1. Adrenergic Agonists

2. Neurotransmitters
Pharm Pearl:
The peripheral nervous system (PNS) employs 3 neurotransmitters
Acetylcholine
Norepinephrine
Epinephrine
Any given junction in the PNS
uses only ONE of these substances

3. Transmitter Recap Acetycholine – employed at most junctions of the PNS
All preganglion neurons of PNS
All preganglion neurons of the SNS
All postganglionic neurons of PNS
All motor neurons to skeletal muscles
Most postganglionic neurons of the SNS that go to sweat glands

4. Transmitter Recap
Norepinephrine – released by practically all postganglionic neurons of the SNS (exception – sweat glands) Epinephrine – major neurotransmitter released by the adrenal medulla. The adrenal medulla also releases some norepinephrine.

5. Adrenergic Agonists
Produce their effects by activating adrenergic receptors
Sympathomimetic
Broad spectrum of applications
CHF
Asthma
Preterm labor 5

6. Mechanisms of Adrenergic Receptor Activation
Direct receptor binding
Promotion of norepinephrine (NE) release
Inhibition of NE reuptake
Inhibition of NE inactivation 6

7. Overview of Adrenergic Agonists
Therapeutic applications and adverse effects of adrenergic receptor activation
Properties of representative adrenergic agonists
Discussion of adrenergic agonists in other chapters 7

8. Overview of the Adrenergic Agonists
Catecholamines
Cannot be used orally
Brief duration of action
Cannot cross the BBB (polar molecules)
Noncatecholamines
Can be given orally
Metabolized slowly by MAO – longer half-life
More able to cross the BBB
Catecholamines: include dopamine, as well as the “fight-or-flight” hormones, adrenalin (epinephrine) and noradrenaline (norepinephrine) released by the adrenal medulla of the in response to stress.
In the human body, the most abundant catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine. Various stimulant drugs are catecholamine analogues. Catecholamines are water-soluble and are 50% bound to plasma proteins, so they circulate in the bloodstream.
Non-catecholamines - adrenergic drugs that are not chemically identical to catecholamines but still activate, directly or indirectly, the α- and β-receptors. They include ephedrine, amphetamine, phenylephrine, and methoxamine. 8

9. Mort & Merv: the story of selectivity
Figure Multiple drug receptors and selective drug action. Mort, All of Mort’s organs are regulated through activation of type A receptors. Drugs that affect type A receptors on one organ will affect type A receptors on all other organs. Hence, selective drug action is impossible. Merv, Merv has four types of receptors (A, B, C, and D) to regulate his four organs. A drug that acts at one type of receptor will not affect the others. Hence, selective drug action is possible.

10. Receptor specificity Most drugs in chapter
Peripherally acting sympathomimetic
Direct receptor activation
Amphetamine, cocaine
Indirect acting sympathomimetic
Ephedrine
Direct receptor activation and promotion of NE release 10

11. Receptor Specificity Beta1 and beta2 Alpha1 and alpha2 Beta2 only
Terbutaline
(Bricanyl)
Beta1 and beta2
Isoproterenol
(Isuprel)
Alpha1 and alpha2
Epinephrine 11

12. Therapeutic Applications Adrenergic Agonists
Clinical applications of alpha1
Two responses for therapeutic use
Vasoconstriction (most common use)
Blood vessels
Skin
Viscera
Mucous membranes
Mydriasis 12

13. Therapeutic Applications and Adverse Effects of Adrenergic Receptor Activation
Drugs capable of activating alpha1 receptors
Epinephrine
Norepinephrine (Levophed)
Phenylephrine (Neosynephrine)
Ephedrine
Dopamine 13

14. Therapeutic Applications and Adverse Effects of Adrenergic Receptor Activation
Therapeutic applications of alpha1 activation
Hemostasis
Arrest bleeding via vasoconstriction
Nasal decongestion
Mucosal vasoconstriction
Adjunct to local anesthesia
Delays absorption of local anesthetic
Elevation of blood pressure
Vasoconstriction
Mydriasis
Radial muscle of the iris 14

15. Therapeutic Applications and Adverse Effects of Adrenergic Receptor Activation
Adverse effects of alpha1 activation
Hypertension
Widespread vasoconstriction
Necrosis
Treatment with alpha1 blocking agent
Bradycardia
Response to vasoconstriction and elevated BP 15

16. Clinical Consequences of Alpha2 Activation
Alpha2 receptors in periphery
Located presynaptically
Regulate transmitter release
Activation inhibits NE release
Alpha2 in CNS
Reduction of sympathetic outflow to heart and blood vessels
Relief of severe pain 16

17. Clinical Consequences of Beta1 Activation
Therapeutic applications of beta1 activation
Cardiac arrest
Not preferred drug of choice
Heart failure
Positive inotropic effect
Shock
Positive inotropic effect; increases heart rate
Atrioventricular heart block
Enhances impulse conduction through AV 17

18. Clinical Consequences of Beta1 Activation
Adverse effects of beta1 activation
Altered heart rate or rhythm
- Tachycardias or dysrhythmias
Angina pectoris
- Increased cardiac oxygen demand 18

19. Clinical Consequences of Beta2 Activation
Therapeutic applications of beta2 activation
Asthma
Delay of preterm labor
Adverse effects of beta2 activation
Hyperglycemia
Tremor 19

20. Clinical Consequences of Dopamine Receptor Activation
Activation of peripheral dopamine receptors causes dilation of the vasculature of the kidneys 20

21. Multiple Receptor Activation: Treatment of Anaphylactic Shock
Pathophysiology of anaphylaxis
Severe allergic response
Hypotension, bronchoconstriction, edema of the glottis
Treatment
Epinephrine, injected IM, is the treatment of choice for anaphylactic shock 21

22. Adrenergic Agonists Epinephrine Norepinephrine Isoproterenol Dopamine
Dobutamine
Phenylephrine (Neo-synephrine)
Terbutaline
Ephedrine 22

23. Epinephrine Therapeutic uses Delay absorption of local anesthetic
Control superficial bleeding
Elevate blood pressure
Mydriasis during ophthalmologic procedures
Overcome AV block
Restore cardiac function in arrest
Bronchial dilation in asthma
Treatment of choice for anaphylactic shock 23

24. Epinephrine Pharmacokinetics Adverse effects Absorption Inactivation
Hypertensive crisis
Dysrhythmias
Angina pectoris
Necrosis following extravasation
Hyperglycemia 24

25. Epinephrine Drug interactions MAO inhibitors Tricyclic antidepressants
General anesthetics
Alpha-adrenergic blocking agents
Beta-adrenergic blocking agents 25

26. Epinephrine Preparations, dosage, & administration
EpiPen (1:1000 or 1:2000)
IV (monitor closely) (1:10,000) IM
SubQ
Intracardiac
Intraspinal
Inhalation
Topical 26

27. Norepinephrine Receptor specificity Chemical classification
Alpha1
Alpha2
Beta1
Chemical classification
Catecholamine
Therapeutic uses
Hypotensive states
Cardiac arrest 27

28. Norepinephrine
Differs from epinephrine – does not activate beta2 receptors
Does not promote hyperglycemia
Cannot be given orally (MAO and COMT)
Necrosis with extravasation
Drug interactions
MAOI, TCA, general anesthetics, adrenergic blocking agents
Catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) are the two enzymes primarily responsible for the initial metabolic disposition of infused catecholamines 28

29. Isoproterenol Receptor specificity: beta1 and beta2
Chemical classification: catecholamine
Therapeutic uses
Cardiovascular
- AV heart block, arrest
Asthma
- Bronchodilation – not used anymore
Bronchospasm
- During anesthesia 29

30. Isoproterenol Adverse effects Drug interactions
Fewer than those of NE or epinephrine (doesn’t activate alpha-adrenergic receptors)
Tachydysrhythmias and angina pectoris
Hyperglycemia in diabetes patients
Drug interactions
MAOI, TCA, beta-adrenergic blockers
Preparations and administration
IV, IM, and intracardiac injections 30

31. Dopamine Receptor specificity Low therapeutic dose – dopamine
Moderate therapeutic dose – dopamine and beta1
Very high dose – apha1, beta1, and dopamine 31

32. Dopamine Therapeutic uses Shock Heart failure Acute renal failure
Increases cardiac output
Increases renal perfusion
Heart failure
Increases myocardial contractility
Acute renal failure
Was used to preserve renal function with ARF
Early ARF – failed to protect renal function, shorten stays, or reduce need for renal transplant 32

33. Dopamine Adverse effects Drug interactions
Tachycardia, dysrhythmias, anginal pain
Necrosis with extravasation
Drug interactions
MAOI, TCA, certain general anesthetics, diuretics
Preparations, dosage, and administration
Preparations: dispensed in aqueous solutions
Dosage: must be diluted
Administration: administered by IV
Monoamine oxidase inhibitors are a class of antidepressants that were developed in the 1950s. They are effective in treating depression, panic disorder, and other anxiety disorders. Although they are generally as effective as selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCAs) , they are used less frequently because of necessary dietary precautions and risks of adverse reactions when mixed with certain drugs.
MAOI – Isocarboxazid (Marplan)
Phenelzine (Nardil)
Selegiline (Emsam, Eldepryl, Zelapar)
Tranylcypromine (Parnate)
Tricyclics - Amitriptyline
Imipramine (Tofranil)
Clomipramine (Anafranil)
Nortriptyline (Pamelor)
Desipramine (Norpramin) 33

34. Dobutamine Receptor specificity: beta1
Chemical classification: catecholamine
Actions and uses
CHF
Adverse effects
Tachycardia
Drug interactions
MAOI, TCA, certain general anesthetics
Preparations, dosage, and administration
Continuous IV infusion 34

35. Phenylephrine Receptor specificity Chemical classification
Alpha1
Chemical classification
Noncatecholamine
Therapeutic uses
Reduce nasal congestion (locally)
Elevate blood pressure (parenterally)
Dilate pupils (eye drops)
Local anesthetic (delay absorption) 35

36. Terbutaline Receptor specificity: beta2
Chemical classification: noncatecholamine
Therapeutic uses
Asthma (selective for beta2)
- Replaced isoproterenol in treatment
Delay of preterm labor
- Relaxes uterine smooth muscle
- Another drug (ritodrine) now preferred
Adverse effects
- Minimal at therapeutic doses
- Tremor most common; also tachycardia 36

37. What’s he got to do with Pharm?

38. Anybody ever taken ephedrine?

39. Are you sure?

40. Ephedrine Receptor specificity: alpha1, alpha2, beta2
Chemical classification: noncatecholamine
Therapeutic uses
Nasal congestion
Other uses
Adverse effects
HTN, dysrhythmias, angina, hyperglycemia, insomnia (crosses BBB) 40

41. Good thing gone bad…

42. Questions