Pharm Ch. 13: Alpha-1 Adrenergic Agonists

Epinephrine: Pharmacodynamics

1. Activation of the receptor 2. Epinephrine is terminated by reuptake into adrenergic nerves OR inactivated by the enzymes COMT and MAO 3. Depending on the location and distribution of receptors, epinephrine exerts a variety of responses in different effector organs and tissues.

INDIRECT stimulation of Adrenergic Receptors

Mechanisms include: 1. Increasing the transmission of NE 2. Inhibiting NE reuptake 3. Inhibiting MAO or COMT (2 and 3 are related to the dissociation and termination of NE binding to adrenergic receptors, which results in the continuation of the effects of NE).

Phenylephrine: Drugs Closely Related

Methoxamine (Vasoxyl) is a parenteral vasopressor agent used for blood pressure support during surgery and for terminating some supraventricular tachycardias. Increases BP by increasing peripheral resistance through the alpha receptors

Epinephrine: Pharmacotherapeutics

Most common indications include: 1. Cardiopulmonary resuscitation 2. Hypersensitivity reaction 3. Anaphylactic shock 4. Ventricular fibrillation 5. Asthma (EPI NEEDS CHAVA)

Is drug selectivity absolute?

NO, although a selective-acting drug is preferential to a given subtype receptor, when given in higher doses it may also stimulate other subtype receptors.

Should epinephrine be used during labor?

NO, it is absolutely contraindicated, because as a beta-2 agonist, epinephrine administered during labor can delay progression to the second stage.

Should epinephrine be used with a severe organic cardiac disease?

NO, it is absolutely contraindicated, because the cardiovascular effects of epinephrine, such as increased myocardial oxygen demand, increased heart rate, vasoactivity, and potential to induce arrhythmias, may be detrimental to patients with severe cardiac disease.

Does stimulation of beta-2 receptors (which cause vasodilation) and stimulation of alpha-1 receptors (which cause vasoconstriction) cancel each other out & create no effect?

NO; 1. Initially, the beta-2 receptor stimulation is prevalent in the body effects and there will be vasodilation in skeletal muscles as well as other organs. 2. As the dose increases, then the alpha-1 effects are evident, and these override the beta-2. (FIRST B2VD, then A1VC)

Drugs closely related to Epinephrine

NOREPINEPHRINE (Levophed) Like epinephrine, NE is a catecholamine and may not be administered orally Unlike epinephrine, NE does not stimulate beta-2 receptors Adverse effects and drug interactions are identical to those of epinephrine, EXCEPT that NE does not promote hyperglycemia Clinically, NE is used in the management of hypotension and cardiac arrest

Nonselective Adrenergic Agonists

Stimulate most receptors; therefore, they have a multitude of uses REMEMBER: These drugs stimulate all of the subtypes, regardless of which subtype would be most helpful for a specific pathology.

2. Vasopressin (DSDE)

1. Also known as antidiuretic hormone, it is classified as an endocrine-metabolic or gastrointestinal agent as large doses will stimulate peristalsis 2. Also used in the management of shock states due to ventricular fibrillation, hypovolemia, sepsis, and cardiopulmonary bypass. 3. During these shock states, exogenous vasopressin increases blood flow to the heart and brain and reduces blood flow to the skin, skeletal muscle, small bowel, and fat. 4. Single dose of vasopressin may be used to replace the first or second dose of epinephrine in the management of VT or VF

Phenylephrine: Contraindications

1. Drug hypersensitivity 2. Sulfite sensitivity 3. Severe hypertension 4. Ventricular tachycardia 5. Closed-angle glaucoma

Drugs Significantly Different from Epinephrine

1. Ephedrine 2. Vasopressin

Epinephrine: Absolute Contraindications

1. Hypersensitivity, sulfite sensitivity, closed-angle glaucoma, and its use during labor. 2. Patients with severe organic cardiac disease, patients receiving cyclopropane, chloroform, or trichloroethylene general anesthesia and in shock states other than anaphylactic shock 3. Septic Shock:

How are adrenergic agonists classified?

According to their SELECTIVITY

Noncatecholamines

Adrenergic Agonist 1. Long duration of action 2. May be given orally 3. DO cross the blood-brain barrier Exact opposite of catecholamines

Catecholamine

Adrenergic Agonist 1. They have a short duration of action, resulting in their need to be administered in a continuous fashion 2. They can't be given orally, because then they won't be given continuously and certain body substances (MAO and COMT) would degrade them before they reached systemic circulation 3. They do not cross the blood-brain barrier because of their chemical structure (CATCH is CONTINUOUS & CAN'T CROSS)

Adrenergic Agonists: 2 groups

Catecholamines and noncatecholamines

Phenylephrine: Pharmacotherapeutics

May be used parenterally for treatment of vascular failure in shock, shock-like states, or drug-induced hypotension Often used topically for relief of nasal and nasopharyngeal mucosal congestion and to produce mydriasis (dilation of the pupil) for ophthalmologic procedures.

Adrenergic Agonists

Drugs that mimic the action of the SNS (Sympathy and agony) Exert their effects by direct or indirect stimulation of adrenergic receptors

Nonselective-acting Drugs

Drugs that stimulate multiple adrenergic subtype receptors

Alpha-1 Adrenergic Agonists

Drugs that stimulate the alpha-1 receptor directly Prototype is PHENYLEPHRINE (Allerest)

Selective-acting Drugs

Drugs that target a specific subtype receptor These drugs are used more frequently than nonselective drugs

What is the prototype for nonselective adrenergic agonists?

EPINEPHRINE: this drug stimulates alpha-1, alpha-2, beta-1, and beta-2 receptors. The only adrenergic receptor it does NOT stimulate is the dopamine receptor (EPI AIN'T DOPE)

Epinephrine: Pharmacokinetics

Epinephrine may be administered parenterally, topically, or by inhalation. Depending on the administration method, epinephrine exerts its effects very quickly and is metabolized rapidly. It is well absorbed after intramuscular (IM) or subcutaneous (SC) injection, and its duration of action ranges from 1-4 hours. It is metabolized in the LIVER & excreted through the KIDNEYS

Should epinephrine be used for septic shock?

In septic shock, epinephrine should be reserved only for extreme cases of cardiac collapse if other catecholamines have failed, as it also impairs gastric blood flow and increases lactate.

Where does epinephrine cause the greatest adverse effects?

In the cardiovascular system and CNS, because it acts directly on the postsynaptic adrenergic receptors

Epinephrine: Pharmacodynamics (Cardiovascular)

In the cardiovascular system, epinephrine exerts these effects on the MYOCARDIUM by stimulating beta-1 adrenergic receptors: 1. Positive (or increased) 2. Inotropic (force or energy of contraction) 3. Chronotropic (heart rate) (EBP1 = Epi Beta-1)

Epinephrine: Pharmacodynamics (Respiratory System)

In the respiratory system, epinephrine causes bronchodilation by stimulation of beta-2 adrenergic receptors and is used in this way to treat patients with asthma or to manage anaphylactic shock.

Epinephrine: Pharmacodynamics (Skin)

In the skin and viscera, epinephrine stimulates alpha-adrenergic receptors, causing vasoconstriction. The overall effect is to increase systolic pressure and slightly decrease diastolic pressure.

1. Ephedrine (DSDE)

Like epinephrine, ephredine stimulates alpha-1, alpha-2, beta-1, and beta-2 receptors. Unlike epinephrine, it is not a catecholamine It is metabolized to norephedrine, which is responsible for the stimulating effects of the drug on the CNS. (Ephedrine doesn't CATCH shit)

Phenylephrine: Adverse Effects

Main adverse effects are headache, restlessness, excitability, and reflex bradycardia following an increase in blood pressure.

Phenylephrine: Drug Interactions

Phenylephrine interacts with monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and oxytocics used in labor and delivery

Phenylephrine: Pharmacokinetics

Phenylephrine is poorly absorbed orally and is usually given parenterally or topically.

Phenylephrine: Pharmacodynamics

Phenylephrine is structurally similar to epinephrine and is a powerful alpha-1 adrenergic agonist with very little activity at beta-adrenergic receptors

Phenylephrine: Precautions

Precautions need to be observed for hyperthyroid states and pregnancy and in patients who are elderly or have diabetes, myocardial disease, arteriosclerosis, uncorrected hypovolemia, or asthma

Where are the predominant actions of phenylephrine?

The vascular system, where it acts as a vasopressor by stimulating alpha-1 vascular receptors and thus causes vasoconstriction. As a result, renal perfusion and cardiac output are decreased, and blood pressure is increased by the heightened peripheral resistance