Adrenoceptor agonists

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. ↓ 1
2. intake of
precursor
3. synthesis
4. storage
5. metabolism
6. release7. reuptake 8. degradation
9. receptor
Sites of Drug Action – Modulation of
Neurotransmission

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. Uterus:
relaxationβciliary muscle
contraction (mydriasis)α
1radial pupillary dilator
Eye:
relaxationα and βGI tract
relaxationβ
2non-pregnant
contraction
relaxation
α
1
β
2
pregnant
dilationβ
2Bronchiole
Other smooth muscle:
constriction or dilationα and β
2Skeletal muscle vessels
constrictionαSkin and splanchnic vessels
Vascular Smooth Muscle:

↑
heart rate

↑
force of contraction
β
1Heart
EffectReceptor typeLocation

8. ↓
release of insulinαPancreas
lipolysisβ
1Adipose tissue

↑
glycogenolysis

↑
gluconeogenesis
β
2Liver
Metabolic effects:
increase secretionα and βSalivary glands
Exocrine glands:
Effect
Receptor
type
Location

9. Direct Acting Sympathomimetics:
Ahlquist designated the receptors as α or β based
on observations that catecholamines act on 2
principal receptors:
α
1
:
Epi ≥ NE >> INE
α
2
:
β
1
:INE > Epi = NE
β
2
: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 β
1
-R.

12. pharmacological actions of NA
1.vessels: contract(α-R)
 coronary vessels dilate (adenosine)
2.heart: excited(β
1
-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)
a
1
, a
2
, b
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 α
1
-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 (β
1
-R)
2.vessels: contract(α-R),dilate(β
2
-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
a
1
, a
2
, b
1
, b
2

22. 012345678910
80
100
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Time (relative)
EpiPBZ
Epi
M
e
a
n

A
r
t
e
r
i
a
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P
r
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u
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(
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)
Epinephrine ReversalEpinephrine Reversal
phenoxybenzamine]

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
2 agonist
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 t
1/2
, not across BBB
 pharmacological actions
activate DA, α, β
1
-R

29. 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
actions

31. Effect of DA to intact CVS
DA
1
, Beta
1
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 β
1
, β
2
-R
1.heart: excited (β
1
-R)
2.vessels: dilate (β
2
-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
b
1
, b
2

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

36. dobutamine
1.selective β
1
-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. α
1
, α
2
-R antagonists
Classification
1.short-term acting phentolamine tolazoline
competitive α-R antagonists
2. long-term acting phentoxybenzamine
noncompetitive α-R antagonists
Ⅱ. α
1
-R antagonists prazosine
Ⅲ. α
2
-R antagonists yohimbine

39. 012345678910
80
100
120
140
160
180
200
Time (relative)
EpiPBZ
Epi
M
e
a
n

A
r
t
e
r
i
a
l

P
r
e
s
s
u
r
e

(
m
m
H
g
)
Epinephrine ReversalEpinephrine Reversal
phenoxybenzamine]

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 α
1
-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. β
1
-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
,β
2
-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