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
