School of Pharmacy, University of Nizwa Adrenergic Agonist Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture-17, 18 & 19 November 12, 2011

Adrenergic Neuron Adrenergic neurons release norepinephrine (NE) as the primary neurotransmitter Found in CNS and in the sympathetic nervous system Adrenergic neurons and receptors are located either presynaptically on the neuron or postsynaptically on the effector organ

Peripheral Nervous System

Neurotransmission at Adrenergic Neurons Six steps in the normal adrenergic transmission process: 1. Synthesis of the NE 2. Storage of the NE 3. Release of the NE by a nerve action potential 4. Binding to receptor 5. Removal of NE from synaptic cleft

Synthesis and Storage of NE

Neurotransmission at Adrenergic Neurons 1. Synthesis Tyrosine is transported by a Na+-linked carrier into axoplasm Tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase Hydroxylation is the rate-limiting step in the formation of NE DOPA is then decarboxylated by the enzyme dopa decarboxylase to form dopamine in the cytoplasm of the presynaptic neuron

Neurotransmission at Adrenergic Neurons 2. Storage Dopamine is transported into synaptic vesicles by an amine transporter system This carrier system is blocked by reserpine Dopamine is hydroxylated to form NE by the enzyme, dopamine β-hydroxylase In adrenal medulla, NE is methylated to yield epinephrine Norepinephrine Epinephrine

Neurotransmission at Adrenergic Neurons 3. Release Propagation of action potential at the nerve ending increases intracellular calcium concentration Elevated calcium levels promote the fusion of vesicles with the cell membrane and release NE into the synaptic space by exocytosis This release can be blocked by guanethidine

Neurotransmission at Adrenergic Neurons 4. Binding to receptor NE binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending Binding of NE to the membrane receptors result in the formation of intracellular second messengers (cAMP) that act as links in the communication between neurotransmitter and effector cell. Binding to a receptor leads to a biologic response

Neurotransmission at Adrenergic Neurons 5. Removal: NE may 1) diffuse out of the synaptic space and enter the general circulation 2) metabolized by catechol O-methyltransferase (COMT) in the synaptic space 3) be recaptured by an uptake system that pumps the NE back into the neuron. Uptake by the neuronal membrane involves a sodium/potassium-activated ATPase Uptake of NE into the presynaptic neuron is the primary mechanism for termination of NE's effects

Adrenergic Receptors (Adrenoceptors) Two families of Adrenoceptors: 1. α receptors 2. β receptors

α Receptors α Adrenoceptors subgroup (based on affinity towards agonists and antagonists): α1 α2

α1 Receptors α1 Receptors are present on the postsynaptic membrane of effector organs Activation of α1 receptors initiates a series of reactions through a G protein coupled reaction

α2 Receptors α2 Receptors are located mainly on presynaptic nerve endings α2 Rreceptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP Stimulation of sympathetic adrenergic nerve released NE, which comes to synaptic cleft and interacts with α1receptors A portion of the released NE circles back and reacts with α2 receptors on the neuronal membrane

β Receptors β Adrenoceptors subgroups (based on affinities for adrenergic agonists and antagonists): β1, β2, and β3 β1: equal affinities for epinephrine and NE, β2: higher affinity for epinephrine than for NE Binding of a neurotransmitter with β receptors results in activation of adenylyl cyclase and increased concentrations of cAMP within the cell

Distribution of Receptors Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor, e.g., tissues such as the vasculature to skeletal muscle have both α1 and β2 receptors, but β2 receptors predominate Other tissues may have one type of receptor exclusively, with practically no significant numbers of other types of adrenergic receptors, e.g., heart contains predominantly β1 receptors

Effects Mediated by Adrenoceptors α1: Vasoconstriction, increased peripheral resistance, increased blood pressure, mydriasis, α2: Inhibition of NE, Ach, and insulin release β1: Tachycardia, increased lipolysis, increased myocardial contractility, increased release of renin β2: Vasodilatation, bronchodilation, increased muscle and liver glycogenolysis, increased release of glucagon Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs

Adrenergic Agonists Most of the adrenergic drugs are derivatives of β-phenylethylamine Substitutions on the benzene ring or on the ethylamine side chains produce a variety of compounds with varying abilities to differentiate between α and β receptors and to penetrate the CNS

Adrenergic Agonists: Catecholamines Epinephrine, NE, and DA are called catecholamines Their common properties are: High potency: Drugs that are catechol derivatives (OH groups in the 3 and 4 positions on the benzene ring) show the highest potency in directly activating α or β receptors Rapid inactivation: Metabolized by COMT and MAO. They have brief period of action when given parenterally, and they are ineffective when administered orally Poor penetration into the CNS: Catecholamines are polar, do not readily penetrate into the CNS

Noncatecholamines Lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT. These include phenylephrine, ephedrine, and amphetamine. These are poor substrates for MAO and, thus, show a prolonged duration of action Increased lipid solubility permits greater access to CNS

Mechanism of Action Direct-acting agonists: Indirect-acting agonists: Act directly on α or β receptors Indirect-acting agonists: Block the uptake of NE and cause the release of NE from the vesicles of the adrenergic neuron Mixed-action agonists: Have the capacity both to stimulate adrenoceptors directly and to release NE from the adrenergic neuron

Direct-Acting Adrenergic Agonists Few names Ephinephrine Norepinephrine Dopamine Isoproterenol Albuterol Phenylephrine Metaproterenol Terbutaline

Epinephrine: Therapeutic Uses Bronchospasm: Primary drug used in the emergency treatment of any condition of the respiratory tract Glaucoma: Used topically to reduce intraocular pressure in open-angle glaucoma Cardiac arrest: Used to restore cardiac rhythm in patients with cardiac arrest Anesthetics: Increases duration of local anesthesia

Epinephrine: Pharmacokinetics Rapid onset but a brief duration of action (due to rapid degradation) In emergency situations, it is given intravenously Also be given subcutaneously, by inhalation, or topically Oral administration is ineffective, because epinephrine is inactivated by intestinal enzymes Metabolites are excreted in the urine

Epinephrine: Adverse Effects CNS disturbances: CNS effects that include anxiety, fear, tension, headache, and tremor Hemorrhage: Induce cerebral hemorrhage as a result of a marked elevation of blood pressure Cardiac arrhythmias: Trigger cardiac arrhythmias Pulmonary edema: Can induce pulmonary edema arrhythmia, the heart can beat too fast, too slow, or with an irregular rhythm Pulmonary edema is an abnormal buildup of fluid in the air sacs of the lungs

Epinephrine: Interactions Hyperthyroidism: Enhances cardio-vascular actions in patients with hyperthyroidism Diabetes: Increases the release of endogenous stores of glucose β-Blockers: Increases in blood pressure Inhalation anesthetics: Leads to tachycardia Hyperthyroidism is a condition in which the thyroid gland makes too much thyroid hormone Tachycardia: heart beats too fast

Norepinephrine Therapeutic Use: Pharmacokinetics: Adverse effects: NE is used to treat shock, because it increases vascular resistance and, therefore, increases blood pressure Pharmacokinetics: Given IV for rapid onset of action Duration of action is 1 to 2 min following the infusion Poorly absorbed after subcutaneous injection and is destroyed in the gut if administered orally Adverse effects: Similar to epinephrine

Isoproterenol Increased cardiac output Useful in the treatment of cardiac arrest Rapidly alleviates an acute attack of asthma Therapeutic uses: Use to stimulate the heart in emergency situations Pharmacokinetics: Absorbed when given parenterally or as an inhaled aerosol Marginal substrate for COMT and is stable to MAO action Adverse effects: Similar to those of epinephrine

Dopamine Immediate metabolic precursor of NE Therapeutic uses: Raises blood pressure by stimulating the α- and β-adrenergic receptors on the heart An increased blood flow to the kidney enhances the glomerular filtration rate

Indirect-Acting Adrenergic Agonists Indirect-acting adrenergic agonists cause NE release from presynaptic terminals or inhibit the uptake of NE Amphetamine Tyramine Cocaine

Amphetamine Drug of abuse Stimulatory action Increases blood pressure by α agonist action on the vasculature as well as β stimulatory effects on the heart

Cocaine Local anesthetics in having the ability to block the Na+/K+-activated ATPase Increase blood pressure by α agonist action and β stimulatory effects

Mixed-Action Adrenergic Agonists Mixed-action drugs induce the release of NE from presynaptic terminals, and they activate adrenergic receptors on the postsynaptic membrane Few names Ephedrine Pseudoephedrine

Ephedrine Plant alkaloids Release stored NE from nerve endings, also directly stimulate both α and β receptors Poor substrates for COMT and MAO; thus, have a long duration of action Absorbed orally and penetrate into the CNS Eliminates largely unchanged in the urine Raises blood pressures by vasoconstriction and cardiac stimulation Produces bronchodilation Produces a mild stimulation of the CNS Used to treat asthma, and as a nasal decongestant