1. Adrenergic agonists
Samuel Aguazim (MD)

2. 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)

3. Name alpha selective direct – acting agonists
Phenylephrine
Methoxamine
Clonidine
methyldopa

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

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

6. Direct- acting agonists considered catecholamines
Epinephrine
Norepinephrine
Isoproterenol
Dopamine
dobutamine

7. INDIRECT ACTING
Amphetamine
Tyramine

8. TWO MIXED AGONISTS
DIRECT & INDIRECT ACTING
Ephedrine
Metaraminol

9. 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

10. 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

11. 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

12. 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

13. 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

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

15. 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

16. 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

17. 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

18. 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.

19. 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

20. 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

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

22. 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

23. 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

25. 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

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

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

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

29. Central Nervous System Effects
Respiratory stimulation
CNS stimulation

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

31. (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)

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

33. Cardiac effects Heart rate increases Cardiac output increases
Oxygen consumption increases

34. 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

35. 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

36. 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

37. 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

38. 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

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

41. Adverse effects palpitations tachycardia arrhythmias
coronary insufficiency

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

43. 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.

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

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

48. Indirectly Acting drugs
Amphetamine
Tyramine

49. 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

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

51. 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

52. 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.

53. 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

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