Adrenergic drugs and the therapeutic action

1. ADRENERGIC AGONISTS
Chapter 15-1

2. Adrenergic agonists
Activate adrenoceptors
Mimic the actions of epinephrine or norepinephrine
• Also called sympathomimetics
Chapter 15-2

3. classification
 Fall into two major chemical classes:
 Catecholamines and Noncatecholamines
 Catecholamines and Noncatecholamines differ in
oral usability
duration of action, and
the ability to act in the CNS
Chapter 15-3

4. A. Catecholamines
Include
• NE, E & DA in addition to the synthetic analog
isoproterenol
They have the following characteristics:
• High potency
• Rapid enzymatic inactivation by MAO & COMT as
well as neuronal & non-neuronal uptake
• Therefore they have short duration when given
parentrally and are inactive orally
• Poor ability to pass the CNS
Chapter 15-4

5. Chapter 15-5

6. B. Non-catecholamines
Are adrenergic agonists lacking the catechol hydroxyl
groups
Therefore they are of longer duration,
Can be given orally and they are not inactivated by
COMT
Are less polar and more able to cross BBB
They include agents like phenylephrine, ephedrine
and amphetamine
Chapter 15-6

7. Chapter 15-7

8. Mechanism Of Action (moa)
• Based on their MOA, they can be classified into:
• Direct-acting
• NE,E, DA, phenylephrine and isoproterenol
• Indirect acting
• displacement of stored catecholamines from the adrenergic
nerve ending (eg.tyramine) or
• inhibition of reuptake of catecholamines already released (eg.
cocaine and tricyclic antidepressants).
• inhibition of NE inactivation
• Mixed acting-eg.ephedrine
Chapter 15-8

9. Chapter 15-9

10. Direct-acting agents
Epinephrine
• Receptor specificity: alpha1, alpha2, beta1, beta2
• Chemical classification: catecholamine
Chapter 15-
10

11. Pharmacokinetics
• Orally not effective
• SC: slow absorption (due to vasoconstriction)
• More rapid absorption through IM
• IV used only in emergency conditions
• Inhalational aerosol to produce local effect
• Metabolism is via hepatic MAO and COMT
Chapter 15-
14

12. Therapeutic use
• Asthma
• Anaphylactic shock
• Prolong action of local anesthetics
• Topical hemostatic agent
• To lower intraocular pressure
Chapter 15-
15

13. Adverse effects and contraindications
• Restlessness, throbbing headache, tremor, palpitations,
cerebral hemorrhage, cardiac arrhythmias
• Angina may be induced in coronary artery disease
• Contraindicated in patients taking -AR blockers
Chapter 15-
16

14. Dopamine: pharmacological effects
• CVS
 Dopamine exerts its cardiovascular actions by
1. Releasing NE from adrenergic neurons
2. Interacting with -and -ARs, and
3. Interacting with specific dopamine receptors
 Low rates of dopamine infusion
 D1-mediated vasodilation in renal, coronary and intercerebral
vascular beds with little effect on other blood vessels or on the
heart.
 ed GFR, renal blood flow, Na+ excretion (appropriate in
management of such states as CHF)
Chapter 15-
19

15. Dopamine
 Higher rate of infusion
1-mediated +ve ionotropy
Releases NE from nerve terminals
ed systolic BP
 Even higher levels
Activates 1-ARs and cause a more generallized
vasoconstriction
Chapter 15-
20

16. Dopamine
Clinical uses
• Treatment of severe congestive failure
• Treatment of cardiogenic and septic shock.
Chapter 15-
21

17. Isoproterenol
• Non-selective  receptor agonist with very low affinity for 
receptors
• Pharmacological Effects
 CVS
ed peripheral vascular resistance
ed Diastolic BP while systolic BP may remain unchanged
or rise
ed cardiac output
Chapter 15-
23

18. Isoproterenol
Pharmacological Effects (Cont’d)
 Smooth muscles
Relaxation especially those of the GI and bronchial
Metabolized primarily by COMT (relatively resistant to MAO
& is uptaken in to sympathetic neurons to a lesser extent than
Epi & NE)
Toxicity and Adverse effects
 Palpitations, tachycardia, headache, and flushing are common
and arrhythmias
Chapter 15-
24

19. Isoproterenol
• Therapeutic Uses
Management of bronchospasm (inhalation)
In emergencies to stimulate heart rate in patients
with bradycardia or heart block and asthma (I.V.)
Chapter 15-
25

20. Dobutamine
• Relatively 1 selective, but also acts on 1
• At therapeutic doses, dobutamine causes selective
activation of beta1-adrenergic receptors
• The only indication for the drug is heart failure
• The major adverse effect is tachycardia
Chapter 15-
26

21. Selective B2-AR agonists
• Adverse effects associated with activation of 1 are
avoided
Chapter 15-
27

22. Terbutaline
 Not a substrate for methylation by COMT
 Effective orally, subcutaneously, or by inhalation
 Effects observed rapidly on inhalation or parenteral
administration
 Therapeutic use
 Long-term treatment of obstructive airway diseases and acute
bronchospasm,
 Emergency treatment of status asthmaticus (Parenteral)
 Control premature labor
Chapter 15-
28

23. Albuterol
 Pharmacological properties and therapeutic indications
are similar to those of terbutaline
 Produces significant bronchodilation within 15 min, &
effects persist for 3 to 4 hours (Inhalation)
Chapter 15-
29

24. Salmeterol
 Has slow onset but prolonged duration of action (>12
hours)
 It also may have antiinflammatory activity
 Salmeterol or formoterol are the agents of choice for
nocturnal asthma in patients who remain symptomatic
despite antiinflammatory agents and other standard
management
Chapter 15-
30

25. Ritodrine
• 2 receptor agonist developed specifically for use as a
uterine relaxant.
 Use: To arrest premature labor (intravenously).
Chapter 15-
31

26. Selective 1-AR Agonists
• Phenylephrine
 Causes marked arterial vasoconstriction
 Used as a nasal decongestant and as a mydriatic
 Not a catechol derivative, hence not a substrate for COMT (acts
longer than the catecholamines)
Chapter 15-
32

27. Selective 2-AR Agonists
Clonidine
• Activates central 2-Ars to reduce sympathetic outflow
to the periphery.
• Also activates peripheral presynaptic 2-ARs
• Stimulates parasympathetic outflow
• IV infusion:
 Acute rise in BP (mediated through 2-ARs in vascular
smooth muscle)
 More prolonged hypotensive response (decreased
sympathetic outflow from the CNS)
Chapter 15-
33

28. Clonidine.......
• Well absorbed orally and has bioavaillability of about
100%
• Adverse effects
 Dry mouth, sedation, sexual dysfunction, marked
bradycardia, Rebound hypertension following abrupt
withdrawal of clonidine therapy.
• Therapeutic use
 Treatment of mild to moderate hypertension
Chapter 15-
34

29. -methyldopa
 Methyldopa, an analog of DOPA, is decarboxylated
to -methyldopamine which is then actively
transported to vesicles where it is -hydroxylated to
the 2-AR agonist -methylnorepinephrine.
 Use: treatment of hypertension (it is the preferred
agent during pregnancy)
 Adverse effects: sedation, dry mouth, bradycardia,
hepatotoxicity, hemolytic anemia
Chapter 15-
35

30. Indirect acting sympathomimetics
• Includes such drugs as amphetamine and its congeners,
tyramine
• Have weak actions on AR but sufficiently resemble NE to
be transported into nerve terminals by uptake 1.
• Inside the nerve terminals, they are taken up into vesicles,
displace the NE which escapes into the cytosol
Chapter 15-
36

31. Chapter 15-
37

32. • Actions
 Include bronchodilatation, raised arterial pressure,
peripheral vasoconstriction, increased heart rate and
force of myocardial contraction, and inhibition of gut
motility.
 They have important central actions, which account for
their significant abuse potential and for their limited
therapeutic applications
 These drugs are no longer used for their peripheral
sympathomimetic effects
Chapter 15-
38

33. Amphetamine: CNS effects
• CNS effects mediated by release of biogenic amines from
their storage sites in nerve terminals.
• Effects include alerting, anorexia
• With higher doses of amphetamine, disturbances of
perception and overt psychotic behaviour occur
Chapter 15-
39

34. • Tyramine in cheese, fermented sausage & wines
• It enters synaptic vesicle and causes
displacement & release of NE & normally
degraded by MAO
• MAO inhibitors in conjunction with tyramine-
containing foods may lead to rapid release of NE
& severe hypertension
Chapter 15-
40

35. • Tricyclic antidepressants (e.g. desipramine)
 Their major effect is on the CNS but also cause
tachycardia and cardiac dysrhythmias
• Cocaine
 Enhances sympathetic transmission, causing
tachycardia and increased arterial pressure.
 Its central effects of euphoria and excitement are
probably a manifestation of the same mechanism acting
in the brain.
Chapter 15-
41

36. Ephedrine
• Mixed acting (causes release of biogenic amines from
nerve terminals and also acts on both - & -AR)
• Has longer duration of action (resistant to metabolism by
MAO and COMT)
• It is used to treat mild cases of asthma
• It crosses BBB giving rise to CNS stimulant action
• It is now replaced by more selective β2 agonists
Chapter 15-
42

37. Pseudoephedrine & Phenylpropanolamine
• They stimulate the release of NE
• They are used as over-the-counter (OTC) nasal
decongestants for symptomatic relief of hay fever
and rhinitis
• Pseudoephedrine has little β2 agonist activity,
limited CNS stimulation
Chapter 15-
43

38. • A 68-year-old man presents to the emergency department
with acute heart failure. You decide that this patient
requires immediate drug therapy to improve his cardiac
function. Which one of the following drugs would be most
beneficial?
A. Albuterol.
B. Dobutamine.
C. Epinephrine.
D. Norepinephrine.
E. Phenylephrine.
Chapter 15-
44

39. Thank you
Chapter 15-
45