephrine has multiple indications.

1. The major use is treatment of anaphylaxis.

2. control of superficial bleeding,

3. delay of local anesthetic absorption,

4. management of cardiac arrest.

5. Acute bronchial asthma (not preferred)

Identifying High-Risk Patients Epinephrine used cautiously in patients with

1. Coronary diseases - angina pectoris

2. Hyperthyroidism

3. Hypertension

4. Cardiac dysrhythmias,

5. Organic heart disease

Dr. Utoor 16/12/2018

• Determine the potential nursing diagnoses related to drug therapy and health problems that the drug might cause.

• Adverse Effects: Because it can activate the four major adrenergic receptor subtypes, epinephrine can produce multiple adverse effects.

• Hypertensive Crisis: Vasoconstriction secondary to excessive alpha1 activation can produce a dramatic increase in blood pressure. Cerebral hemorrhage can occur.

• Dysrhythmias: Excessive activation of beta1 receptors in the heart can produce dysrhythmias.

• Angina Pectoris: By activating beta1 receptors in the heart, epinephrine can increase cardiac work and oxygen demand.

• Necrosis Following Extravasation: If an IV line containing epinephrine becomes extravasated, the ensuing localized vasoconstriction may result in necrosis.

• Hyperglycemia: secondary to activation of beta2 receptors in liver and skeletal muscle

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• Planning: patient goals and expected outcomes including specific interventions directed to solving or preventing the problem

• Implementation: Administration

• Routes: Topical, inhalation, and parenteral (IV, IM, subQ, intracardiac, intraspinal). Rapid inactivation by MAO and COMT prohibits oral use. The concentration of epinephrine solutions varies according to the route of administration.

• Ongoing Evaluation and Interventions

Continues observation to ensuring therapeutic effects and minimizing adverse effects

Minimizing Adverse Effects

• Cardiovascular Effects: anginal pain, tachycardia, and dysrhythmias. These responses can be reduced with a beta-adrenergic blocking agent (eg, metoprolol).

Dr. Utoor 16/12/2018

• Severe hypertension. Blood pressure can be lowered with an

alpha-adrenergic blocking agent (eg, phentolamine).

• Necrosis: Exercise care to avoid extravasation. If

extravasation occurs, infiltrate the region with phentolamine

to minimize injury.

• Hyperglycemia. Epinephrine may cause hyperglycemia in

diabetic patients. If hyperglycemia develops, insulin dosage

should be increased.

Evaluate the effectiveness of drug therapy by confirming

that the patient goals and expected outcomes have been met

•

Dr. Utoor 16/12/2018

Dr. Utoor 16/12/2018