1. Adrenergic Agonists (Sympathomimetics)

2. Characteristics of Adrenergic Agonists
Most of adrenergic agonists are β-phenylethylamine derivatives.
Substitution on either the benzene ring or on the ethylamine side chain give a great variety of compounds which can be divided into:
Catecholamines
non-catecholamines

3. Catecholamines Contain 3,4 dihydroxybenzene group
Examples: Epinepheine, Norepinephrine, Isoproterenol & Dopamine
Substitiution on the amine nitrogen
They have common characters:
Highest potency in activating α or β-receptors
Rapid inactivation by MAO & COMT when given parenterally and inactive orally
Poor penetration of CNS (anxiety, tremor & headache)

4. Noncatecholamines Characters:
Example: Phenylepheine, Ephedrine & Amphetamine
Characters:
They are poor substrate for COMT & MAO i.e. longer duration of action
Increased lipid solubility i.e. enter CNS

6. Pharmacokinetics Catecholamines Non-Catecholamines
Metabolized by
MAO & COMT
Not metabolized
by MAO & COMT
Substrate for uptake 1
Rapid onset
Shorter duration
Longer duration &
higher bioavailability
Orally ineffective
Only metabolites are
Excreted in urine (VMA)
Orally effective
Excreted unchanged in urine
↑ by urine acidification
Cross BBB

7. Mechanism of action of the Adrenergic agonists
Direct-acting agonists:
Epinephrine, Norepinephrine, Isoproterenol, Dopamine, Dobutamine & Phenylephrine
-produce their effect by directly stimulating the receptor site.
Indirect-acting agonists:
Amphetamine & Tyramine
- release endogenous norepinephrine which then stimulates the receptor.
Mixed-action agonists:
Ephedrine & Metaraminol
either directly stimulate the receptor or release endogenous NA.

8. Direct-Acting Agonist:
e.g. Phenylephrine (α1)
Clonidine (α2) (sympathomimetic ?)
Isoprenaline & Dobutamine (β1)
Salbutamol & Terbutaline (β2)

9. Effects of Adrenergic Agonists
Cardiovascular:
Heart: ↑HR, contractility » ↑CO + O2 consumption
↑Conductivity (atria, AV node & ventricles)
↑Excitability » arrhythmia
BV: VD or VC depending on the selective activity of drug and the anatomic site of vessels
e.g. Skin, Splanchnic, Sk.M., renal BV
BP: Depends on effect on heart, PR & venous return
The effect of α-agonist is different from β-agonist

10. CVS Effect of α-agonist
Vasoconstriction leading to rise in PR & BP
↑ Systolic & diastolic BP (abolished by α-blocker)
Baroreceptor reflex causing ↑ vagal supply to the heart leading to bradycardia (blocked by atropine)
CO is not decreased in proportion to the decrease in HR because the venous return increase the stroke volume

11. CVS Effect of β-agonist
β1 : +ve chronotropic effect (↑ HR)
+ve inotropic effect (↑ force of contraction)
↑ CO and so ↑ systolic BP
β 2: Dilation of arterioles of Sk.M. (↓PR) and so ↓both of systolic & diastolic BP
No vasoconstriction
Slightly ↑ of systolic BP & ↓ diastolic BP

13. Summary Adrenalin (α & β): ↑ systolic BP & slight ↓diastolic BP
NA: (α & β1) ↑ systolic & diastolic BP + Reflex bradycardia
Isoproterenol (β-agonist): slight ↑ systolic BP & ↓diastolic BP
Indirect acting sympathomimetics: ↑ BP (hypertensive crisis)
Dopamine: ↑ D receptors (renal vasculature VD) + ↑ β1 (heart) + ↑ α1 at high doses (VC)

14. Effects of I.V. infusion of Norepinephrine and Isoprenaline in Humans
Blood pressure
Reflex bradycardia
isoprenaline decrease DBP because they act on β2
Peripheral
resistance
Isoprenaline decrease resistance because it acts on β only without α

16. Effects of Adrenergic Agonists
Smooth Muscles:
Bronchi: bronchodilation (β2) & ↓ bronchial secretion (α1)
GIT: relax wall & contract sphincter (constipation)
Urinary Bladder: relax wall & contract sphincter (urinary retention)
Eye:
Ciliary muscle (β2)
Vasoconstriction of conjunctival BV (decongestion)
Active mydriasis (α1)

17. Effects of adrenergic agonists (cont.)
METABOLISM
Hyperglycemia:
Increase liver glycogenolysis (β2)
Increase glucagon release (β2)
Decrease insulin release (α2)
Lipolysis:
Increase hydrolysis of TG into free fatty acids & glycerol (β3)
cAMP

18. Central Nervous System (CNS)
These drugs produce CNS excitation or alertness
Higher doses produce anxiety, apprehension, restlessness, and tremors.

19. Dopamine Immediate precursor of NE Occurs in Activates:
CNS (act as neurotransmitter)
Adrenergic nerve ending
Adrenal medulla
Activates:
α1(at high doses)
β1 (at small doses)
D1(occurs in renal vascular bed)
D2 (occurs in presynaptic adrenergic neurons)

20. Pharmacological Effects of Dopamine
CVS:
+ve chronotropic & inotropic effects
At high doses: VC of BV
Renal & visceral:
VD of renal and splanchnic arterioles
Effective in treatment of shock (the drug of choice taken by continuous infusion)

21. Indirect-Acting Adrenergic Agonists
They are structurally related to NA but lack one or two OH gp of catechol ring (Not metabolized by COMT)
They are taken by uptake-1 and displace NA from vesicles without exocytosis, so their action do not require calcium ions
They have CNS effect particularly amphetamine which depends on their ability to release, not only NA, but also 5-HT and dopamine from nerve terminals in the brain
Tachyphylaxis

22. Indirect-Acting Adrenergic Agonists (cont.)
Drug Interactions
Reserpine: Abolishing their effect
Depleting the stored vesicles
MAOI: Potentiation
They inhibit the metabolism of released NA & also tyramine
TCA: Interfere with their effect
Uptake-1 inhibitor

23. Inhibit storage

24. Ephedrine Plant origin, synthetic compound Mixed-action acting drug
It is not a catechol and is a poor substrate for COMT and MAO
Pharmacological effects:
↑ systolic & diastolic BP by VC and cardiac stimulation
Bronchodilation (slowly and less than EP & isoproterenol), so used as prophylactic in chronic asthma (not acute)
Mild CNS stimulation (↑ alertness, ↓ fatigue & prevent sleep)
Improve athletic performance
Nasal decongestant

25. Clinical Uses of Adrenergic Agonists
Cardiovascular:
Cardiogenic Shock, Cardiac arrest:
β agonist: Adrenaline, dobutamine or dopamine
Dopamine is clinically more useful in the treatment of shock, in which significant increase in sympathetic activity might compromise renal function and worsens the peripheral circulation
Malignant hypertension: α2 agonist: Clonidine
HYPOTENSION: α1 agonist phenylephrine
Heart block : β agonist: isoprenaline
It’s only used now to reverse the block which is produced by overdoses of β – blockers

26. N.B. cardiac arrest means : complete cessation of heart’s activity.
While heart block means : partial or complete inhibition of the spread of conduction of the electrical impulse from the atria to the ventricles
Anaphylactic reactions:
Ad is the first line of treatment for bronchoconstriction & CV collapse
Both β and α agonist required.
We use EP with steroid and antihistamine to cause Bronchodilation, Increase BP

27. Clinical Uses of Adrenergic Agonists (cont.)
ritordine
Respiratory:
Asthma and premature labor contractions: For treatment » Isoprenaline (β agonist), Salbutamol, Terbutalin & Salmeterol (selective β2 is preferred)
For prophylaxis » Salmeterol & Formoterol
Norepinephrine is NOT used in treatment of asthma
Nasal Decongestion: Ephedrine
Haemostatic in epistaxis: Adrenaline & Ephedrine
Miscellaneous:
Mydriatic: Ephedrine
Glaucoma: Adrenaline decrease IOP in open angel glaucoma, decrease aqueous humor production by VC of ciliary body BV.
Depression: Amphetamine

28. With local anesthetics: Adrenaline & NA
These drugs are used in dentistry because of their vasoconstrictive actions on blood vessels.
They are added to local anesthetics because they prolong the action of the local anesthetic, reduce the risk for systemic toxicity, and help to create a dry field.

29. Central Nervous System Stimulation
These medications are used for the treatment of attention deficit hyperactivity disorder, narcolepsy, and as diet aids.

30. Adverse Effects
CNS disturbance: anxiety, fear, tension, headache & tremors
Cerebral hemorrhage
Tachycardia & Cardiac arrhythmias
Tachyphylaxis occurs with indirectly acting drugs

31. Contraindications to use of adrenergics
Cardiac dysrhythmias, angina pectoris
Hypertension
Hyperthyroidism
Cerebrovascular disease
Distal areas with a single blood supply such as fingers, toes, nose and ears
Renal impairment use caution

32. Toxicity of adrenergics in critically ill patients
Affects renal perfusion
Can induce cardiac dysrhythmias
Increases myocardial oxygen consumption
May decrease perfusion of liver
Tissue necrosis with extravasation

33. Phenylephrine Clinical uses:
As a mydriatic agent to examine the fundus of the eye
It acts on α1 – receptors in the radial dilator pupillary muscle
As a decongestant
Used as nasal drops to cause VC in the nasal blood vessels & relief congestion
As a vasopressor agent in case of hypotension
α1 stimulation causes VC leading to increase BP

34. Clinical use of Amphetamine-like drugs
To suppress appetite
In very obese persons Amphetamine can act centrally on the hunger center in the hypothalamus to suppress appetite
In narcolepsy
Narcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night
Amphetamine stimulates the CNS & makes the patient awake
In ADHD “Attention Deficit Hyperactivity Disease”

35. Ephedrine Clinical uses:
Pressor agent (used to increase BP)
Decongestant
It is no longer used to treated bronchial asthma. (because it’s less potent + slow onset of action)

36. Pseudoephedrine: Has similar pharmacological activities to ephedrine
It is not controlled : OTC (over the counter)
It is commonly used as a decongestant

37. Phenylpropranolamine:
Again it is similar to pseudoephedrine, and was used as decongestant, but it was stopped because it may cause cerebral hemorrhage

38. Dobutamine: It is direct acting β 1 – selective agonist
Given only parenterally (not orally)
It causes increases in CO
Uses: Inotropic agent for Heart Failure; in septic and cardiogenic shock.

39. Salbutamol: It is β2 – selective agonist
Can be used orally, IV and by inhalation
Formulations: (Tablets; Syrup; Injection; solution and Inhalation)
Clinical Uses
bronchial asthma by β2 stimulation, which leads to relaxation of bronchial smooth muscle and bronchodilation.
Treatment of refractory hyperkalemia (I.V)

40. Salmetrol and Formoterol:
These selective beta agonists, have longer duration of action as compared to Salbutamole.
Uses: As inhalors for bronchial Asthma

41. Clonidine: It is a selective α2 – agonist
Mechanism of action : (Acts centrally as a central sympatholytic drug.)
Clonidine is Lipid – soluble, so, it freely passes BBB & reaches CNS to stimulate α2 – receptors in medulla and pons causing decreased sympathetic tone and finally decrease BP
It act by it self not like Methyldopa
Clinical use include:
Treatment of mild to moderate hypertension
Treatment of morphine withdrawal symptoms
As analgesic during labour
The dose = 1.25 ug/day
It can be given I.M

42. Adverse affects of Clonidine
Depression
Dizziness, insomnia, & nightmares
Impotence
Alopecia تساقط الشعر
Urticaria
Weight gain
Fluid retention
Sudden withdrawal leads to rebound hypertension
Metyldopa and the comparison between it and clonidine are in the lecture (adrenergic antagonists)

43. 3. Apraclonidine
Like clonidine it is selective α2 adrenoceptor agonist, however, main uses as adjuvant therapy for glaucoma via decrease of aqueous humour formation.