NUR 210 PHARMACOLOGY UNIT 4 CHAPTERS 15-16

• Adrenergic agonists/sympathomimetics and antagonists/sympatholytics affect the sympathetic nervous system, including dosages and uses.
• The central nervous system (CNS) consists of the brain and spinal cord, serving as the body's main nervous system
• The peripheral nervous system (PNS), consists of the autonomic and somatic divisions
• The ANS, or visceral system, regulates involuntary actions on smooth muscles and glands
• The somatic nervous system, unlike the ANS, controls voluntary skeletal muscle movements
• Autonomic PNS neurons include afferent (sensory) and efferent (motor) types
• Afferent neurons send impulses to the CNS for interpretation
• Efferent neurons receive impulses from the brain and transmit through the spinal cord to effector organ cells
• Efferent pathways divide into sympathetic and parasympathetic nerves, together forming the sympathetic and parasympathetic nervous systems
• The sympathetic and parasympathetic nervous systems create homeostasis by acting oppositely on the same organs
• Drugs influence these systems through stimulation or depression

Sympathetic Nervous System

• The sympathetic nervous system, also called the adrenergic system, uses norepinephrine as a neurotransmitter
• Adrenergic receptor organ cells are of four types: alpha1, alpha2, beta1, and beta2 that stimulate cell receptors to produce a response

Adrenergic Agonists

• Adrenergic agonists, adrenergics, or sympathomimetics mimic sympathetic nervous system stimulation
• They act on adrenergic receptor sites in muscles like the heart, bronchioles, GI tract, bladder, and eye ciliary muscles
• The main adrenergic receptors include alpha1, alpha2, beta1, and beta2, which mediate responses

Alpha-Adrenergic Receptors

• Alpha1 receptors are in blood vessels, eyes, bladder, and prostate
• Stimulation leads to arteriole and venule constriction, increasing peripheral resistance, blood return to the heart, and blood pressure which improves circulation
• Excessive stimulation impairs blood flow to vital organs
• Alpha2 receptors are in postganglionic sympathetic nerve endings
• Stimulation inhibits norepinephrine release, reducing vasoconstriction, and blood pressure

Beta Receptors

• Beta1 receptors are mainly in the heart and kidneys
• Stimulation increases myocardial contractility and heart rate
• Beta2 receptors are mostly in lung and GI tract smooth muscles, the liver, and the uterine muscle
• Stimulation causes bronchodilation, decreases GI tone and motility, activates liver glycogenolysis(increasing blood glucose), and relaxes uterine muscle

Other Adrenergic Receptors

• Dopaminergic receptors in renal, mesenteric, coronary, and cerebral arteries dilate vessels and increase blood flow when stimulated
• Only dopamine activates these receptors

Inactivation of Neurotransmitters

• Transmitters are inactivated by reuptake into the neuron, enzymatic transformation/degradation, and diffusion away from the receptor
• Norepinephrine reuptake plays a more important role in inactivation than enzymatic action

Enzymes that Inactivate Norepinephrine

• Monoamine oxidase (MAO) is inside the neuron
• Catechol-O-methyltransferase (COMT) is outside the neuron
• Drugs can prolong neurotransmitter action by preventing reuptake or enzymatic degradation

Classification of Sympathomimetics

• Direct-acting sympathomimetics stimulate adrenergic receptors directly, like epinephrine or norepinephrine
• Indirect-acting sympathomimetics stimulate norepinephrine release, like amphetamine
• Mixed-acting sympathomimetics stimulate adrenergic receptor sites and release norepinephrine, like ephedrine

Pseudoephedrine

• It is a controlled, mixed-acting sympathomimetic and helps relieve nasal and sinus congestion
• This drug is contraindicated in hypertension, closed-angle glaucoma, bronchitis, emphysema, and urinary retention; use cautiously in diabetes mellitus
• Pseudoephedrine increases heart rate

Catecholamines

• These are substances with chemical structures (either endogenous or synthetic) that produce a sympathomimetic response
• Examples of endogenous catecholamines are epinephrine, norepinephrine, and dopamine
• Synthetic catecholamines are isoproterenol and dobutamine

Noncatecholamines

• Examples are phenylephrine, metaproterenol, and albuterol
• They stimulate adrenergic receptors and have a longer duration of action

Nonselective Adrenergic Agonists

• Many adrenergic agonists stimulate multiple adrenergic receptor sites
• Epinephrine acts on alpha1, beta1, and beta2 receptors and increases blood pressure, dilates pupils, and causes bronchodilation
• Additional side effects result when more responses occur than are desired

National Regulatory Measures

• Limits pseudoephedrine sales to 3.6 g/day and 9 g within 30 days
• Identifications are scanned with each purchase
• The database is linked nationally and keeps a 2-year tally

Albuterol Sulfate

• It is a beta2-adrenergic agonist and prevents/treats bronchospasm by relaxing bronchial smooth muscle
• Patients with asthma may tolerate it better than isoproterenol because of its selectivity
• Fewer undesired effects will occur by using selective sympathomimetics, but high dosages may affect beta1 receptors, increasing heart rate
• Common side effects of oral/inhalation albuterol include tremors, headache, and nervousness
• Other side effects include tachycardia, palpitations, dizziness, dysrhythmia, nausea, vomiting, and urinary retention
• Beta antagonists (beta blockers) may inhibit the action of albuterol

Epinephrine

• Given intramuscularly, intravenously or endotracheally
• Rapidly metabolized in the GI tract and liver, which results in unstable serum levels if given orally
• Use cautiously in patients with cardiac dysrhythmias, narrow-angle glaucoma, or cardiogenic shock

Epinephrine Pharmacodynamics

• Used frequently in emergencies to treat anaphylaxis
• Potent inotropic drug that increases cardiac output, promotes vasoconstriction and systolic blood pressure elevation, increases heart rate, and produces bronchodilation
• High doses can cause cardiac dysrhythmias, necessitating ECG monitoring
• Also cause renal vasoconstriction, decreasing renal perfusion and urinary output

Epinephrine Drug Interactions

• Use of decongestants with epinephrine has an additive effect
• When administered with digoxin, cardiac dysrhythmia may occur
• Beta blockers can antagonize epinephrine action
• Tricyclic antidepressants and MAOIs allow epinephrine effects to be intensified and prolonged

Side Effects and Adverse Reactions of Adrenergic Agonists

• Hypertension, tachycardia, palpitations, restlessness, tremors, dysrhythmia, dizziness, urinary retention, nausea, vomiting, dyspnea, and pulmonary edema are common

Central-Acting Alpha Agonists

• Clonidine is a selective alpha2-adrenergic agonist used primarily to treat hypertension
• Alpha2 drugs are central-acting and produce vasodilation by stimulating alpha2 receptors in the CNS, leading to decreased blood pressure
• Clonidine acts by decreasing norepinephrine release from sympathetic nerves and decreasing peripheral adrenergic receptor activation
• May produce bradycardia, hypotension, sedation, and dry mouth at very low doses.
• Methyldopa is an alpha-adrenergic agonist that acts within the CNS by being converted to alpha-methylnorepinephrine, leading to alpha2 activation
• The decrease of sympathetic outflow from the CNS reduces peripheral resistance, resulting in vasodilation and reduced blood pressure
• Headache, nasal congestion, drowsiness, nightmares, constipation, and edema are additional undesired effects of central-acting alpha-adrenergic agonists.
• Ejaculation dysfunction and elevated hepatic enzymes may also occur.

Adrenergic Antagonists

• They block the effects of adrenergic neurotransmitters

Alpha- and Beta-Receptor Blockers

• Most adrenergic blockers block either the alpha or beta receptor
• They either directly occupy receptors or indirectly inhibit neurotransmitter release

Alpha-Adrenergic Antagonists

• These are called alpha blockers and block or inhibit a response at the alpha-adrenergic receptor site -Selective types block alpha₁, and nonselective types block alpha₁/ alpha2
• Many are not frequently prescribed due to causing orthostatic hypotension and reflex tachycardia
• Alpha antagonists (alpha blockers) promote vasodilation, decreasing blood pressure, which if long-standing, can cause orthostatic hypotension and dizziness
• Pulse rate usually increases to compensate for low blood pressure and blood flow -Alpha antagonists can treat peripheral vascular disease like Raynaud disease, causing vasodilation, permitting more blood flow to the extremities
• They also decrease symptoms of benign prostatic hyperplasia (BPH)

Beta-Adrenergic Antagonists

• These, called beta blockers, decrease heart rate, and a decrease in blood pressure usually follows
• Some beta blockers are nonselective, blocking both beta₁ and beta2 receptors
• Nonselective beta blockers should be used with extreme caution with COPD or asthma patients, blocking both beta₁ and beta2
• Propranolol hydrochloride was the first beta blocker and is used to treat angina, cardiac dysrhythmia, hypertension, and heart failure and may also be given for migraine prophylaxis
• A selective adrenergic antagonist has a greater affinity for certain receptors; such as atenolol or metoprolol tartrate -Intrinsic sympathomimetic activity (ISA) describes certain beta blockers' ability to bind with a beta receptor to prevent strong agonists from binding, preventing complete activation
• Nonselective beta blockers that have ISA are carvedilol, penbutolol, and pindolol
• The selective blocker that has ISA is acebutolol and may be good for hypertensive patients with bradycardia
• Beta blockers are useful in treating mild to moderate hypertension, angina, heart failure, and myocardial infarction (MI)
• Beta blockers should not be abruptly discontinued but rather should be tapered off over 1 to 2 weeks to avoid adverse effects
• Side effects are dose related and include bradycardia, hypotension, headache, dizziness, cold extremities, and bronchospasm.