1. Adrenergic & Antiadrenergic Drugs

2. Adrenergics & Antiadrenergics
Anatomy of the sympathetic nervous system
Neurotransmission at adrenergic neurons
Adrenoceptors
Adrenergic Drugs
Centrally-acting sympatholytic drugs

3. Anatomy of the sympathetic nervous system
The origin is from thoracolumbar segments “all thoracic + lumbers L1, L2, L3 and L4 ”
They have short preganglionic fibers, and it relays in sympathetic chain ganglia & release Ach in these ganglia
They have long postganglionic fibers that innervate their body organs & release Norepinephrine as a neurotransmitter there

4. Neurotransmission at adrenergic neurons
Synthesis of NE
Storage of DA and NE in vesicles
Release of NE
Metabolism (COMT 20% + MAO 80%)
Binding to receptors
Uptake mechanism

5. Adrenoceptors The adrenergic receptors are classified intoα1 α2 β1 β2 β3
There are some subtypes

6. α1– Adrenoceptors Mechanism of action
Site of α1 – adrenoreceptor & the effects of their stimulation
Drugs effects at these receptors

7. Molecular Mechanism of Action of Sympathomimetics

8. α1 stimulation cause VC :
α1– adrenoceptors (continue) Site of α1– adrenoceptors & the effects of their stimulation
In vascular smooth muscle.
α1 stimulation cause VC :
Vasoconstriction in the skin & viscera cause increase TPR causing increase BP
α1 – adrenoreceptorare the most determine of arteriolar tone. When their stimulated no others receptors have an affects on BP. So, hypertension may be treated by blocking α1
Vasoconstriction in the nasal blood vessels cause relief congestion
In the radial muscle of iris.
α1 stimulation causes contraction of the radial muscle causing mydriasis (dilation of the pupil)

9. Cont…. In the smooth muscle of the sphincters of GIT.
α1 stimulation cause contraction of all sphincters. opposite to ACH
In the smooth muscle of internal sphincter of urinary bladder (Very important).
α1a subtypes stimulation cause contraction and closure of the sphincters (ppt urinary retention) opposite to ACH
In the seminal vesicles. (with α2)
α stimulation cause ejaculation. Thus, all α blockers inhibit ejaculation
In the liver.
α1 stimulation causes increase glycogenolysis & gluconeogenesis
In the fat cells.
α1 stimulation causes increased lipolysis

10. Adrenoceptors α 1 – adrenoceptors Drugs effects :
α1 selective agonist
E.g.
Phenyl ephrine
α1 selective antagonists
Prazosin
Terazosin
Doxazosin
Tamsolusin ( α1a) (has a different clinical use)

12. α2 – adrenoceptors Mechanism of action
Site of α2– adrenoreceptors & the effects of their stimulation
Drugs effects at these receptors

13. Molecular Mechanism of Action of Sympathomimetics

14. α2– adrenoceptors Mechanism of action
α2 stimulation leads to either
Decreased adenylyl cyclase activity.
Lead to decrease cAMP causing decrease NE release causing
relaxation of smooth muscle &
decreased glandular secretion
Increase K+ - channel activity.
This is mediated by the inhibitory regulatory Gi protein
What is the main difference between α1 and α2 adrenoceptors?

15. In adrenergic nerve terminals (presynaptic).
α2–adrenoceptors Site of α2– adrenoceptors & the effects of their stimulation
In adrenergic nerve terminals (presynaptic).
α2 stimulation cause decreased Norepinephrine release (autoregulatory mechanism). Very important effect Why?
In pancreas.
causes decreased insulin release
In platelets.
Increase platelets aggregation via c-AMP
In liver (same as α1– adrenoceptors)
Fat cells (same as α1– adrenoceptors).

16. Cont… In ciliary epithelium. Increase the out flow of aqueous humor.
Is it good for glaucoma or not?.
In the smooth muscle of GIT wall. (with β2)
α2 stimulation cause relaxation of the wall causing decreased peristalsis (This is attributed to decrease in ACH release)

17. α2– adrenoceptors (Continue) Drugs effects :
α2 selective agonists
E.g.
Clonidine; Methyldopa (Antihypertensive)
α2 selective antagonists
Yohimbine; Mertazapine (Antidepressant)
Apraclonidine (Topical for Eye)

18. β1 – adrenoceptors Mechanism of action
Site of β1– adrenoreceptors & the effects of their stimulation
Drugs effects at these receptors

19. Molecular Mechanism of Action of Sympathomimetics

20. Adrenoceptors β 1 – adrenoceptors Site of β 1 – adrenoceptors & the effects of their stimulation
In the heart.
β 1 stimulation causes
In S.A node : increase HR (+ve chronotropic)
In Myocardium tissue : increase contractility (+ve inotropic)
In Conducting system : increase conduction velocity (+ve dromotropic)
Increase ectopic beats
In the Juxtaglomerular Apparatus of the kidney.
β 1 stimulation cause increased renin release. Then causes increase in BP
In fat cells (with α1, α2 & β 3)
β 1 stimulation causes increased Lipolysis

21. Adrenoceptors β 1 – adrenoceptor Drugs affecting them
β 1 selective agonists
E.g.
Dobutamine
β 1 selective antagonists
Atenolol
Esmolol
Metoprolol

22. β2 – adrenoceptors Mechanism of action
Site of β2– adrenoreceptors & the effects of their stimulation
Drugs affecting these receptors

23. Molecular Mechanism of Action of Sympathomimetics

24. In the bronchial smooth muscle (very important clinically).
β 2 – adrenoceptor Site of β 2–adrenoceptor & the effects of their stimulation
In the bronchial smooth muscle (very important clinically).
β2 stimulation causes relaxation of smooth muscle (bronchodilatation)
In the smooth muscle of blood vessels supplying the skeletal muscle.
β2 stimulation causes relaxation of smooth muscle (Vasodilatation)
This VD effects is usually masked by the potent VC effect of α1 – receptors

25. Cont…. In the smooth muscle of GIT wall.
β2 stimulation cause relaxation of the wall leading to decreased peristalsis
In the smooth muscle of the wall of urinary bladder.
β 2 stimulation causes relaxation of the wall (opposite to ACH)
Note: Adrenergic stimulation is opposite to the cholinergic in the wall and sphincters in GIT and GUS.

26. Cont…. In the smooth muscle of the uterus In the liver.
β2 stimulation causes relaxation of the uterus
So, β2 agonists
In the liver.
β2 stimulation causes increased Glycogenolysis & Gluconeogenesis
In the pancreas.
β2 stimulation causes slight increase in insulin secretion
Then, what is the effect of β2 stimulation on blood sugar?
Effect on potassium .
β2 stimulation increase potassium influx. Useful Clinically

27. Adrenoceptors β 2 – adrenoceptors Drugs affecting them
β 2 selective agonists
E.g.
Salbutamol
Salmetrol
Terbutaline
Ritodrine
Formetrol
β 2 selective antagonists
ICI (still under investigation)

28. b1 and b2 – adrenoceptor agonists Mechanism of action
β stimulation causes increase adneylyl cyclase activity leading to increase cAMP leading to cellular effect. E.g.
β 1 in the heart cause increase c-AMP leading to increased intracellular Ca++ release leading to increased contractility
β 2 in smooth muscle cause increase cAMP leading to inhibition of myosin kinase enzyme causing relaxation
β 2 in the liver cause increase in cAMP leading to increased Glycogen phosphorylase enzyme activity causing increased glycogenolysis

29. β 3 – adrenoceptors
Site of β 3 – adrenoceptors & the effects of their stimulation
Drugs affecting them
Mechanism of action

30. In brown adipose tissue
Adrenoceptors β 3– adrenoceptors Site of β 3 – adrenoceptors & the effects of their stimulation
In brown adipose tissue
β 3 stimulation causes increased Lipolysis

31. Adrenoceptors β 3– adrenoceptors Drugs affecting them
β 3 selective agonist
E.g.
BRL 37344
β 3 selective antagonist
CGP 20712A

32. Adrenergic Drugs Adrenoreceptor Agonists Adrenoreceptor Antagonists
Non selective
Selective
Adrenoreceptor Antagonists
α– blockers
β– blockers

33. Adrenoceptor Agonists I. Non selective drugs
These drugs include
1) Catecholamine Drugs
A. endogenous:
Norepinephrine
Epinephrine
Dopamine
b) Synthetic (exogenous)
Isoprenaline
2) Non-catecholamine Drugs
Amphetamine
Ephedrine
Pseudo ephedrine
Phenylpropranolamine
What are the differences between catechoamines and non-catecholamines?

34. Norepinephrine (Noradrenaline)
Introduction
Synthesis
Metabolism of NE
Pharmacokinetics

35. Norepinephrine Introduction
NE is a neurotransmitter released from the postganglionic sympathetic fiber in most organs
It also released from the adrenal medulla (20% of medulla secretion)
It is a direct non–selective adrenergic agonist which acts on all adrenoceptors, Except β2

36. Cont…. Sites of metabolism In adrenergic nerves
80% by MAO in presynaptic nerve terminals after reuptake (This is very important clinically)
If MAO is inhibited, NE will be reuptake but not metabolized, leads to release of NE again
15% by COMT in postsynaptic membrane (This is not important clinically)
5% reach the blood and metabolized In the Liver

37. Norepinephrine Pharmacokinetics
T1/2 of NE = 2 – 3 min
Very short because it has rapid metabolism
NE causes increased SBP & DBP
So, in shock, it will increase BP
Why NE cannot be given orally?

38. Clinical Uses:
Note: NE is not commonly used in clinical practice like Epinephrine, However it can be used in:
Cardiac Arrest
Shock

39. Epinephrine (Adrenaline)
Introduction
Synthesis (Methylated form of NE)
Therapeutic uses

40. P.70 lippin 3rd edi

41. Epinephrine Introduction
EP is released from adrenal medulla 80% and in certain areas of the brain
EP is a direct acting non-selective adrenergic agonist in all receptors including β2 receptor.
T1/2 = 2 – 5 min
Like NE, It is given parenterally (SC, I.V and I.M) not orally
Does PK of Epinephrine different from NE?

42. Epinephrine Therapeutic use
Epinephrine is commonly used in practice as compared to NE.
In bronchial asthma
It is given SC to act on β2 receptors to cause bronchodilation
Now it is not commonly used because of its side effects (tachycardia and arrhythmia)
In cardiogenic shock
It is given I.V to increase SBP, BP, HR and CO
In anaphylactic shock
It is given SC to act on
α1 cause VC, lead to increase BP & relief of congestion
β 1 cause increase HR leading to increase CO, so, increase BP
β 2 cause bronchodilation so, relieve bronchospasm
What are the main differences between Epinephrine and NE? b

43. Cont… In cardiac arrest (for Bradycardia) During surgery
It is given I.V. if there is no response, EP given directly into the lung, and if there is no response, it given intracardially, and if there is no response, direct current is applied for 3 times at most
During surgery
EP is added to the local anesthetic to cause VC in the surgery area in order to
Decrease bleeding
Decrease the amount of local anesthetic which will reach the systemic circulation. Therefore, it will decrease the cardiodepressant effect of the local anesthetic

44. Iso pre naline
Introduction
Actions
Therapeutic uses

45. Iso pre naline Introduction
It is directly acting synthetic adrenoreceptor agonist acting only on β–receptors, with no effects on a adrenoceptos.
T1/2 = 5 – 7 min
Like all catecholamines, It is given parenterally (not orally)
The I.V must be given carefully because the overdoses cause cardiac arrest

46. Iso pre naline Action Isoprenaline will stimulate
β1 in the heart to cause
Increased HR & cause arrhythmia & may lead to cardiac arrest
β2 in the blood vessels to cause
VD leads to decreased BP (mainly DBP)
It has no effects on α receptors

47. P.75 lippin 3rd.ed.

48. Isoprenaline Therapeutic uses:
It is no longer used to treat the bronchial asthma because of it’s side effects on the heart
It’s only used now to reverse the heart block which is produced by overdoses of β – blockers
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

49. Effects of I.V. infusion of Epinephrine, Norepinephrine & Isoprenaline in Humans

50. Dopamine
DA is a non–selective adrenergic agonist, which acts either directly on DA – receptors in addition to b1- adrenergic receptors or indirectly by releasing NE
B1 and a – receptores causing vaso constriction
Like all catecholamines, It is given parenterally only (not orally)
It doesn’t cause tolerance
T1/2 = 3 – 5 min
Metabolized by either
Converted to NE in adrenergic neurons or
By MAO in the Liver

51. Dopamine (Cont…) Clinical Uses :
In small dose of DA (=< 5ug / Kg / min by I.V infusion) Renal dose:
It will stimulate DA–receptors only
It will cause vasodilatation (VD) in:
Renal vascular bed
Cerebral vascular bed
Coronary vascular bed
Mesenteric vascular bed
Therefore, it is useful in treatment of shock to save these vital organs from hypoxia (also see Dobutamine)
N.B : At higher doses, VD effect of DA – receptors is masked by the VC effect of α1–receptors

52. dopamin In medium dose : (5-15ug/Kg/min by I.V infusion) Cardiac dose
It will stimulate β1 – receptors to cause increase HR, CO and BP
In high dose of DA (> 15ug / Kg / min by I.V infusion)
MAX 50 ug/Kg/min
In child 1-5 ug/Kg/min usual dose 2-20 ug/Kg/min
Iv route imfusion

53. dopamin exteravasation
Phentolamine 10 mg/15 ml NS inject area

54. Side ffects Headache Anxity Tachycardia- ectopic beat-angina
Nausea vomiting - diarrhea
Necrosis
dypenea

55. contraindication Hypersensivity- VF Tachy arrthemia Pheochromocythoma
Hypovalemia

56. precautionc Pregnancy Breast feeding Atrial embolism
Preiphral vascular disease
Acute MI

57. What is the effect of Dopamine on Bronchioles?

58. Centrally Acting Sympathomimetic Agents: e.g: 1. Amphetamine
Introduction
Clinical uses
Side – effects

59. Amphetamine Introduction
It is non-selective adrenergic agonist, non-catecholamine
Acts mainly, indirectly via enhancing NE release and DA.
Since it is non-catecholamine, it can be given orally
It is lipid–soluble enough to be absorbed from intestines and goes to all parts including CNS (This leads to CNS stimulation like Restlessness and Insomnia).
t1/2 = 45 – 60 min (long duration of action)
It is metabolized in the Liver

60. 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 & make the patient awake
In ADHD “Attention Deficit Hyperactivity Disease”

61. Clinical use of Amphetamine-like drugs (controlled Drugs)
Note: Amphetamine is a drug of abuse, that should not be prescribed. However, amphetamine-like drugs can be prescribed for the following conditions:
In ADHD “Attention Deficit Hyperactivity Disease:
(Methylphenidate, Dexamfetamine)
In narcolepsy
Narcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night
Amphetamine-like drugs stimulats the CNS & make the patient awake (Dexamfetamine and Modafinil)
To suppress appetite
In very obese persons Amphetamine can act centrally on the hunger center in the hypothalamus to suppress appetite (Considers as obsolete use)

62. Amphetamines Side effects
The side effects are due to chronic use
These include :
Tolerance
Dependence
Addiction
Paranoia
Psychosis
Hypertension

63. 2. Ephedrine It is non selective adrenergic agonist It
Directly acts on the receptors (a,b1,and b2)
Indirectly by releasing NE
PK almost similar to amphetamine
It causes tolerance but no addiction
Like amphetamine, it is CNS and respiratory stimulants.
It does not suppress the appetite Why?

64. Ephedrine Clinical uses:
Pressor agent
Decongestant
It is no longer used to treated bronchial asthma. Why?

65. 3. Pseudoephedrine:
Has similar pharmacological activities to ephedrine
It is not controlled : OTC (over the counter)

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

67. Side – effects of centrally acting sympathomimetics:
Sympathomimetic means :
These drugs can produce sympathatic actions similar to EP and Nor EP
They include:
Amphetamine
Ephedrine
Pseudo ephedrine
Phenyl Pro Pranolamine
They are lipid – soluble and can pass BBB to cause
Insomnia
Restlessness
Confusion
Irritability
Anxiety
Loss of appetite
Hypertension
Amphetamine has additional side effect see slide 57

68. Adrenoreceptor Agonist Selective drugs
These drugs include :
Phenyl Ephrine relatively α1 – agonist
Clonidine α2 – agonist
Dobutamine β 1 – agonist
Salbutamol β 2 – agonist
Ritodrine β 2 – agonist

69. Adrenoreceptor Agonists 1
Adrenoreceptor Agonists 1. Phenyl Ephrine (others: methoxamine, metaraminol, mephentermine
Introduction
Metabolism
Clinical uses

70. Adrenoreceptor Agonists 1. Phenyl Ephrine
It is relatively selective α1–agonist
It is directly acting
PK: not-catecholamine and thus not metabolized by COMT
It has longer duration of action than other catecholamines
Uses: see next

71. 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
In case of paroxysmal tachycardia
It cause VC & elevate BP. This stimulate the baroreceptors resulting in increased reflex vagal discharge which brings the heart into the normal sinus rhythm (not used any more)

72. Adrenoreceptor Agonists (Cont…) 2. Clonidine:
It is α2 – selective agonist
However, this is sympatholytic agent,
used in treatment of hypertension
It acts centrally at presynaptic α2-adrenoceptor. This leads to decrease in NE release and to decrease in TVR.
Note: Although it is adrenergic agonist, clonidine acts as a central sympatholytic drug.

73. What is methyldopa and does it differ from clonidine?
3. Apraclonidine (Like clonidine it is selective alpha 2 adrenoceptor agonist, however, main uses as adjuvant therapy for glaucoma via decrease of aqueous humor
formatiom
What is methyldopa and does it differ from clonidine?

74. Adrenoreceptor Agonists (Cont..) 4. Dobutamine:
It is direct acting β 1 – selective agonist (only)
T1/2 = 10 – 15 min
It is metabolized in the liver by oxidative deamination
There is tolerance to its action
Given only parenterally (not orally)
It causes increases in CO with minimal effect on HR. Why?
It has less arrhythmogenic effects than dopamine
Uses: Inotropic agent for Heart Failure; in septic and cardiogenic shock.
Can you make comparison between Dopamine and Dobutamine?

75. Adrenoreceptor Agonists 5. Salbutamol:
It is β2 – selective agonist
Can be used orally, IV and by inhalation
Clinical Uses
Formulations: (Tablets; Syrup; Injection; solution and Inhalation)
bronchial asthma by β2 stimulation, which leads to relaxation of bronchial smooth muscle and bronchodilation.
Treatment of refractory hyperkalemia (I.V)

76. 6 Salmetrol and Formoterol:
These selective beta agonists, have longer duration of action as compared to Salbutamole.
Uses: As inhalors for B. Asthma

77. Adrenoreceptor Agonist 7. Ritodrine:
It is another β2 – selective agonist but
It is used to delay premature labour
β 2 stimulation leads to relaxation of uterine smooth muscle leading to delay of labour
This is done to ensure adequate maturation of foetus

78. Adrenoreceptor Agonists Side – effects of sympathomimetic drugs:
On the CVS
Hypertension
Cardiac arrhythmia
Myocardial infarction
Increased severity of angina pectoris and of myocardial infarction
On the eye
Increased I.O.P leading to Glaucoma
On the CNS
See slide 64

79. Glaucoma
a disease of the eye characterized by increased intraocular pressure and excavation and atrophy of the optic nerve; produces defects in the visual field and may result in blindness.

80. Clinical applications of Sympathomimetic drugs
In hypotension
we use Phenyl Ephrine
In shock
Type of shock include
Hypovolamic shock
Septic shock
Anaphylactic shock
Symptoms include
Congestion in the Lung, Heart & Kidney due to VD & V.Per
Bronchoconstriction
Hypotension
We use EP with steroid and antihistamine to cause
Bronchodilation
Increase BP
Decongestant
Neurogenic shock
Cardiogenic shock
We use DA & Dobutamine together
All type lead to increases in BP

81. Cont…. To reduce BF in certain organs
We use Adrenaline with local anesthetic for minor surgery in order to
Decrease bleeding
Prevent spread of local anesthetic into systemic circulation
In paroxysmal tachycardia
In bronchial asthma
In cardiac arrest
For mydriasis
For delaying of labor
For hyper kinetic children syndrome
For narcolepsy

82. Adrenoreceptor Antagonists
α– blockers
Non selective
Relatively selective
Selective
β– blockers