pharmacology II Dr Mahmoud Taleb Lama El Banna Al Azhar university Gaza

1. Dr. Mahmoud H. Taleb
Assistant Professor of Pharmacology and Toxicology
Head of Department of Pharmacology and Medical Sciences,
Faculty of Pharmacy- Al azhar University
The Autonomic Nervous System
Adrenergic SystemAdrenergic System

2. • Adrenergic neurons release norepinephrine as the
primary neurotransmitter.
• These neurons are found in the central nervous system
(CNS) and also in the sympathetic nervous system, where
they serve as links between ganglia and the effector
organs.
• The adrenergic neurons and receptors, located either
presynaptically on the neuron or postsynaptically on the
effector organ, are the sites of action of the adrenergic
drugs.
THE ADRENERGIC NEURON

3. 2- Sympathetic nervouS SyStem
 Sympathetic Nervous System (adrenergic)
Norepinephrine = neurotransmitter
- Drugs that mimic = adrenergic drugs,
sympathomimetics, or adrenomemetics
* Adrenergic agonists - Drugs initiate a
response
- Drugs that block = adrenergic blockers, sympatholytics
or adrenolytics
* Adrenergic antagonists - prevent a response
Dr. Mahmoud H. Taleb 3

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Adrenergic Agonists
The adrenergic drugs affect receptors that are stimulated by
norepinephrine or epinephrine. Some adrenergic drugs act
directly on the adrenergic receptor (adrenoceptor) by
activating it and are said to be sympathomimetic. Others,
which will be dealt with in, block the action of the
neurotransmitters at the receptors (sympatholytics), .

6. Agonist affinity of α :
-Adrenalin < Noradrenalin <
isoproterenol
-Antagonist : phenoxybenzamine
-IP3/DAG , cAMP ↓and k+ channel
opening.
Agonist affinity of β :
-Iso < Adrenalin < Noradrenalin
-Propraolol
-cAMP and Ca +2 channel opening.

7. Where are the adrenergic receptors?

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9. -D1-receptors are postsynaptic receptors located in
blood vessels and CNS.
- D2-receptors are presynaptic present in CNS ,
ganglia, renal cortex.

10. SYNTHESIS AND RELEASE OF NOREPINEPHRINE
FROM THE ADRENERGIC NEURON

11. 1. The amino acid tyrosine is transported into the sympathetic nerve axon.
2. Tyrosine (Tyr) is converted to DOPA by tyrosine hydroxylase (rate-limiting step for NE
synthesis).
3. DOPA is converted to dopamine (DA) by DOPA decarboxylase.
4. Dopamine is transported into vesicles then converted to norepinephrine (NE) by dopamine β-
hydroxylase (DBH); transport into the vesicle can by blocked by the drug reserpine.
5. An action potential traveling down the axon depolarizes the membrane and causes calcium to
enter the axon.
6. Increased intracellular calcium causes the vesicles to migrate to the axonal membrane and
fuse with the membrane, which permits the NE to diffuse out of the vesicle into
the extracellular (junctional) space. DBH, and depending on the nerve other
secondary neurotransmitters (e.g., ATP), is released along with the NE.
7. The NE binds to the postjunctional receptor and stimulates the effector
organ response

13. 1. Most (~90%) of the NE is transported back into the nerve terminal by a
neuronal reuptake transport system. This transporter is blocked by cocaine;
therefore, cocaine increases junctional NE concentrations by blocking its
reuptake and subsequent metabolism. (This is a major mechanism by which
cocaine stimulates cardiac function and raises blood pressure.)
2. Some of the junctional NE diffuses into capillaries and is carried out of the
tissue by the circulation. Therefore, high levels of sympathetic activation in
the body increase the plasma concentration of NE and its metabolites.
3. Some of the junctional NE is metabolized within the extracellular space before
reaching the capillaries.
4. A small amount of NE (~5%) is taken up by the postjunctional
tissue (termed "extraneuronal uptake") and metabolized.

14. NE (and epinephrine) is
metabolized by catechol-O-
methytransferase (COMT) and
monoamine oxidase (MAO).
The final product of these
pathways is vanillylmandelic acid
(VMA).
This final product, along with its
precursors normetanephrine and
metanephrine, is measured in
urine and plasma in the diagnosis
of pheochromocytoma, which can
cause severe hypertension and
cardiac arrhythmias.

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17. • Sympathomimetic amines that contain the 3,4-dihydroxybenzene group:
(such as epinephrine, norepinephrine, isoproterenol, and dopamine)
are called catecholamines.
• These compounds share the following properties:
1. High potency
2. Rapid inactivation
3. Poor penetration into
the CNS

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A. Catecholamines
Sympathomimetic amines that contain the 3,4-dihydroxybenzene group (such
as epinephrine, norepinephrine, isoproterenol, and
dopamine) are called catecholamines. These compounds share the
following properties:
High potency: Drugs that are catechol derivatives (with OH groups in the 3
and 4 positions on the benzene ring) show the highest potency in directly
activating α or β receptors
Rapid inactivation: Not only are the catecholamines metabolized by COMT
postsynaptically and by MAO intraneuronally, they are also metabolized in
other tissues. For example, COMT is in the gut wall, and MAO is in
the liver and gut wall. Thus, catecholamines have only a brief period of action
when given parenterally, and they are ineffective when administered orally
because of inactivation2.
Poor penetration into the CNS: Catecholamines are polar and, therefore, do
not readily penetrate into the CNS. Nevertheless, most of these drugs have
some clinical effects (anxiety, tremor, and headaches) that are attributable
to action on the CNS.

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B. Noncatecholamines
Compounds lacking the catechol hydroxyl groups
have longer half-lives, because they are not
inactivated by COMT. These include phenylephrine,
ephedrine, and amphetamine. Phenylephrine, an
analog of epinephrine, has only a single OH at
position 3 on the benzene ring, whereas ephedrine
lacks hydroxyls on the ring but has a methyl
substitution at the α-carbon. These are poor
substrates for MAO and, thus, show a prolonged
duration of action, because MAO is an important
route of detoxification. Increased lipid solubility of
many of the noncatecholamines permits greater
access to the CNS.

20. • Compounds lacking the catechol hydroxyl groups
have longer half-lives, because they are not
inactivated by COMT.
• These include:
 phenylephrine,
 ephedrine, and
 amphetamine.

23. • Epinephrine is synthesized from
tyrosine in the adrenal medulla and
released, along with small quantities of
norepinephrine, into the bloodstream.
• Epinephrine interacts with both α and
β receptors.
• At low doses, β effects (vasodilation)
on the vascular system predominate,
whereas at high doses, α effects
(vasoconstriction) are strongest.

24. • Adrenaline is a catecholamine, produced only by
the adrenal glands from the amino acid,
phenylalanine and tyrosine. That acts as both a
neurotransmitter and hormone is also known as
(epinephrine).
• Adrenaline is produced in the medulla of the
adrenal glands and in some neurons of the central
nervous system. They are released into the
bloodstream and serve as chemical mediators, and
also convey the nerve impulses to various organs.

25. Adrenaline has many different actions depending on the type
of cells it is acting upon. However, the overall effect of
adrenaline is to prepare the body for the ‘fight or flight’
response in times of stress, i.e., for vigorous and/or sudden
action. Key actions of adrenaline include increasing the heart
rate, increasing blood pressure, expanding the air passages
of the lungs, enlarging the pupil in the eye (mydriasis),
redistributing blood to the muscles and altering the body’s
metabolism, so as to maximise blood glucose levels
(primarily for the brain).
Adrenaline interacts with both α and β receptors. At low
doses, β effects (vasodilation) on the vascular system
predominate, whereas at high doses, α effects
(vasoconstriction) are the strongest.

26. CARDIOVASCULAR RESPIRATORY HYPERGLYCEMIA LIPOLYSIS
Epinephrine strengthens
the contractility of the
myocardium (positive
inotropic: β1 action) and
increases its rate of
contraction (positive
chronotropic: β1 action).
Epinephrine causes
powerful
bronchodilation by
acting directly on
bronchial smooth
muscle (β2 action).
Epinephrine has a
significant
hyperglycemic effect
because of increased
glycogenolysis in the
liver (β2 effect),
increased release of
glucagon (β2 effect), and
a decreased release of
insulin (α2 effect).
Epinephrine initiates
lipolysis through its
agonist activity on the β
receptors of adipose
tissue, which upon
stimulation activate
adenylyl cyclase to
increase cAMP levels.

27. •ACTIONS OF ADRENALINE
• HERT :
• Beta-1 mediated action - Powerful Cardiac stimulant ( +ve chronotropic, +ve
inotropic)
• Acts on beta-1 receptors in myocardium, pacemaker cells and conducting tissue
– Heart rate increases by increasing slow diastolic depolarization of cells in SAN
– High doses cause marked rise in heart rate and BP causing reflex depression of
SAN – unmasking of latent pacemaker cells in AVN and PF – arrhythmia.
– Cardiac systole is shorter and more powerful
– Cardiac output is enhanced and Oxygen consumption is increased
– Cardiac efficiency is markedly decreased
• Conduction velocity in AVN, atrial muscle fiber, ventricular fibre and Bundle of His
increased – benefit in partial AV block
– Reduced refractory period in all cardiac cells
•

28. • Blood Vessels :
• Seen mainly in the smaller vessels – arterioles
– Vasoconstriction (alpha) and vasodilatation
(beta) .
• Decreased blood flow to skin and mucus
membranes and renal beds – alpha effect (1
and 2)
• Increased blood flow to skeletal muscles,
coronary and liver vessels - (Beta-2 effect)
counterbalanced by vasoconstrictor effect of
alpha receptors.
•

29. • Respiratory :
– Powerful bronchodilator
– Relaxes bronchial smooth muscle (not NA)
• Beta-2 mediated effect
• Physiological antagonist to mediators of
bronchoconstriction e.g. Histamine

30. • GIT :
• Relaxation of gut muscles (alpha and beta
effect) and constricted sphincters – reduced
peristalsis – not clinical importance.

31. • Uterus :
• Adrenaline contracts and relaxes Uterus
(alpha and beta action) but net effect depends
on status of uterus and species – pregnant
relaxes but non-pregnant – contracts.
• Skeletal Muscle :
– Facilitation of Ach release in NM junction (α -1).
– Beta-2 acts directly on Muscle fibres.
– Abbreviated active state and less tension in slow
conducting fibres and enhanced muscle spindle
firing – tremor.

32. • Hyperglycemia :
• Epinephrine has a significant hyperglycemic
effect because of increased glycogenolysis in
the liver (β2 effect),increased release of
glucagon (β2 effect), and a decreased release
of insulin (α2 effect).
• Lipolysis :
• Epinephrine initiates lipolysis through agonist
activity on the β receptors of adipose tissue.
Increased levels of cAMP stimulate a
hormone-sensitive lipase, which hydrolyzes
triglycerides to free fatty acids and glycerol.

33. • Metabolic effects :
• Increases concentration of glucose and lactic acid
• Calorigenesis (β-2 and β-3)
• Inhibits insulin secretion (α-2)
• Decreases uptake of glucose by peripheral tissue
• Simulates glycogenolysis - Beta effect
• Increases free fatty acid concentration in blood
• Hypokalemia – initial hyperkalemia

34. BRONCHOSPASM GLAUCOMA ANAPHYLACTIC
SHOCK
CARDIAC ARREST ANESTHETICS
Epinephrine is the
primary drug used in
the emergency
treatment of any
condition of the
respiratory tract
when
bronchoconstriction
has resulted in
diminished
respiratory
exchange.
In ophthalmology,
a two-percent
epinephrine
solution may be
used topically to
reduce
intraocular
pressure in open-
angle glaucoma.
Epinephrine is the
drug of choice for
the treatment of
Type I
hypersensitivity
reactions in
response to
allergens.
Epinephrine may
be used to restore
cardiac rhythm in
patients with
cardiac arrest
regardless of the
cause.
The effect of the
drug is to greatly
increase the
duration of the
local anesthesia.

35. • Because norepinephrine is the
neuromediator of adrenergic nerves, it
should theoretically stimulate all types of
adrenergic receptors.
• In practice, when the drug is given in
therapeutic doses to humans, the α-
adrenergic receptor is most affected.

36. VASOCONSTRICTION BARORECEPTOR REFLEX EFFECTS OF ATROPINE PRE-
TREATMENT
Norepinephrine causes a rise in
peripheral resistance due to
intense vasoconstriction of most
vascular beds, including the
kidney (α1 effect).
In isolated cardiac tissue,
norepinephrine stimulates
cardiac contractility; however, in
vivo, little if any cardiac
stimulation is noted.
If atropine, which blocks the
transmission of vagal effects, is
given before norepinephrine,
then norepinephrine stimulation
of the heart is evident as
tachycardia.

37. • Isoproterenol is a direct-acting
synthetic catecholamine that
predominantly stimulates both
β1- and β2-adrenergic receptors.
• Its nonselectivity is one of its
drawbacks and the reason why it
is rarely used therapeutically.
• Its action on α receptors is
insignificant.

38. CARDIOVASCULAR PULMONARY OTHER EFFECTS
Isoproterenol produces
intense stimulation of the
heart to increase its rate and
force of contraction, causing
increased cardiac output.
Isoproterenol is as active as
epinephrine and rapidly
alleviates an acute attack of
asthma when taken by
inhalation (which is the
recommended route).
Other actions on β
receptors, such as increased
blood sugar and increased
lipolysis, can be
demonstrated but are not
clinically significant.

39. • Dopamine, the immediate metabolic
precursor of norepinephrine, occurs
naturally in the CNS in the basal ganglia,
where it functions as a neurotransmitter, as
well as in the adrenal medulla.
• Dopamine can activate α- and β-adrenergic
receptors.

40. CARDIOVASCULAR RENAL & VISCERAL
Dopamine exerts a stimulatory effect on the
β1 receptors of the heart, having both
inotropic and chronotropic effects.
Dopamine dilates renal and splanchnic
arterioles by activating dopaminergic
receptors, thus increasing blood flow to the
kidneys and other viscera.
Therefore, dopamine is clinically useful in
the treatment of shock, in which significant
increases in sympathetic activity might
compromise renal function.

41. • Dobutamine is a synthetic, direct-acting
catecholamine that is a β1-receptor agonist.
• One of the stereoisomers has a stimulatory
activity.
• It increases cardiac rate and output with few
vascular effects.
• Dobutamine is used to increase cardiac
output in congestive heart failure as well as
for inotropic support after cardiac surgery.

42. • Oxymetazoline is a direct-acting
synthetic adrenergic agonist that
stimulates both α1- and α2-adrenergic
receptors.
• It is primarily used locally in the eye or
the nose as a vasoconstrictor.
• Oxymetazoline is found in many over-
the-counter short-term nasal spray
decongestant products as well as in
ophthalmic drops for the relief of redness
of the eyes associated with swimming,
colds, or contact lens.

43. • Phenylephrine is a direct-acting, synthetic
adrenergic drug that binds primarily to α
receptors and favors α1 receptors over α2
receptors.
• It is not a catechol derivative and,
therefore, not a substrate for COMT.
• Phenylephrine is a vasoconstrictor that
raises both systolic and diastolic blood
pressures.

44. • Methoxamine is a direct-acting, synthetic adrenergic drug
that binds primarily to α-receptors, with α1 receptors favored
over α2 receptors.
• Methoxamine raises blood pressure by stimulating α1
receptors in the arterioles, causing vasoconstriction.
• This causes an increase in total peripheral resistance.

45. • Clonidine is an α2 agonist that is used in
essential hypertension to lower blood pressure
because of its action in the CNS.
• It can be used to minimize the symptoms that
accompany withdrawal from opiates or
benzodiazepines.
• Clonidine acts centrally to produce inhibition of
sympathetic vasomotor centers, decreasing
sympathetic outflow to the periphery.

46. • Albuterol, pirbuterol, and terbutaline are short-
acting β2 agonists used primarily as bronchodilators
and administered by a metered-dose inhaler.

47. • Salmeterol and formoterol are β2-adrenergic selective, long-
acting bronchodilators.
• Salmeterol and formoterol are the agents of choice for
treating nocturnal asthma in symptomatic patients taking
other asthma medications.

49. • The marked central stimulatory action of
amphetamine is often mistaken by drug
abusers as its only action.
• The CNS stimulant effects of amphetamine and
its derivatives have led to their use for treating
hyperactivity in children, narcolepsy, and
appetite control.
• Its use in pregnancy should be avoided because
of adverse effects on development of the fetus.

50. • Tyramine is not a clinically useful
drug, but it is important because it is
found in fermented foods, such as ripe
cheese and Chianti wine.
• It is a normal by-product of tyrosine
metabolism.
• Normally, it is oxidized by MAO in the
gastrointestinal tract, but if the
patient is taking MAO inhibitors, it can
precipitate serious vasopressor
episodes.

51. • Cocaine is unique among local anesthetics in having
the ability to block the Na+
/K+
-activated ATPase
(required for cellular uptake of norepinephrine) on the
cell membrane of the adrenergic neuron.
• Like amphetamines, it can increase blood pressure by
α-agonist actions and β-stimulatory effects.

53. • Ephedrine, and pseudoephedrine are plant
alkaloids, that are now made synthetically.
• These drugs are mixed-action adrenergic
agents.
• They not only release stored norepinephrine
from nerve endings but also directly
stimulate both α and β receptors.
• Thus, a wide variety of adrenergic
actions ensue that are similar to those
of epinephrine, although less potent.

54. • Ephedrine enhances contractility and improves motor
function in myasthenia gravis.
• Ephedrine has been used to treat asthma, as a nasal
decongestant (due to its local vasoconstrictor action), and to
raise blood pressure.
• Pseudoephedrine is primarily used to treat nasal and sinus
congestion or congestion of the eustachian tubes.

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