Adrenergic agonists Samuel Aguazim (MD)

What are adrenergic agonist Drugs or endogenous catecholamine's that activate alpha and/ or beta receptors. These drugs are also knows as sympathomimetics According to mechanism of action ( direct vs indirect) as well as receptor site specificity (a1,a2,b1,b2)

Name alpha selective direct – acting agonists Phenylephrine Methoxamine Clonidine methyldopa

Identify the major beta selective direct-acting agonist Dobutamine Isoproterenol Albuterol Metaproterenol Terbutaline

List the major alpha and beta direct-acting agonists Epinephrine Norepinephrine dopamine

Direct- acting agonists considered catecholamines Epinephrine Norepinephrine Isoproterenol Dopamine dobutamine

INDIRECT ACTING Amphetamine Tyramine

TWO MIXED AGONISTS DIRECT & INDIRECT ACTING Ephedrine Metaraminol

Where are alpha 1 and alpha 2 receptors located Alpha 1 receptors are located on the effector organ’s postsynaptic membrane. Alpha 2 receptors are predominantly located on the presynaptic membrane. Postsynaptic alpha 2 receptors are limited to the CNS and bloodvessels

RESPONSES ASSOCIATED WITH TYPES OF ADRENOCEPTORS Alpha1 Stimulation leads to release of intracellular calcium from the endoplasmic reticulum via inositol triphosphate (IP3 ). This leads to Arterial and arteriolar constriction (cutaneous, visceral, skeletal & pulmonary) Venous constriction Uterine contraction Pupillary dilation ( mydriasis ) (contraction of radial smooth muscle of iris) Contraction of ureter Contraction of pilomotor muscles

Alpha 2 When alpha 2 presynaptic membrane receptors are stimulated, intracellular cyclic adenosine monophosphate ( c CAMP ) production is inhibited. Inhibition of NE release Inhibition of ganglionic transmission Reduction of BP and heart rate Vasoconstriction (quantitatively less important than α1) Decrease insulin secretion Platelet aggregation

Name the direct-acting agonists that are selective for α1 and α2 adrenergic receptors Alpha 1 receptors- phenylephrine and methoxamine Alpha 2 receptors- clonidine and methyldopa

Phenylephrine Physiologic action Primarily vasoconstriction Therapeutic uses Nasal decongestant Treat hypotension For ocular examinations( mydriasis) To terminate episodes of paroxysmal atrial tachycardia( PAT) SE: REBOUND MUCOSAL SWELLING AND HYPERTENSIVE HEADACHE

METHOXAMINE THERAPEUTIC USES: Treatment of hypotension and paroxysmal atrial tachycardia( PAT) Adverse effect: similar to those of phenylephrine

Alpha 2 selective agonists Clonidine --- Central action REDUCES SNS OUTFLOWS FROM THE BRAIN Therapeutic use – treat essential HTN, withdrawal from benzodiazepines and opiates, treatment of diarrhea in diabetic patients who have autonomic neuropathies Adverse Effects: dry mouth sedation sexual dysfunction Other drug : Guanfacine

Direct – acting beta selective agonists LOCATION: β1 receptors are primarily located on the postsynaptic membrane. β2 receptors are found on both the pre and postsynaptic membranes

Beta 1 Beta 1 stimulation activates adebylate cyclase, which opens calcium channels leading to:cardiac stimulation with both increased chronotropic, inotropic, dromotropic effects. stimulation of lipolysis stimulation of renin secretion

Beta 2 Beta 2 receptors work via adenylate cyclase stimulation as well. In this case, however, bronchial smooth muscle as well as skeletal muscle vasculature are dilated. The uterus, ciliary and detrusor muscles are relaxed and glucagon release is increased. Both beta 1 and beta 2 receptors produce decreased intestinal tone and motility.

DOBUTAMINE A dopamine analogue that acts primarily on beta 1 but it does have some action on beta 2 receptors as well. Physiologic effects: increased heart rate and contractility (β1) and smooth muscle relaxation (β2) Uses: treatment of unstable CHF and shock Route: iv Adverse effects: arrthymias, headache, hypertension, palpitation, angina and nausea

Isoproterenol Activates ß adrenergic receptors (both ß1 - and ß2 -receptor subtypes) Activation of cardiac ß1 - adrenergic receptors: increased contractility and heart rate. Activation of ß2 - adrenergic receptors: Bronchial and GI smooth muscle relaxation

Isoproterenol: Limited therapeutic uses Emergency settings to treat heart block or severe bradycardia Management of torsade de pointes (a ventricular arrhythmia)

Beta 2 selective agonists Drugs used as medication for broncho dilation due to smooth muscle dilatation 1. Albuterol 2. Salmeterol – long acting with late onset 3. Metaproterenol 4. Terbutaline Therapeutic uses: rx of bronchospasm/asthma COPD, bronchitis. Adverse effect: arrhythmias, tachycardia, headache and vomiting

Norepinephrine Synthesis, Storage & Metabolism Tyrosine is converted to dihydroxyphenylalanine (DOPA) via tyrosine hydroxylase DOPA is converted to dopamine (DA) via L-aromatic amino acid decarboxylase (DOPA decarboxylase) DA is converted to NE via DA beta-hydroxylase and is taken up and stored in granules Inactivation of NE via monoamine oxidase (MAO) may regulate prejunctional levels in mobile pool , but not granular NE

NE Release & Actions Membrane excitation opens voltage-dependent Ca2+ channels Ca influx NE release from granules into the neuroeffector junction NE activates postjunctional receptors tissue specific responses depending on alpha or beta adrenoceptor subtype

Increased heart rate (positive chronotropic effect) Cardiac Effects Increased heart rate (positive chronotropic effect) Increased contractility (positive inotropic effect)

Metabolic Effects Increase in rate of muscle and liver glycogenolysis Increase in free-fatty acid release from fat

Endocrine Regulation/modulation of insulin, pituitary, and renin secretion

Central Nervous System Effects Respiratory stimulation CNS stimulation

Vascular smooth muscle contraction…… Vascular smooth muscle contraction……. Αlpha1 Inhibition of transmitter release…… α2

(alpha1 and ß1 at high doses) Catecholamines Drug   Receptors Epinephrine alpha1, alpha2 ß1, ß2 Norepinephrine alpha1, alpha2, ß1 Isoproterenol ß1, ß2 Dobutamine ß1 (alpha1) Dopamine (alpha1 and ß1 at high doses)  

Direct- acting alpha and beta agonist EPINEPHRINE Epinephrine is a potent activator of alpha and ß adrenergic receptors Prominent Cardiovascular Effects

Cardiac effects Heart rate increases Cardiac output increases Oxygen consumption increases

Vascular effects Over renal system – decreased blood flow Renin – release Respiratory system-Broncho - dilatation -- Beta 2 Decreased secretions Metabolic- increased glycogenolysis and release glucagon and a decreased release of insulin results in hyperglycemia

Epinephrine Anaphylactic shock Used mainly for bronchospasm Acute asthma Anaphylactic shock Open angle glaucoma Increase the duration of local anesthesia SE: Cardiac arrhythmias, hypertension,palpitations, dizziness, anxiety, headache and tremor. etc

NOR EPINEPHRINE Activates alpha and beta 1 receptors physiologic effects: vasoconstriction and reflex bradycardia Therapeutic uses Shock Never used for asthma SE: TISSUE HYPOXIA DECREASED PERFUSION TO KIDNEY TISSUE NECROSIS

Dopamine Dopamine is the immediate precursor of norepinephrine. It is synthesized in the CNS, sympathetic ganglia and adrenal medulla acts on alpha 1, beta 1 and beta 2 and dopamine ( D1&D2) receptors

Cardiovascular Effects (Dopamine) Treatment of shock- raises BP by stimulating the beta 1 receptors of the heart Acute renal failure to increase renal blood flow Treatment of acute CHF

Therapeutic use (Dopamine) Drug of choice for shock Both cardiogenic and hypovolemic shock. Continuous infusion to be given.

Adverse effects palpitations tachycardia arrhythmias coronary insufficiency

alpha methyl DOPA very effective alpha 2 agonist, and so prevents the release of NE. · It is used as an antihypertensive

OTHER ADRENERGIC DRUGS Ephedrine – alpha , beta and CNS Mainly used for treatment of asthma and nasal decongestant. Phenylpropanolamine – nasal decongestant and bronchodilator Tetrahydrozoline – related to ephedrine used as topical nasal and conjunctival decongestant.

Naphazoline - used as topical vasoconstrictor. Oxymetazoline – to reduce congestion and swelling of the nasal mucosa. Xylometazoline -- nasal decongestant.

Indirectly Acting Sympathomimetics -act by releasing NE - Pharmacological Effects Vasoconstriction Bronchodilation CNS effects: stimulation anorexigenic Applications Nasal decongestion Asthma Narcolepsy Hyperkinetic Syndrome Obesity

Indirectly Acting drugs Amphetamine Tyramine

Amphetamine Alpha, beta . It releases stores NE and dopamine. It can enter CNS Used as CNS stimulant in treatment of children with attention deficit syndrome. (hyperactivity is the feature) Narcolepsy Obesity

Side effects Headache, palpitations, dysphoria Appetite suppression Weight loss due to decrease food intake Psychological tolerance/dependence

TYRAMINE It is a by-product of tyrosine metabolism; tyrosine is a precursor to dopamine, epinephrine and norepinephrine MOA: tyramine is taken up by sympathetic neurons, which causes a release of catecholamines. Is there a therapeutic use: NO

What are tyramine’s adverse effects ? It can cause a hypertensive emergency in patients who take monoamine oxidase (MAO) inhibiting drugs since MAO is responsible for metabolism of tyramine. It is important to warn patients who are taking MAO inhibitors not to eat foods with high tyramine concentrations, such as red wine, beer, chocolate and cheese.

Drugs used as inhalation medication for broncho dilation are 1.Epinephrine – short acting 2. Isoproterenol 3. Albuterol 4. Salmeterol – long acting with late onset 5. Metaproterenol 6. Terbutaline

Mixed action adrenergic agonists Ephedrine Stimulates both alpha and beta receptors Plant alkaloid now made synthetically Used in asthma Nasal decongestant