1. Adrenergic Agonists
Dr. Asmah Nasser, M.D.

3. Steps of Catecholamie Synthesis
Tyrosine tyrosine hydroxylase DOPA
DOPA DOPA decarboxylase dopamine
DA DA β-decarboxylase NE
NE is taken up and stored in granules
NE not stored in storage granules are called as mobile pool (MAO can metabolize these)
NE releases via exocytosis as Ca++ enters.
NE attaches to receptors in the post-synaptic neuron

4. Routes of NE after metabolism/after release
NE can be transported back into the pre- synpatic neuron (reuptake)
NE can activate the presynaptic receptors (α- 2 for negative feedback)
NE can be metabolized by COMT enzyme
End product of EPI metabolism  VMA
End product of DOPA metabolism  VHA

5. Know the rate limiting enzyme
Know routes of NE after release
Know about metabolism within pre- synapse

6. Theoretical drug targets
MAO inhibitors: increase the prejunctional levels of NE
Mobile pool: displace NE from mobile pool
Uptake: inhibit the uptake into nerve cell increases levels of NE)
Activation of pre-synapse alpha receptors
Postsynaptic receptors

7. About the adrenergic system….
Sympathetic nervous system exerts its effects by acting on:
 , β, and D receptors
 receptors are subdivided into 1 and 2
β receptors are subdivided into β1 and β2 and β3
D = Dopamine receptors

8. Role of SSNS
Important regulator of the activities of heart and peripheral vasculature, especially in responses to exercise and stress
Drugs that mimic the actions of epinephrine are called sympathomimetic drugs or adrenergic drugs
Has a wide range of effects and uses

9. Indirectly acting drugs
Two types of drugs, which involve:
Displacement of stored catecholamines from the pre-synaptic nerve (amphetamine and tyramine)
Inhibition of reuptake of catecholamines already released (cocaine)
Some drugs have both direct and indirect actions.
Both types of sympathomimetics, direct and indirect, ultimately cause activation of adrenoceptors, leading to the characteristic effects of catecholamines

10. Review of the receptors of the SNSA1
Blood vessels
Pupil (Iris)
Smooth muscle (GI/GU)
Vasoconstriction
Mydriasis
sphincter contraction Constipation and Urinary retention A2
Presynaptic neurons
Reduces release of norepinephrine (as a negative feedback mechanism)  bradycardia,hypotension B1
Heart
Contraction  Increased heart rate B2
Smooth muscles
Relaxation Bronchodilation, urinary retention, constipation, uterus relaxation D
Arteries
Arteriodilation of Arteries (Renal, Mesenteric, Coronary)

11. Net activity of a drug depends on its affinity for the receptor.

12. Cardiovascular System
Blood Vessels
Vascular smooth muscle tone is regulated by adrenoceptors
1 increase arterial resistance.
β1 increases heart rate.
β2 causes smooth muscle relaxation with slight decrease in arterial resistance  decrease BP

13. Blood Pressure
A relatively pure 1 agonist such as phenylephrine increases peripheral arterial resistance
This leads to a dose-dependent rise in blood pressure
A relatively pure β agonist such as isoproterenol decreases peripheral resistance by activating β2 receptors (smooth muscle relaxation )

16. Organ system effects: CNS
Catecholamines do not cross the BBB effectively
Some drugs i.e. amphetamine/cocaine does cross the BBB and produces stimulant effects
Starts with reducing fatigue and progresses as anorexia, euphoria and insomnia
Very high doses-aggressiveness, marked anxiety and convulsions

17. Amphetamine Used and misused as a CNS stimulant
Amphetamine easily enters the CNS
It has marked stimulant effects on mood and alertness and a depressant effect on appetite.
Its peripheral actions are mediated primarily through the release of catecholamines
Methamphenidate (N-methylamphetamine) is very similar to amphetamine with a higher ratio of central to peripheral actions .
??? Lipolysis from Beta3

18. Eye
The radial pupillary dilator muscle of the iris contains 1 receptors
Activation causes mydriasis
 and β stimulants also have important effects on intraocular pressure.
 agonists decreases the outflow of aqueous humor from the eye and β antagonists (timolol) decrease the production of aqueous humor.

19. Respiratory Tract
Bronchial smooth muscle contains β2 receptors that cause bronchodilation
The blood vessels of the upper respiratory tract mucosa contain α1 receptors. Decongestants are α1 agonists, causes vasoconstriction.

20. Genitourinary Tract
The bladder base, urethral sphincter, and prostate contain 1 receptors that mediate contraction and therefore promote urinary rentention.
β are found in the Uterus causing smooth muscle relaxation.

21. Epinephrine A very potent vasoconstrictor and cardiac stimulant.
The rise in systolic blood pressure that occurs after epinephrine is due to its positive inotropic and chronotropic actions on the heart (predominantly β1 receptors) and the vasoconstriction induced in many vascular beds (1 receptors).
Epinephrine also activates β2 receptors in skeletal muscle blood vessels, leading to their dilation. Consequently, TPR may fall,
Contributes to increased blood flow during exercise.
Not absorbed if given orally. Must be given IV

22. Epinephrine Uses: Contraindications: Anaphylactic Shock
Increases local anesthestic action (by vasoconstriction)
Cardiac arrest
Contraindications:
Hyperthyroidism
HTN
Arrthymias

23. Anaphylaxis Anaphylaxis Immediate (type I) IgE-mediated reactions
Characterized by bronchospasm, mucous membrane congestion, angioedema, and severe hypotension
Treatment: Epinephrine and Steroids

24. 1 Selective Agonists Phenylephrine : MOA: Alpha 1 receptor agonist
Metabolism: Degraded rapidly by MAO
Very low Bioavailability
Causes vasoconstriction of vessels.
Nasal and ophthalmic preparations.
Uses:
Nasal Decongestant
Mydriasis (doesn’t cause cycloplegia)
Side effects/Contraindications: Closed angle Glaucoma. Rebound congestion.

25. 2 Selective Agonists Clonidine
Alpha 2 receptor agonist  negative feedback  Decreased release of NE
Used in Hypertension, diabetic diarrhea, narcotic addicts and to treat benzodiazepam withdrawal effects
Crosse BBB
Side effects: Orthostatic hypotension, dry mouth, sedation, rebound hypertension, Sexual Dysfunction

26. 2 Selective Agonists -methyldopa Doesn’t cross placenta
Uses: HTN, Gestational HTN, Chronic HTN during Pregnancy

27. Non-selective  agonists
Oxymetazoline and Xylometazoline
Higher affinity for 1 than 2 (partial  2 agonist)
Also causes vasoconctriction.
Used as a nasal decongestant

28. Dopamine
At low concentrations: Stimulates D receptors, causes Vasodilation of arteries (renal, coronary, GI)
At intermediate doses: Stiumates Beta 1 receptors  tachycardia
At high doses: – stimuates alpha 1 receptors  Vasoconstriction
Uses: Cardiogenic shock (beta 1 stimulation), CHF, Hypotension (alpha 1 stimulation)
Adverse effects: HTN, Tachycardia, arrythmias

29. Special Sympathomimetics
Cocaine:
is a local anesthetic with a peripheral sympathomimetic action
The action results from inhibition of transmitter reuptake at pre-synapse.
Readily enters the CNS and produces an amphetamine-like effect that is shorter lasting and more intense.
The major action of cocaine in the central nervous system is to inhibit dopamine reuptake into neurons in the "pleasure centers" of the brain.
Increased epinephrine leads to systemic symptoms of sympathetic effects.

30. Tri-cyclic Anti-depressants
Drugs used in Depression
Like Cocaine, TCA inhibits the reuptake of NE to the pre-synaptic neuron, as well as serotonin.
If TCA Is given in adjunct with another adrenergic agonist  Hypertensive Crisis

31. Tyramine It is a normal by-product of tyrosine metabolism in the body
Also found in high concentrations in fermented foods such as cheese and fish.
If administered parenterally, it has an indirect sympathomimetic action caused by the release of stored catecholamines.
Just like amphetamines, it increases the number of catecholeamines at the synapse.

32. Clinical implications
In patients treated with MAO inhibitors (drug used in Depression and Parkinson’s disease) – causes an increase in NE levels.
Effect of tyramine is greatly intensified, leading to marked increases in BP and HR – hypertensive crsis, AKA “Cheese syndrome”
 Arrythemia or Stroke
Patients taking MAO inhibitors must be very careful to avoid tyramine-containing foods.

33. Amphetamines Legitimate indications of amphetamine include:
Causes released of stored NE from the pre- synapse into the synapse.
Narcolepsy & ADHD
Obesity???
Side effects: Insomnia, Decreased apetite, decreases respiratory center

35. Isoproterenol
Very potent β-receptor agonist and has little effect on  receptors.
Leads to an increase and Heart rate (β1) with a decrease in blood pressure (β2)
This lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure

36. Beta 1 agonists
Dobutamine: Increases heart rate. Used in cardiogenic shock, acute heart failure.

37. Beta 2 agonists
Terbutaline – used in pre-term labor. Causes smooth muscle relaxation in the uterus.
Ritodrine – Also used in preterm labor

38. Beta 2 agonists for Asthma
Short acting (rescue drugs): Albuterol, Terbutaline
Long acting (maintenance drugs): Salmetrol
Inhaled Beta agonists is used in Asthma. Causes smooth muscle relaxation at the bronchus (bronchodilaton)
Adverse drug effects: Tachycardia, tremors, palpitations

39. Summary Know about production and metabolism of NE
Know the different receptors of the SNS, the organs they are in, and their net effects
Know about SNS effect of Eyes, BP, HR, Respiratory system, and GU tract
Know about Cocaine, Amphetamine, and Tyramine, TCA
Know about alpha 1 agonists, alpha 2 agonists, and Beta agonists. Mechanism, Indictions, Side effects 

40. Pretest Question
Of the many types of adrenergic receptors found throughout the body, which is most likely responsible for the cardiac stimulation that is observed following an intravenous injection of epinephrine?
a. α1-adrenergic receptors
b. α2-adrenergic receptors
c. β1-adrenergic receptors
d. β2-adrenergic receptors
e. β3-adrenergic receptors

41. Pretest Question Ritodrine hydrochloride is used in the treatment of
a. Parkinson’s disease
b. Bronchial asthma
c. Depression
d. Hypertension
e. Premature labor

42. Pretest Question
Epinephrine may be mixed with certain anesthetics, such as procaine, in order to
a. Stimulate local wound repair
b. Promote hemostasis
c. Enhance their interaction with neural membranes and their ability to depress nerve conduction
d. Retard their systemic absorption
e. Facilitate their distribution along nerves and fascial planes

43. Pretest Question
The drug of choice for the treatment of anaphylactic shock is
a. Epinephrine
b. NE
c. Isoproterenol
d. Diphenhydramine
e. Atropine

44. Pretest Question
A 60-year-old male with congestive heart failure (CHF) is treated with dobutamine. Select the mechanism of action of dobutamine.
a. α-adrenergic agonist
b. α-adrenergic antagonist
c. β-adrenergic agonist
d. β-adrenergic antagonist
e. Mixed α and β agonist
f. Mixed α and β antagonist

45. Pretest Question
Of the following structures, which does not respond to β-adrenergic receptor stimulation?
a. Ciliary muscle of the iris
b. Radial muscle of the iris
c. Bronchial muscle
d. Atrioventricular (AV) node
e. Sinoatrial (SA) node

46. Pretest Question
A 16-year-old male treated for bronchial asthma develops skeletal muscle tremors. Which of the following agents may be responsible for this finding?
a. Ipratropium
b. Zileuton
c. Beclomethasone
d. Cromolyn
e. Salmeterol

47. Pretest Question
Which of the following agents should a patient take for a stuffy, runny nose?
a. Oxymetazoline
b. Albuterol
c. Clonidine
d. Terbutaline
e. Metoprolol

48. Pretest Question
A 10-year-old male displays hyperactivity and is unable to focus on his schoolwork because of an inability to focus on the activity. Which of the following might prove effective in this patient?
a. Methylphenidate
b. Terbutaline
c. Dobutamine
d. Pancuronium
e. Prazosin
f. Scopalamine