1. Adrenergic & Antiadrenergic Drugs
By Prof. Alhaider

2. 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 norepinephrine (NE)
Storage of dopamine (DA) and NE in vesicles
Release of NE
Metabolism (COMT 20% + MAO 80%)
Binding to receptors
Uptake mechanism

6. We ask the doctor about the drugs are they included in the exam he said “it’s up to you”

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

8. α1– Adrenoceptors

9. α1 stimulation cause vasoconstriction (VC) :
α1– adrenoceptors (continue) Site of α1– adrenoceptors & the effects of their stimulation
In vascular smooth muscle.
α1 stimulation cause vasoconstriction (VC) :
Vasoconstriction in the skin & viscera cause increase total vascular resistance (TVR) causing increase blood pressure (BP)
α1 – adrenoceptors 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 of congestion
In the radial muscle of iris.
α1 stimulation causes contraction of the radial muscle causing mydriasis (dilation of the pupil)

10. Cont…. In the smooth muscle of the sphincters of GIT.
α1 stimulation cause contraction of all sphincters
In the smooth muscle of internal sphincter of urinary bladder (Very important).
α1a subtypes stimulation cause contraction and closure of the sphincters (precipitate urinary retention)
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

11. 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
α2 stimulation leads to either
Decreased adenylyl cyclase activity(mediated by the inhibitory regulatory Gi protein)
Lead to decrease cAMP causing decrease NE release causing
relaxation of smooth muscle &
decreased glandular secretion
Increase K+ channel activity  hyperpolarization
So α1 receptors are stimulatory while α2 receptors are inhibitory

14. 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). It opposes the action of sympathetic stimulation.
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).

15. Cont… In ciliary epithelium.
Increase the out flow of aqueous humor.(good for glaucoma)
In the smooth muscle of GIT wall. (with β2)
α2 stimulation cause relaxation of the wall causing decreased peristalsis (indirectly by reducing the release of ACH)

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

17. β1 – adrenoceptors β 1 stimulation causes
In the heart.
β 1 stimulation causes
In S.A node : increase heart rate (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

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

19. β2 – adrenoceptors In the bronchial smooth muscle
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(VD)
This VD effects is usually masked by the potent VC effect of α1 – receptors

20. 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
Note: Adrenergic stimulation is opposite to the cholinergic in the wall and sphincters in GIT and genitourinary tract .

21. Cont…. In the smooth muscle of the uterus In the liver.
β2 stimulation causes relaxation of the uterus (Ritodrine delay the labor)
In the liver.
β2 stimulation causes increased Glycogenolysis & Gluconeogenesis
In the pancreas.
β2 stimulation causes slight increase in insulin secretion (hypoglycemia), but the effect on the liver is predominant.
Effect on potassium .
β2 stimulation increase potassium influx.

22. Cont…. In ciliary muscle. In the ciliary epithelium
β2 stimulation causes relaxation of the ciliary muscle leading to
Accommodation for far vision
Decrease outflow of aqueous humor via the canal of Schlemm
In the ciliary epithelium
β2 stimulation causes increased production of aqueous humor

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

24. 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 intracellular Ca++ release leading to increased contractility
β 2 in smooth muscle cause inhibition of myosin kinase enzyme causing relaxation
β 2 in the liver cause increase Glycogen phosphorylase enzyme activity causing increased glycogenolysis

25. β 3 – adrenoceptors In brown adipose tissue β 3 selective agonist
β 3 stimulation causes increased Lipolysis
β 3 selective agonist
E.g.
BRL 37344
β 3 selective antagonist
CGP 20712A

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

27. Adrenoceptor Agonists I. Non selective drugs
noncatecolamines
catecholamines
Low potency
High potency
Long t1/2
Short t1/2
Can be Given orally
Given parenterally
Non polar
polar
Not inactivated by COMT
Inactivated by COMT
These drugs include
1) Catecholamine Drugs
A. endogenous:
Norepinephrine
Epinephrine
Dopamine
b) Synthetic (exogenous)
Isoprenaline
2) Non-catecholamine Drugs
Amphetamine
Ephedrine
Pseudo ephedrine
Phenylpropranolamine

28. Norepinephrine (NE)(Noradrenaline)
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

30. 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

31. Norepinephrine Pharmacokinetics
T1/2 of NE = 2 – 3 min
Very short because it has rapid metabolism
NE causes increased systolic blood pressure (SBP) & diastolic blood pressure (DBP)
So, in shock, it will increase BP
Not given orally because it will be inactivated by intestinal enzymes

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

33. Epinephrine (EP)(Adrenaline)
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
Has the same pharmacokinetics as NE

34. Epinephrine Therapeutic useb
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 cardiac output (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

35. 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

36. Isoprenaline (isoproterenol)
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

37. 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)

38. 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

39. Effects of I.V. infusion of Epinephrine, Norepinephrine & Isoprenaline in Humans
Epinepherine and isoprenaline decrease DBP because they act on β2
Reflex bradycardia
Isoprenaline decrease resistance because it acts on β only without α

40. Dopamine It doesn’t cause tolerance
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
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

41. 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(see next slide)

42. Cont…. 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)
It will stimulate α1 receptors (direct + Via release of NE) to cause VC leading to increase BP and decrease organ perfusion
So, the high dose of DA is not recommended in shock.

43. What is the effect of Dopamine on Bronchioles?
It has no effect on the bronchioles because it doesn’t stimulate β2 receptors (even indirectly , because NE does not stimulate β2 receptors ).

44. Centrally Acting Sympathomimetic Agents: e.g: 1. Amphetamine
It is non-selective adrenergic agonist, noncatecholamine
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 Restlessnessقلق and Insomnia الارق).
t1/2 = 45 – 60 min (long duration of action)
It is metabolized in the Liver.

45. 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”

46. 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
(Methylphenidate, Dexamfetamine)
In narcolepsy
(Dexamfetamine and Modafinil)
To suppress appetite

47. Amphetamines Side effects
The side effects are due to chronic use
These include :
Tolerance
Dependence
Addiction
Paranoia (thought process heavily influenced by anxiety or fear)
Psychosis (loss of contact with reality)

48. 2. Ephedrine It is non selective adrenergic agonist It
Directly acts on the receptors (a,b1,and b2) It is Like an oral form of Epinephrine.
Indirectly by releasing NE
PK almost similar to amphetamine
It causes tolerance but no addiction
Like amphetamine, it is CNS and respiratory stimulant.
It does not suppress the appetite

49. 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)

50. 3. Pseudoephedrine:
Has similar pharmacological activities to ephedrine
It is not controlled : OTC (over the counter) يباع بدون وصفة طبية
It is commonly used as a decongestant.

51. 4. Phenylpropranolamine:
Again it is similar to pseudoephedrine, and was used as decongestant, but it was stopped because it may cause cerebral hemorrhage
Oxymetazoline:
Has a1 and a2 agonistic activity. Used as a decongestant.

52. Side – effects of centrally acting sympathomimetics:
Sympathomimetic means :
These drugs can produce sympathatic actions similar to EP and NE
They include:
Amphetamine
Ephedrine
Pseudo ephedrine
Phenyl Pro Pranolamine
They are lipid – soluble and can pass BBB to cause
Insomnia
Restlessness
Confusion
Irritability
Anxiety
Hypertension
Remember that amphetamine has additional side effects

53. Adrenoreceptor Agonists Selective drugs
These drugs include :
Phenyl Ephrine (relatively α1)
Clonidine (α2)
Dobutamine (β1)
Salbutamol (β2)
Ritodrine (β2)

54. It is relatively selective α1–agonist It is directly acting
Adrenoreceptor Agonists 1. Phenyl Ephrine (others: methoxamine, metaraminol, mephentermine)
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

55. 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 in use nowadays)

56. 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
It can be used in patients with renal failure because it dose not affect renal blood flow or GFR & CO

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

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

59. Adrenoreceptor Agonists (Cont..) 4. Dobutamine:
It is direct acting β 1 – selective agonist
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.(because of the baroreceptor reflex)
It has less arrhythmogenic effects than dopamine
Uses: Inotropic agent for Heart Failure; in septic and cardiogenic shock.

60. Adrenoreceptor Agonists 5. 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)

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

62. It is another β2 – selective agonist but
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 fetus

63. Clinical applications of Sympathomimetic drugs
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??? (I think shock is associated with increased BP)