1. 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

2. 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

3. Peripheral Nervous System

4. 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

5. Synthesis and Storage of NE

6. 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

7. 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

8. 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

9. 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

10. 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

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

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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

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

31. 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

32. 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

33. 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

34. 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