1. Adrenoceptor agonists

2. Overview
 The study of the sympathetic nervous system is
important from a clinical perspective. The SNS is
involved in controlling heart rate, contractility, blood
pressure, vasomotor tone, carbohydrate and fatty
acid metabolism etc. Stimulation of the SNS occurs in
response to physical activity, psychological stress,
allergies etc. Drugs influencing the SNS are used in
treatment of hypertension, shock, cardiac failure and
arrhythmias, asthma and emphysema, allergies and
anaphylaxis.

3. Sites of Drug Action – Modulation of
Neurotransmission
↓1
2. intake of
precursor
3. synthesis
4. storage
5. metabolism
7. reuptake 6. release 8. degradation
9. receptor

4. Direct acting adrenergic drugs:

5. Sympathomimetics:
Drugs that mimic or facilitate the actions of the
sympatho-adrenal system.
a) Direct acting:
– Drugs that can act directly or specific adrenergic receptors
– Mimic the effects of NE and Epi
b) Indirect acting:
– Drugs that do not activate the adrenergic receptor directly
i. Facilitate release of NE
ii. Block neuronal uptake of NE
iii. Block metabolism of NE

6.  classifications
 α-R agonists: NA, metaraminol
 α, β-R agonists: AD,ephedrine
 α, β, DA-R agonists: dopamine
 β-R agonists: Isop,dobutamine

7. Location Receptor type Effect
↑ heart rate
Heart β1
↑ force of contraction
Vascular Smooth Muscle:
Skin and splanchnic vessels α constriction
Skeletal muscle vessels α and β2 constriction or dilation
Other smooth muscle:
Bronchiole β2 dilation
Uterus:
α1 contraction
pregnant
β2 relaxation
non-pregnant β2 relaxation
GI tract α and β relaxation
Eye:
radial pupillary dilator α1 contraction (mydriasis)
ciliary muscle β relaxation

8. Receptor
Location Effect
type
Exocrine glands:
Pancreas α ↓ release of insulin
Salivary glands α and β increase secretion
Metabolic effects:
↑ glycogenolysis
Liver β2
↑ gluconeogenesis
Adipose tissue β1 lipolysis

9. Direct Acting Sympathomimetics:
Ahlquist designated the receptors as α or β based
on observations that catecholamines act on 2
principal receptors:
α1:
Epi ≥ NE >> INE
α2:
β1: INE > Epi = NE
β2: INE > Epi >> NE

10. Chemistry and Pharmacokinetics of
Sympathomimetics:

11. α-R agonists
noradrenaline(norepinephrine,NA,NE)
pharmacokinetics :
pharmacological actions: strongly activate α-
R, slightly activate β1-R.

12. pharmacological actions of NA
 1.vessels: contract(α-R)
 coronary vessels dilate (adenosine)
 2.heart: excited(β1-R)
 3.BP: small dose: SBP↑ DBP
large dose: SBP↑ DBP↑
 4.others: metabolism, CNS

13. clinical uses
 1.shock
 2.hypotension caused by drugs’
intoxication
 3.upper digestive tract hemorrhage

14. adverse reactions
 1.local ischemia and necrosis
 2.acute renal failure
contraindications
 HT
 In pregnant females, NE should not be
used because it stimulates alpha 1
receptors in the uterus that cause
contraction

16. Effect of NE to intact CVS
Mean arterial pressure
(MAP) = DBP + 1/3 of
(SBP-DBP)
α 1 ,α 2 ,β 1

17. metaraminol (aramine )
 Mechanisms: 1.direct actions 2.indirect actions
 Characteristics:
 1.action is weaker and longer than NA
 2.little adverse reactions: renal failure,
arrhythmias
 3.stable, im.
 4.tachyphylaxis
 Uses: substitute for NA in treatment of shock

18. phenylephrine(neosynephrine)
and methoxamine
 1.selective α1-R agonists: shock,
hypotension
 2.paroxysmal atrial tachycardia
 3.renal vasoconstriction significant
 4.phenylephrine→mydriasis

19. Adrenaline (epinephrine,AD)
 source Stress hormone released from the adrenal
medulla
 Pharmacokinetics: comt mao
 pharmacological actions: activate
1.heart: strongly excited (β1-R)
2.vessels: contract(α-R),dilate(β2-R)
3. smooth muscle: bronchial smooth muscle relax
4.metabolism: ↑ 20%-30%; blood Glu ↑, blood fatty acid
↑

20. Epinephrine:
 Dose-dependent effects:
α
β
Dose of epinephrine →

21. Effect of Epi to intact CVS
a1 ,a2 ,b1,b2

22. Epinephrine Reversal
(m m H g )
200
180
M e a n Arte ri a l Pre s s u re
160
phenoxybenzamine] 140
120 Epi PBZ
Epi
100
80
0 1 2 3 4 5 6 7 8 9 10
Tim e (re lative )

23.  5.BP
 Low doses: β-adrenergic effects predominate
 ↑ HR, vasodilation of vascular smooth muscle
in skeletal muscle, other smooth muscle
effects
 High doses: α-adrenergic effects predominate
 Vasoconstriction of blood vessels in skin and
peritoneal cavity
 ↑ BP and reflex slowing of the heart
(baroreceptor reflex)

24. clinical uses
 1. Relief of bronchospasm
 2. Relief of hypersensitivity reactions and
anaphylaxis
 3. To prolong the duration of action of local
anesthetics.
 4. As a topical hemostatic to control superficial
bleeding from skin and mucosae
 5. To restore cardiac rhythm in patients with
cardiac arrest.

25.  Adverse effects:
 Extensions of their effects in the CVS and the
CNS
 Anxiety, tenseness, headache and paranoia
 tachycardia, dysrhythmias
 Large dose IV – cerebral hemorrhage,
pulmonary edema
 Route of administration:
 Inhalation
 Injection (IM, SC, IV), not PO
 Topical application
 Rapidly degraded

26. Phenylephrine:
 Acts on α receptors
 Vasoconstriction (↑ BP)
 Longer lasting than epinephrine
 Clinical use:
 Hypotension and shock
 Nasal decongestant
Salbutamol:
 Selective β agonist
2
 Dilates bronchial smooth muscle
 Clinical use:
 Antiasthmatic

27. Adrenergic Drugs cont’d:
Ephedrine
Acts directly and indirectly
 Acts on α and β receptors and causes release of NE
 Less potent and longer acting than epinephrine
 Available OTC
 Orally administered
 Clinical use
 Bronchodilation
 Nasal decongestant

28. α, β,DA-R agonists
dopamine (DA)
 Pharmacokinetics:
ivd, MAO/COMT; short t1/2, not across BBB
 pharmacological actions
activate DA, α, β1-R

29. actions
 1.Cardiovascular system: dilate (DA-
R),contract(α-R)
 10µg/kg·min SBP→ DBP↓
 20µg/kg·min SBP↑ DBP↑→
 >25µg/kg·min SBP↑ DBP↑
 2. Ren: renal vessels small dose dilate
large dose contract

31. Effect of DA to intact CVS
 DA1, Beta1
 Moderate Dose

32. clinical uses
 1.shock
 2.chronic heart failure(CHF)
 3.acute renal failure(ARF)
toxicity
high doses of DA is similar to that noted above
for NE. Since the drug has an extremely short
half life in plasma, DA toxicity usually disappear
quickly if the administration is terminated.

33. β-R agonists--
isoprenaline
 Pharmacokinetics:
 pharmacological actions: activate β1, β2-R
 1.heart: excited (β1-R)
 2.vessels: dilate (β2-R)
 3.BP: small dose: SBP↑ DBP↓
large dose: SBP↓ DBP↓
 4.bronchial smooth muscle: relax
 5.others; metabolism, CNS

34. Effect of Iso to intact CVS
b1,b2

35. clinical uses
 1.bronchial asthma
 2.atrial ventricular block(AVB)
 3.cardiac arrest
 4.shock
adverse reactions and contraindication

36. dobutamine
 1.selective β1-R agonist
 2.inotropic effect>chronotropic effect in
therapeutic dose
 3.short-term treatment for CO↓
following cardiac surgery or CHF
caused by AMI
 4.tachyphylaxis

37. Clinical Use of Adrenergic Agonists:
α – agonists:
 Anaphylactic shock
 Hypotension
 Nasal congestion
 Hemorrhage
 Co-administration with local anesthetics
β – agonists:
 Congestive heart failure – short term
 Asthma – bronchial dilation
 Tocolytic – stopping premature labour

38. Adrenoceptor antagonists
Section 1 α-R antagonists
Ⅰ. α1, α2-R antagonists
Classification
 1.short-term acting phentolamine tolazoline
competitive α-R antagonists
 2. long-term acting phentoxybenzamine
noncompetitive α-R antagonists
Ⅱ. α1-R antagonists prazosine
Ⅲ. α -R antagonists yohimbine

39. Epinephrine Reversal
(m m H g )
200
180
M e a n Arte ri a l Pre s s u re
160
phenoxybenzamine] 140
120 Epi PBZ
Epi
100
80
0 1 2 3 4 5 6 7 8 9 10
Tim e (re lative )

40. phentolamine (regitine)
pharmacological actions
 1.vessels : vessels dilate; BP ↓
“adrenaline reversal ”
 2.heart: excited, CO ↑ HR ↑
a. vessel relaxation>BP ↓, baroreflex (+)
b. alpha2 blockade , NE release↑
 3.other effects: cholinergic action
histamine-like action

41. Clinical uses
 1.peripheral vasospasmatic disorders
 2.local vasoconstrictor excess (eg, NA)
 3.diagnosis and treatment of
pheochromocytoma
 4.shock
 5.CHF and AMI
 6.others: male sexual dysfunction

42. adverse reactions
 1.cardiovascular reaction: hypotension,
tachycardia, angina, arrhythmia
 2.gastrointestinal reaction: stomachache,
diarrhea, vomiting, ulceration
 3.histamine-like reaction:

43. tolazoline
 The action of blocking α1-R is more
weakly than regitine.
 While cholinergic action and histamine-
like action are stronger than regitine.

44. phenoxybenzamine
 Pharmacokinetics: only iv, high liposolubility
 pharmacological actions:
similar to phentolamine, but slow, strong and
long. it also can block the receptors of 5-HT
and HA.

45. Prazosin
 the prototype of a family of potent and very selective
alpha 1 receptor antagonists. It has 1000X greater
affinity for alpha 1 vs alpha 2 receptors.
 It blocks all alpha one receptor subtypes
equipotently. It is a short acting drug with a duration
of action of about 7 to 10 hours. Prazosin causes a
decrease in total peripheral resistance, but not an
increase in heart rate (since alpha 2 receptors are not
inhibited).

46. phenoxybenzamine
 clinical uses:
 1.peripheral vasospasmatic disorders
 2.pheochromocytoma
 3.shock
 4. Urinary obstruction caused by benign
prostatic hyperplasia
 adverse reactions:
Postural hypotension, tachycardia (palpitation),
arrhythmia, nasal congestion

47. Section 2 β-R antagonists
pharmacological actions:
 1. β1-R blocking action:
 1) cardiovascular effects: heart depressed, BP↓
 2)bronchial smooth muscle
 3)metabolism
 4)renin release↓
 2.intrinsic sympathominetic activity(ISA)
 3.membrane stabilizing action at high dose
 4.other effects: antiplatelet aggregative(propranolol)
↓intraocular pressure (timolol)

48. clinical uses
 1.arrhythmias
 2.angina pectoris, myocardial infarction
 3.hypertension
 4.CHF
 5.others: hyperthyroidism, glaucoma,
migraine

49. adverse actions and
contraindications
 1.nausea, vomiting, PLT↓
 2. cardiovascular reaction
 3. bronchial asthma
 4.withdrawal syndrome
 5.others

50. classification
 β 1,β2-R antagonist
 Propranolol, Timolol: most potent,glaucoma;
pindolol
 β 1-R antagonist
 atenolol , metoprolol, Acebutolol
 α, , β -R antagonist
 Labetalol, carvedilol

51. Thank you for your attention