Adrenoreceptor agonists, also known as sympathomimetic drugs, mimic the effects of adrenergic sympathetic nerve stimulation. They can be classified based on their chemical structure, mechanism of action, and receptor selectivity. Norepinephrine, epinephrine, and isoproterenol are examples of these drugs. Norepinephrine and epinephrine act on multiple receptor types, while isoproterenol is more selective for beta receptors. They have various effects on cardiovascular, pulmonary, gastrointestinal, renal and metabolic systems by stimulating alpha and beta adrenoreceptors.

1. Adrenoceptor agonists and sympathomimetic
drugs
1

2. • Adrenomimetic drugs
– Refers to drugs which mimic the effects of
adrenergic sympathetic nerve stimulation
on sympathetic effectors
– These drugs are also called sympathomimetic
agents
– They have a wide range of effects
Eg. they can be used to maintain blood pressure or to
relieve a life-threatening attack of acute bronchial
asthma
– Can be classified into different groups, based on
• Chemical structure
• Mechanism of action
• Receptor selectivity
2

3. 3
Based on chemical structure
– Adrenomimetics can be divided into two:
• Catecholamines
– They have catechol ring in their structure
– E.g. NE, EP, DA, Isoproternol, Dobutamine, Colterol,
ethyl NE, Metaproternol
• Non catecholamines
– They don’t have catechol ring
– E.g. ephedrine, phenylephrine, albuterol,
metaraminole, tyramine, amphetamine, terbutaline,
methamphetamine, ritodrine, salmiterol,
methoxamine

4. 4

5. 5

6. 6
 Based on mechanism of action
– Adrenomimetics can be classified into three groups
1. Direct acting adrenomimetics
• Directly interact & stimulate adrenoceptors
• May exhibit receptor selectivity
 Eg. phenylephrine for ἀ1, terbutaline for β2
• May have no or minimal selectivity and act on several receptor
types
 E.g., epinephrine for ἀ1, ἀ2, β1, β2, and β3 receptors; NE for ἀ1, ἀ2, and
β1 receptors
• Their effects are not reduced by prior treatment with
reserpine or guanethidine
• Rather prior treatment with reserpine or guanethidine can
increase their effects
Due to receptor up regulation
• Examples: NE, EP, DA, isoproterenol(IP), dobutamine,
phenylephrine, albuterol, salmiterol, metaraminole,
terbutaline, clonidine, oxymethazoline, xylomethazoline,
midodrine, methoxamine

7. 7
2. Indirect acting adrenomimetics
– They don’t interact with the adrenoceptors
– They increase availability of NE/EP to stimulate
the adrenoceptors
– Their action emanates from one of the following
• Displaced stored neurotransmitters from the vesicles
E.g. amphetamine, tyramine, methamphetamine,
phenmetrazine, methylphenidate, modafinil
• Inhibit reuptake of neurotransmitters into the neuron
E.g. cocaine, TCAs
• Inhibit the metabolizing enzymes (MAO & COMT)
E.g. pargyline/selegiline, entacapone
– Their response is abolished by prior
administration of reserpine or guanethidine

8. 8
3. Mixed acting adrenomimetics
– Work by both direct & indirect mechanisms
– Increase release of NE & also activate
adrenoceptors
– Eg.
Ephedrine
Pseudoephedrine
Phenylpropanolamine- it was a common component in over-
the-counter appetite suppressants
It was removed from the market because its use was associated
with hemorrhagic strokes in young women
It can increase blood pressure in patients with impaired autonomic
reflexes
– Their responses are blunted but not abolished by
prior treatment with reserpine or guanethidine

9. Summary
9

10. Fig. Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists
10

11. 11
 Based on selectivity to adrenoceptors
– They are grouped into many classes
a. Non selective between α & β adrenoceptors
• NE, EP
b. α1 selective adrenomimetics
• Phenylephrine, methoxamine, metaraminole, midodrine,
mephentermine
c. α2 selective adrenomimetics
• Clonidine, methyldopa, guanfacine, guanbenz,
moxonidine, rilmenidine
• Dexmedetomidine- used for sedation
• Tizanidine is used as a central muscle relaxant

12. 12
d. Non selective α1 & α2 adrenomimetics
• EP, NE, oxymethazoline, xylomethazoline, naphazoline
e. β1 selective adrenomimetics
• Dobutamine
• A partial agonist, prenalterol
f. β2 selective adrenoceptor agonists
– Albuterol, terbutaline, salmeterol, formoterol
metaproternol, bitolterol, ritodrine, isoetharine
g. β1β2 nonselective adrenoceptor agonists
– Isoproternol, EP,NE

13. The main effect of adrenoreceptor activation
I. α1-receptor
– Arterial and venous vasoconstriction(blood vessel)
– GUT
Contraction of the sphincter tone of the bladder/prostate
contraction/
Contraction of uterus in non pregnant women
 Decreased contractile response to vasoconstrictors in uterine and non uterine
vessels contributes to increased blood flow to the uterine circulation during
normal pregnancy
– Decrease salivary secretion(salivary glands)
– Increase force of contraction of heart
– Contraction of pupillary dilator muscle(dilate the pupil)
(eye)
– Hepatic glycogenolysis and gluconeogenesis (liver)
– Pilomotor smooth muscle erects hair
– Intestinal smooth muscle: relaxation (membrane
hyperpolarization) 13

14. II. α2- receptors
• On pre-synaptic:
Inhibition of transmitter release (autoreceptor)
Eg. reduction in NE release
• Post-synaptic
platelet aggregation
Contraction of vascular smooth
muscle(vasoconstriction)
Decrease sympathetic outflow in CNS
Inhibition of insulin release (B-cell of pancreas)
Decrease aqueous humor secretion
In fat cells it inhibits lipolysis
III. B1- receptor
– Increased heart rate , force of contraction and AV nodal conduction
– Increased renin secretion in kidney juxtaglomerular cells
14

15. IV. Β2-receptor
– Bronchodilation and vasodilatation(in skeletal blood vessel)
– Relaxation of visceral smooth muscle of GIT
– GUT :
• Bladder relaxes
• Uterus (in pregnant women) relaxes
– Hepatic glycogenolysis
– Mast cell decrease histamine secretion
– Increased secretion of aqueous humour
– In skeletal muscle –it promotes potassium uptake
V. β3-receptor
– Lipolysis (fat cell)
vi. D1-receptor
– Dilates renal blood vessels
Vii.D2-receptor
– Modulates transmitter release
15

16. • Adrenaline/EP
– This is the prototype of adrenergic drugs
• Pharmacokinetics
– It is rapidly destroyed in the GIT, conjugated, and
oxidized in the liver
– It is therefore ineffective when given orally and
should be given through IM or SC
– It can be administered topically to the eye
– In emergency case, the IM route is most commonly
employed, because there is no much delay in the
onset of action by IM/IV route
– IV use is not commonly employed because it can lead
to development of fatal arrhythmias or it is likely to
precipitate ventricular fibrillation
16

17. – However, in severe cases, adrenaline can be
administered through IV as a diluted infusion
with constant monitoring of heart function
– It can be given by nebulizer for inhalation when
its relaxing effect on the bronchi is desired or it
may be applied topically to mucus membranes to
produce vasoconstriction
– It is metabolized by two enzymatic pathways:
MAO, and COMT, which has S-
adenosylmethionine as a cofactor
– The final metabolites found in the urine are
metanephrine and vanillylmandelic acid
17

18. Fig. Pharmacokinetics of epinephrine 18

19. • Drug-drug interactions and drug disease
interaction
• Hyperthyroidism
 EP may have enhanced cardio-vascular actions in
patients with hyperthyroidism
 If EP is required in such an individual, the dose must be
reduced
 The mechanism appears to involve increased production
of adrenergic receptors on the vasculature of the
hyperthyroid individual
 This is leading to a hypersensitive response
• Cocaine
 In the presence of cocaine, epinephrine produces
exaggerated cardiovascular actions
 This is due to the ability of cocaine to prevent reuptake of
catecholamines into the adrenergic neuron
 Thus, like NE, epinephrine remains at the receptor site for
longer periods of time 19

20. • Diabetes
– EP increases the release of endogenous stores of
glucose
– In the diabetic, dosages of insulin may have to be
increased
• β-Blockers
– These agents prevent epinephrine's effects on β-
receptors, leaving ἀ-receptor stimulation unopposed
– This may lead to an increase in peripheral resistance
and an increase in BP
• Inhalation anesthetics
– Inhalational anesthetics sensitize the heart to the
effects of epinephrine, which may lead to
tachycardia
20

21. • Norepinephrine (levarterenol, noradrenaline)
 It is the neurochemical mediator
 It is released by nerve impulses and various drugs from
the postganglionic adrenergic nerves
 It also constitutes 20% of the adrenal medulla
catecholamine out put
– It should theoretically stimulate all types of adrenergic
receptors
– In practice, when the drug is given at therapeutic doses to
humans, the ἀ-adrenergic receptor is most affected
• Pharmacokinetics
 Like adrenaline, noradrenaline is ineffective orally
 So it has to be given intravenously with caution
 It is not given through SC or IM because of its strong
vasoconstrictor effect producing necrosis and sloughing
 The metabolism is similar to adrenaline; only a little is
excreted unchanged in urine
21

22. • Isoproterenol(IP)
– It is a direct-acting synthetic catecholamine
– Predominantly stimulates both β1- and β2-
adrenergic receptors
– Its non-selectivity is one of its drawbacks and the
reason why it is rarely used therapeutically
• Pharmacokinetics
– IP can be absorbed systemically by the sublingual
mucosa
– However, it is more reliably absorbed when given
parenterally or as an inhaled aerosol
– It is a marginal substrate for COMT and is stable
to MAO action
22

23. 23
Pharmacologic responses of NE, EP & Isopreternol
1. Vascular effects
 Blood vessels of skin & Mucus membranes
– Predominantly contain α-adrenoceptors
– So, both NE & EP can produce potent constriction
• Because both NE & EP are non selective adrenomimetics
– Isoproternol has very low affinity for α-
adrenoceptors & so produce no effect on these
vessels
 Blood vessels of visceral organs
– Predominantly contains α-adrenoceptors & some β-
adrenoceptors
– NE & EP produce vasoconstriction
– Isoproternol produces minor vasodilation

24. 24
Blood vessels of skeletal organs
– Contain both α & β adrenoceptors
• NE
 It causes a rise in peripheral resistance
This is due to intense vasoconstriction of most
vascular beds, including the kidney (ἀ1 effect)
• Both systolic and diastolic blood pressures increase
• NE causes greater vasoconstriction than does EP
because it does not induce compensatory
vasodilation via β2receptors on blood vessels
supplying skeletal muscles

25. • Baroreceptor reflex
– Increase in BP induces a reflex rise in vagal activity
by stimulating the baroreceptors
– This reflex bradycardia is sufficient to counteract the
local actions of NE on the heart
– However, the reflex compensation does not affect the
positive inotropic effects of the drug(b/c of ἀ1
stimulation)
• Effect of atropine pretreatment
– If atropine, which blocks the transmission of vagal
effects, is given before NE
– Then NE stimulation of the heart is evident as
tachycardia
25

26. Fig
.
Cardiovascular
effects
of
intravenous
infusion
of
norepinephrine
26

27. • IP dilates the vessels by its effect on β
adrenoceptors
– However, it increases HR, FC and cardiac
output
– Nevertheless, the overall effect is decrease in
BP
27

28. Fig. Cardiovascular effects of intravenous infusion of isoproterenol
28

29. • EP has complex effect depending on its
dose
– Low dose produces vasodilation
– High dose produces vasoconstriction
Therefore, the cumulative effect of EP is an
increase in systolic BP, coupled with a slight
decrease in diastolic pressure
29

30. Fig. Cardiovascular effects of intravenous infusion of low doses of epinephrine30

31. 31

32. 32
2. Effects on intact cardiovascular system
– Increased sympathetic neural activity produces
Increased heart rate, force of contraction
Increased stroke volume & cardiac output
Constricts most of blood vessels, so increases TPR
Increased blood pressure

33. 33
3. Effects on nonvascular smooth muscles
 Bronchial smooth muscles
– Predominantly β2 receptors are found
– Bronchodilation by EP & IP due to β2 action
– EP relieves all known allergic- or histamine-induced
bronchoconstriction
– It also inhibits the release of allergy mediators such as
histamines from mast cells
– NE has very low affinity & so weaker effects
 GIT smooth muscles
– Motility of the gut is reduced
• Due to activation of the α2 hetroreceptors (inhibit Ach)
– GI sphincters are contracted
• Through an action on α1 adrenoceptors
 Eye
– Radial muscle of the iris contain ἀ1 adrenoceptors
• NE/EP cause contraction of this muscle & lead to mydriasis

34. 34
 Kidney
– Detrusor muscle contains β2 adrenoceptors
• So, EP & IP relax the detrusor muscle
– Trigon & sphincter muscles contain α1 adrenoceptors
• Contracted by NE & EP, which inhibits the voiding of urine
• EP decrease renal blood flow
 Uterine muscle
– Contains both α1 & β2 adrenoceptors
• NE causes uterine contraction
• EP/IP cause uterine relaxation
 CNS effects
– Though catecholamines minimally cross the BBB, they
cause CNS stimulation (mechanism not well known)
• Apprehension(anxiety, fear), restlessness & increased
respiration

35. 35
5. Metabolic effects
– Catecholamines, primarily EP/IP, exert a number of
important effects on metabolism
• Most effects are due to β-adrenoceptors activity
– NE is usually effective only in large doses
– So, EP & IP in therapeutic doses
Increase oxygen consumption
Increase hepatic glycogenolysis
EP>IP>NE
Mediated by both α2 & β2 Adrenoceptors due to:
Increased glycogenolysis in the liver (β2 effect)
Increased release of glucagon (β2 effect)
Decreased release of insulin (ἀ2 effect)
Overall effect is an increase of blood glucose
level/hyperglycemia

36. 36
Increases skeletal muscle glycogenolysis
–IP>EP>NE
–Mediated by β-adrenoceptors
–Increases blood lactic acid level than
blood glucose level
–Because skeletal muscle lacks glucose-6-
phosphatase enzyme which converts G-
6-P to glucose

37. 37
 Increased lipolysis
– They initiates lipolysis through their agonist activity on the
β-receptors of adipose tissue
– This stimulation activate adenylyl cyclase to increase cAMP
levels
– Cyclic AMP stimulates a hormone sensitive lipase, which
hydrolyzes triacylglycerols to free fatty acids and glycerol
– Therefore, they increase blood free fatty acid levels
– Mediated by β3 adrenoceptors
– IP>EP>NE
 K+ homeostasis
– Catecholamines play an important role in the short term
regulation of plasma K+ levels
 Stimulation of hepatic a adrenoceptors will result in the
release of K+ from the liver
 In contrast, stimulation of β2 adrenoceptors, particularly
in the skeletal muscles, will lead to uptake of K+ into the
tissue
β2 adrenoceptors are linked to Na+/K+ ATPase

38. 38
Clinical uses of catecholamines
– Their uses are based on their actions on bronchial
smooth muscles, blood vessels & the heart
 Allergic reactions
– EP is mainly used in allergic reactions which are due
to histamine release
Because it produces to certain physiological responses that
are opposite to those produced by histamine
– So, EP is used in the treatment of
Anaphylactic shock
 It is the drug of choice for the treatment of Type I hypersensitivity
reactions in response to allergens
 The syndrome of bronchospasm, mucous membrane congestion,
angioedema, and severe hypotension usually responds rapidly to the
parenteral administration of epinephrine
 IM route is preferred
Urticaria
Angioneuretic edema
Serum sickness
Serum
sickness
Angioneure
tic edema

39. • Bronchospasm
– Epinephrine is the primary drug used in the
emergency treatment
– In treatment of acute asthma, it is the drug of choice
– Selective β2agonists, such as albuterol, are presently
favored in the chronic treatment of asthma
because of their longer duration of action and minimal
cardiac stimulatory effect
 Cardiac applications
– IP and EP have been used in the temporary
emergency management of complete heart block
and cardiac arrest
– EP may be useful in part by redistributing blood flow
during cardiopulmonary resuscitation to coronaries
and to the brain
39

40. Open-angle glaucoma
– EP has been used to lower IOP in open-angle
glaucoma
It reduces the production of aqueous humor by
vasoconstriction of the ciliary body blood vessels
Works by increasing outflow of aqueous humor
probably by stimulating β2-adrenergic receptors in the
trabecular meshwork
– In ophthalmology, a two-percent epinephrine
solution may be used topically
– It is available as hydrochloride, bitartarate and
borate salt for topical ophthalmic use
– EP is contraindicated in closed-angle glaucoma
• Because it reduces the filtration angle further &
hinders outflow of fluid in this case
40

41. 41
 Used with local anesthetics(LAs)
– NE/EP is coadministered with LAs
– Local anesthetic solutions usually contain 1:100,000 parts
epinephrine
– It greatly increase the duration of the local anesthesia
– By producing vasoconstriction at the site of injection, it allows
the local anesthetic to persist at the injection site before being
absorbed into the circulation and metabolized
– Prevent systemic absorption & toxicity of the LAs
– However, EP can potentiate the neurotoxicity of local
anesthetics used for peripheral nerve blocks or spinal
anesthesia
 Control of bleeding
– EP is used as topical hemostatic agent for the control of local
hemorrhage
– EP is usually applied topically in nasal packs (for epistaxis) or in
a gingival string (for gingivectomy)
– Very weak solutions of EP 1:100,000 is used

42. 42
Management of hypotension
– Sympathomimetic drugs may be used in a hypotensive
emergency to preserve cerebral and coronary blood flow
– The treatment is usually of short duration
– When NE is used as a drug, it is sometimes called
levarterenol
– NE is infused IV to combat systemic hypotension during
spinal anesthesia
– However, metaraminol is favored, because it does not
reduce blood flow to the kidney, as does NE
– NE is also useful in controlling hypotension in which
TPR is low
• Because it increases vascular resistance and increases BP
• But NE is not used to combat hypotension due to most types of
shock

43. 43
Side effects of catecholamines
– Tachycardia
– Reflex bradycardia
• By NE, but not with EP or IP(because they have β 2 effects)
– CNS disturbances
• Epinephrine can produce adverse CNS effects that include anxiety, fear,
tension, headache, and tremor
– Tissue sloughing & necrosis
• Local ischemia from extravasation of NE at site of injection
– Arrhythmia
• EP can trigger cardiac arrhythmias, particularly if the patient is
receiving digitalis
– Hypertension (mainly by NE and EP)
– Pulmonary edema
• Epinephrine can induce pulmonary edema
• Hemorrhage
– EP and NE may induce cerebral hemorrhage as a result of a
marked elevation of BP

44. Contra indications
 Coronary diseases
 Hyperthyroidism
 Hypertension
 Digitalis therapy
 Injection around end arteries
44

45. 45
Other adrenomimetic agents
– A number of adrenomimetics are not catecholamines
– Noncatecholamines are resistant to enzymatic
degradation(COMT)
• They have longer duration of action
• They are orally active
α1-selective adrenomimetic agents
– Phenylephrine, metaraminol & methoxamine
– They are all directly acting adrenomimetics
– However, metaraminol also is an indirectly acting agent that
stimulates the release of NE
• Exert their effect primarily by activating α1-adrenoceptor
– Has no/little direct effect on the heart
– All have vasoconstrictor effect
• Increase both the systolic & diastolic blood pressure
o They don’t cause cardiac arrhythmias
o They don’t stimulate CNS

46. 46
• Their vasoconstrictor effect is accompanied by
– Reflex increment in the vagal input to the heart
• Reflex bradycardia
• No change in the contractile forces
– They have considerably longer duration of action
than NE
• Phenylephrine resistant to COMT metabolism
• Metaraminol & methoxamine are resistant to both
COMT & MAO

47. 47
 Clinical uses
– Associated with their potent vasoconstrictor
effects
 They are used to restore or maintain Bp during spinal
anesthesia & certain other hypotensive states
 Phenylephrine is commonly used
oAs nasal decongestant
oAs mydriatic agent
oWith local anesthetics in dental procedures
– Metaraminol also off-label used to relieve attacks of
paroxysmal atrial tachycardia, particularly those
associated with hypotension

48. • Midodrine
– It is a prodrug that is enzymatically hydrolyzed to
desglymidodrine
– It is selective α1 -receptor agonist
– It is an orally effective
– It is used for the treatment of orthostatic hypotension, typically
due to impaired autonomic nervous system function
 Because it rises BP that associated with both arterial and venous
smooth muscle contraction
– It reduces the fall of blood pressure when the patient is in
standing position
– It may cause hypertension when the subject is supine
– This can be minimized by :
 Administering the drug when the patient will remain upright position
 Avoiding dosing within 4 hours of bedtime
 Elevating the head of the bed
– FDA considered withdrawing approval of this drug in 2010
48

49. • Mephentermine
– It is a sympathomimetic drug that acts both directly and
indirectly
– It has many similarities to ephedrine
– Since the drug releases NE, cardiac contraction is
enhanced, and cardiac output and systolic and diastolic
pressures usually are increased
– The change in heart rate is variable, depending on the
degree of vagal tone
– Mephentermine is used to prevent hypotension, which is
frequently accompanies with spinal anesthesia
– Adverse effects
CNS stimulation
Excessive rises in blood pressure
Arrhythmias
– The drug has been discontinued in the U.S
49

50. 50
α2 selective adrenomimetics
– Includes: methyldopa, clonidine, guanfacine, apraclonidine,
brimonidine, tinazidine
 Methyldopa
– It is a centrally acting adrenomimetic agent
– It is a prodrug & produces its effects via active
metabolite
– In adrenergic neurons, it is metabolized by DOPA
decarboxylase enzyme to α-methyl dopamine
– α-methyl dopamine is then converted to α-methyl NE
– α-methyl NE, by activating α2 adrenoceptors in the
brainstem attenuates further release of NE
Produces its vasodilatory effects
 Uses: it is the preferred drug for the treatment of
hypertension during pregnancy
Because it is safe for both the mother & infant

51. 51
 Adverse effects
– Sedation
– Occasional depression
– Dryness of mouth
– Reduction in libido
– Hyperprolactinemia
• Gynacomastia, galactorrhea
– Serious but rare hepatotoxicity
• Contraindicated in patients with hepatic disease
– Can also cause hemolytic anemia

52. 52
 Clonidine, guanbenz & guanfacine
– They are all α2 selective agonists
MOA
– They stimulate presynaptic α2A receptors in the
brainstem reducing sympathetic outflow from
the CNS
• Reduce arterial pressure by an effect on both Cardiac
Output & peripheral resistance
– At higher doses, these drugs can stimulate
postsynaptic α2B receptors (found on the
vascular smooth muscles) causing
vasoconstriction
• This explains the initial vasoconstriction that is seen
when overdoses of these drugs are taken

53. • Clinical use
– Treatment of essential hypertension
 However, in patients with pure autonomic failure, characterized by neural
degeneration of postganglionic noradrenergic fibers, clonidine may
increase BP
 This is because of the fact that the central sympatholytic effects of
clonidine become irrelevant, whereas the peripheral
vasoconstriction remains intact
– Clonidine has been found to be useful in reducing diarrhea in
some diabetic patients with autonomic neuropathy
 Because stimulation of ἀ2 receptors in the GI tract may increase
absorption of sodium chloride and fluid and inhibit secretion of
bicarbonate
– Useful in treating and preparing addicted subjects for
withdrawal from narcotics, alcohol, and tobacco
– Clonidine and related drugs such as dexmedetomidine (a
relatively selective ἀ2 receptor agonist with sedative properties)
used in anesthesia to produce preoperative sedation and
anxiolysis, drying of secretions, and analgesia
– Transdermal administration of clonidine may be useful in
reducing the incidence of menopausal hot flashes
53

54. 54
• Adverse effects
– Sedation & xerostemia
– Postural hypotension & erectile dysfunction
– Sleep disturbances & night mares
– Depression
– Sudden withdrawal of clonidine & other α2
agonists may cause withdrawal syndrome
consisting of:
• Headache, sweating, tremors, abdominal pain,
tachycardia & rebound HTN
• Therefore, dose tapering must be followed to withdraw
the patients from the drug

55. • Apraclonidine
– It is a relatively selective ἀ2 receptor agonist
– It can reduce elevated as well as normal IOP
whether accompanied by glaucoma or not
– The reduction in IOP occurs with minimal or no
effects on systemic cardiovascular parameters
– Thus apraclonidine is more useful than clonidine
for ophthalmic therapy
– Apparently apraclonidine does not cross the BBB
– The mechanism of action of apraclonidine is
related to ἀ2 receptor–mediated reduction in the
formation of aqueous humor
55

56. • Clinical uses
– It is used topically to reduce IOP as short-term
adjunctive therapy in glaucoma
– Especially in patients whose IOP is not well
controlled by other pharmacological agents such
as β-receptor antagonists,
parasympathomimetics, or carbonic anhydrase
inhibitors
– It is used to control or prevent elevations in IOP
that occur in patients after laser trabeculoplasty
or iridotomy
56

57. • Brimonidine
– It is another clonidine derivative
– It is ἀ2-selective agonist
– It is administered ocularly to lower IOP in patients
with ocular hypertension or open-angle glaucoma
– It reduces IOP both by decreasing aqueous humor
production and by increasing outflow
– Its efficacy in reducing IOP is similar to that of the
receptor antagonist timolol
– Unlike apraclonidine, brimonidine can cross the BBB
and can produce hypotension and sedation
– However, these CNS effects are slight compared to
those of clonidine
– As with all ἀ2 agonists, this drug should be used with
caution in patients with cardiovascular disease
57

58. • Tizanidine
– It is also an ἀ2 agonist
– It is a muscle relaxant used for the treatment of
spasticity associated with cerebral and spinal disorders
• Dexmedetomidine
– It is an ἀ2 agonist used for sedation under intensive
care circumstances and during anesthesia
– It blunts the sympathetic response to surgery
it may be beneficial in some situations
– It lowers opioid requirements for pain control and does
not depress ventilation
58

59. • Drugs with both ἀ1- and ἀ2-receptors
agonist
• Oxymetazoline and Xylometazoline
– They are a direct-acting synthetic adrenergic agonist
that stimulates both ἀ1- and ἀ 2-adrenergic
receptors
– They are 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
– By directly stimulating ἀ-receptors on blood vessels
supplying the nasal mucosa and the conjunctiva, it
reduces blood flow and decrease congestion
59

60. – Oxymetazoline may cause hypotension,
presumably because of a central clonidine-like
effect
– Oxymetazoline is absorbed in the systemic
circulation regardless of the route of
administration and may produce nervousness,
headaches, and trouble sleeping
– When administered in the nose, burning of the
nasal mucosa and sneezing may occur
– Rebound congestion is observed with long-term
use
60

61. 61
β1-selective adrenomimetics
• Dobutamine
– It acts directly on β1-adrenoceptors in the heart
– It exerts a greater effect on the contractile force of the
heart relative to its effect on the heart rate
– At higher doses, it produces vasodilation of the renal
& mesenteric blood vessels
– It has a fast onset of action & short half life (2mins)
• Therapeutic uses
– Indicated for short term treatment of cardiac
decompensation that may occur
After surgery
In patients with CHF

62. 62
– Dobutamine increases the stroke volume &
cardiac output in such patients, usually without
marked increase in the heart rate
– It is also useful in the treatment of cardiogenic
shock
 Adverse effects
– May increase the size of myocardial infarct
• By further increasing the oxygen demand
– Increased risk of atrial fibrillation

63. • Dopamine
– It is the immediate metabolic precursor of NE
– It occurs naturally in the CNS in the basal ganglia
– It functions as a neurotransmitter in the CNS and adrenal
medulla
– Dopamine can activate ἀ- and β-adrenergic receptors
– For example,
at higher doses, it can cause vasoconstriction by activating ἀ1
receptors
at lower doses, it stimulates β1 receptors on the cardiac cells
– D1 and D2 dopaminergic receptors occur in the peripheral
mesenteric and renal vascular beds, where binding of
dopamine produces vasodilation
– D2 receptors are also found on presynaptic adrenergic
neurons, where their activation interferes with NE
release
63

64. • Dopamine action
• CVS
– Dopamine exerts a stimulatory effect on the β1- receptors of
the heart
– It has both positive inotropic and chronotropic effects
– At very high doses, it activates ἀ1-receptors on the vasculature,
resulting in vasoconstriction
• Renal and visceral
– Dopamine dilates renal and splanchnic arterioles
– It increases 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
 Dopamine hydrochloride is used only intravenously, preferably
into a large vein to prevent perivascular infiltration(i.e given by
continuous infusion)
 Because extravasation may cause necrosis and sloughing of the
surrounding tissue
64

65. 65
β2-selective adrenomimetic agents
– They are agents used in the management of
asthma
– The main difference in the available β2
adrenomimetics is their pharmacokinetic
profiles
– So, in the management of asthma, β2 agonists
• Work by activating pulmonary β2 adrenoceptors &
relax the bronchial smooth muscles & decrease
airway resistance

66. 66
 Metaproterenol
– It is resistant to metabolism by COMT
– Available for inhalational & oral dosage forms
– It is less β2 selective, compared to albuterol &
terbutaline
• More prone to cause cardiac stimulation than the two
drugs
Uses:
• Metaproterenol is used for
– Long term treatment of obstructive airway disease
– Treatment of acute bronchospasm

67. 67
 Terbutaline
– It is β2 selective
• Resistant to COMT
– Effective when given by oral, Sc or inhalational
routes
• Onset of action is rapid from inhalational & SC routes
Uses:
• Long term treatment of obstructive airway disease
• Treatment of acute bronchospasm
• Emergency treatment of status asthmaticus
 Albuterol/salbutamol
– β2 selective, given by inhalational or oral route
– Has similar therapeutic indications as terbutaline
– Oral albuterol has the potential to delay preterm
labor

68. 68
 Salmeterol
– It is a β2 selective agent with the longest duration
of action (>12 hours)
– At least 50 times more β2 selective than
albuterol
– Highly lipophilic & has sustained action
– It has slow onset of action
• Not suitable monotherapy for acute attacks of asthma
– Due to its sustained duration of action, salmeterol
• It is drug of choice for treatment of nocturnal asthma
• It shouldn’t be used more than twice daily
• It shouldn’t be used to treat acute asthma

69. 69
 Formoterol
– It is another long acting, β2 selective agonist
– It is highly lipophilic, resulting in storage in
adipocytes
• Responsible for sustained action
– It is an alternative to salmeterol for treatment of
nocturnal asthma
 Ritodrine
– Selective β2 agonist, developed specifically for
use as uterine relaxant
– Up to 30% absorbed after oral dose
• 90% of drug excreted in urine as inactive conjugate
– Uses: given through IV in selected patients to
arrest premature labor

70. • Indacaterol, olodaterol, and vilanterol
– They are new ultralong ß2 agonists
– They have been approved by the FDA for once-a-
day use in COPD
70

71. 71
• Adverse effects of β2 selective adrenomimetics
– Tremor
It is due to stimulation of 2 receptors in skeletal muscle
It is the most common side effect
– Feeling of restlessness, apprehension & anxiety
– Tachycardia, which may result from
• β1 stimulation
• Reflex response to peripheral vasodilation
– Cardiac arrhythmias or myocardial ischemia
• Less likely in patients without pre-existing cardiac disease
• High risk of occurrence in patients with underlying coronary
artery disease or pre-existing arrhythmia
– Pulmonary edema
• In women who receive ritodrine or terbutaline for preterm
labor

72. 72
• Larger doses of β2 adrenomimetics may
– Increase plasma glucose level
– Increase lactate & free fatty acids level in plasma
– Lower plasma concentration of K+
• Note:
– All the adverse effects are far less likely with
inhalational therapy than with parentral or oral
therapy

73. 73
Indirect acting adrenomimetics
• Includes: amphetamine, methamphetamine,
cocaine, methylphenidate, TCAs
Amphetamine
– Indirectly acting agent
• Works by displacing NE/EP from its storage vesicles
– Pharmacological effects
• CVS effects
– Increases both systolic & diastolic blood pressure
– Heart rate is reduced reflexively

74. 74
• CNS effects
– It is one of the most potent sympathomimetic
amines in stimulating the CNS
– Amphetamine:
• Stimulates medullary respiratory centres
• Lessens degree of central depression caused by
various drugs
 Alters psych of individuals
Elevation of mood, self-confidence & ability to
concentrate
Increase in elation (excitement) & euphoria, wakefulness,
decreased fatigue

75. 75
Increases motor & speech activities
Improved performance of tasks (errors may
increase)
Prolonged or large dose use is nearly always
followed by depression & fatigue
 Therapeutic uses
– Amphetamine is used chiefly for its CNS effects
– Dextroamphetamine, with more CNS actions than
peripheral actions
• Was used for reducing obesity
– Due to its anorexic effects
– No more approved by FDA for this purpose
• It is approved by FDA for treatment of
– Narcolepsy
– Attention deficient hyperactivity disorder

76. 76
 Methamphetamine
– Chemically, a close relative of amphetamine
– Works by
• Increasing dopamine & other biogenic amines
• Inhibiting neuronal & vesicular transporters
• Inhibiting MAO
– Has a prominent central than peripheral action
– Has high potential for abuse
• Widely used as a cheap, accessible recreational drug
• Its abuse is a widespread phenomenon
 Methylphenidate
– Mild CNS stimulant, with essentially similar
pharmacological actions as amphetamines
– Has also the abuse potentials of amphetamines

77. Modafinil
– It is a new amphetamine substitute
– It is approved for use in narcolepsy
– It has fewer disadvantages (excessive mood
changes, insomnia, and abuse potential) than
amphetamine in this condition
– It is not approved for ADHD because of safety
issue in children
77

78. 78
 Toxic & adverse effects of amphetamines
o They are extensions of pharmacological actions of
amphetamine
o CNS effects
• Restlessness, dizziness, tremor, hyperactive reflexes, insomnia,
talkativeness & euphoria
• If dose is large enough or in mentally ill patients
– Confusion, aggressiveness, changes in libido, anxiety,
suicidal or homicidal tendencies may occur
• Fatigue & depression usually follow central stimulation
o CVS effects
• Pallor or flushing, palpitations, cardiac arrhythmias, anginal
pain, hypertension/hypotension, circulatory collapse
o Excessive sweating
o GI effects: dry mouth, metallic taste, anorexia, nausea,
vomiting & abdominal cramps

79. 79
 Treatment of acute amphetamine toxicity
– Acidification of urine with ammonium chloride
• Increases the excretion of amphetamine
– Sedatives may be required for CNS effects
– Severe hypertension may require administration of
• Sodium nitroprusside or α1 antagonists

80. 80
 Mixed acting adrenomimetic drugs
 Ephedrine
– It is naturally occurring plant alkaloid
– Can cross BBB
• Has strong CNS stimulating effect, in addition to its peripheral
actions
• CNS stimulatory effect is less, compared to amphetamine
– It has longer duration of action than NE
• Because it is very resistant to both COMT & MAO metabolism
– Unlike NE/EP, ephedrine is effective when taken orally
• Less potent compared to NE/EP
– Tachyphylaxis develops after repeated use
– It is absorbed from the GIT and from all parenteral sites
– A major proportion of the drug is excreted unchanged in
the urine

81. 81
 MOA
– Actions mainly depend on release of NE/EP
– Has also some direct receptor stimulatory effects
• Particularly in its bronchodilating effects
 Clinical uses
– Ephedrine is useful in
• Relieving bronchoconstriction & mucosal congestion
associated with bronchial asthma
• Prophylactic prevention of asthmatic attacks
• Nasal decongestion
• Producing mydriasis
– Terbutaline & albuterol are replacing ephedrine for
treatment of asthma
• Less side effects, effective bronchodilation

82. 82
 Adverse effects
• Tachycardia
• Insomnia
• Nervousness, nausea, vomiting
• Emotional disturbances

83. Adrenoceptor antagonists
 They are drugs that inhibit responses mediated by
adrenoceptor activation
 They have affinity for adrenoceptors
• Lack intrinsic activity, so won’t initiate receptor responses
 Works by competing with adrenomimetics for access
to adrenoceptors
• Reduce effects produced by both sympathetic nerve
stimulation & exogenous adrenomimetics
– Adrenoceptor antagonists
• They don’t prevent release of NE/EP from adrenergic
neurons
• They are not catecholamine depleting agents
• Are also called, sympathoplegics, sympatholytics
83

84. Classification of adrenoceptor antagonists
1. α- Adrenoceptor antagonists
a) Non selective α1, α2- Adrenoceptor antagonists
• Phentolamine, Phenoxybenzamine, Tolazoline
b) α1- selective adrenoceptor antagonists
• Prazosin, Terazosin, Doxazosin, Tamsulosin, Alfuzosin
c) α2- selective adrenoceptor antagonists: Yohimbine
2. β- Adrenoceptor antagonists
a) Non selective β1, β2 adrenoceptor antagonists
• Propranolol, Pindolol, Nadolol, Timolol
b) β1- selective adrenoceptor antagonist
• Atenolol, acebutolol, Metoprolol, Esmolol, Bisoprolol
C) β2- selective adrenoceptor antagonists
• Butoxamine
84

85. 85
3. Nonselective α, β-Adrenoceptor antagonists
• Labetalol, Carvedilol, Bucindolol
• Pharmacological effects of α-blockers
1. Cardiovascular system: ( 1 receptors on blood vessels )
– Dilatation of arteries & veins   BP
2. Eye:
– Radial muscle of iris (1 receptors) -> relaxes -> miosis
3. Nose:
– Dilatation of blood vessels  nasal congestion
4. Genitourinary system:
–  resistance to urine flow
– Inhibition of ejaculation

86. Non-selective α-blockers
– Block both α1 & α2 adrenoceptors
– E.g. Phenoxybenzamine, Phentolamine, Tolazoline
Phenoxybenzamine
– Is a haloalkylamine that blocks both α1 & α2 receptors
irreversibly
– Major pharmacological effect (vasodilation) occurs from
blockade of α-receptors in blood vessels
• Causes reduced TPR (due to α1 & α2B blockade)
• Increased CO (due to reflex sympathetic nerve stimulation)
• Tachycardia
– Reflex to hypotension, enhanced release of NE/EP due to activation
of presynaptic α2A adrenoceptors
– In addition to antagonism of α-receptor, it can
• Inhibit uptake of catecholamines (inhibit both uptake 1 & 2)
• Irreversibly inhibit responses to 5HT, histamine & Ach 86

87. • Half life of phenoxybenzamine is less than 24 hours, but
duration of action is maintained for days
– Due to irreversible inactivation of α-receptors
• Therapeutic uses
– Treatment of pheochromocytoma
• Tumors of the adrenal medulla & sympathetic neurons
– Secrete enormous amounts of NE/EP, which leads to hypertension
• Phenoxybenzamine, by antagonizing α-receptors is used to
treat symptoms of pheochromocytoma
– Treatment of benign prostatic hyperplasia (BPH)
• Used to reduce obstructive symptoms of BPH
• It is no more used for treatment of BPH
• Adverse effects
– Reflex tachycardia, postural hypotension, inhibit ejaculation 87

88.  Phentolamine & tolazoline
– Are competitive antagonists at α adrenoceptors
• Antagonism is reversible
• So, have short duration of action
– Nonselective antagonist b/n α1 & α2 adrenoceptors
– Tolazoline is less potent than phentolamine
• Pharmacological action
– ↓BP by blocking α-receptors (α1 & α2B)
– Reflex increase in HR, CO↑
Mechanism for increase in HR & CO
① BP↓ as result of vasodilation → reflex excited heart
② block presynaptic α2A receptors →release of NE/EP ↑ → activate
β1R
88

89. • Therapeutic uses
– Benign prostetic hyperplasia
– Hypertensive emergencies
– Local vasoconstrictor excess
– Pheochromocytoma
 Side effects
• Postural hypotension
• Reflex tachycardia
• GI stimulation
• Abdominal pain
• Nausea
• Exacerbation of peptic ulcer
89

90. Selective α1-antagonists
– Includes: prazosin, terazosin, doxazosin, tamsulosin
– They are highly selective for α1 receptors
• Exhibit greater clinical utility than the non-selective blockers
• Replaced the non-selective blockers clinically
– Leads to relaxation of both arterial and venous smooth muscle due to
blockade of α1 receptors
• Leads to fall in TPR which leads to lowered preload as well as after load
– They generally differ in their pharmacokinetics
– Well absorbed after oral use, highly bound to plasma proteins
– Metabolized in the liver & excreted in the fece & urine
– Except tamsulosin, others are non-selective among α1-receptor subtypes
(α1A, α1B, α1D )
– Tamsulosin is a selective ἀ1A antagonist that is used to treat benign
prostate hyperplasia
– Although all of the long-acting α1-blockers are well tolerated, only
tamsulosin and alfuzosin sustained release are administered without
the requirement for dose titration
– Alfuzosin has the additional advantage over tamsulosin of a lower
incidence of ejaculatory dysfunction
90

91. • Therapeutic uses
– Treatment of essential hypertension
– Congestive heart failure
• Because, they reduce both preload & after load
– Benign prosthetic hyperplasia
• Produces symptomatic urethral obstruction in a significant
number of older men
– Urinary frequency, nocturia
• α1 antagonists have efficacy in treating BPH, owing to
– Relaxation of smooth muscles in the bladder neck,
prostate capsule & prostatic urethra
– Rapidly improve urine flow
91

92. • Side effects
– Major adverse effect is 1st dose phenomenon
• Marked postural hypotension & syncope are seen 30-90
minutes after patient takes the 1st dose of α1 blockers
• Can be minimized by limiting initial dose & gradually
increasing the dose
– Headache, dizziness
– Asthenia (abnormal loss of strength)
– Tamsulosin may cause impaired ejaculation
• Tamsulosin at therapeutic doses doesn’t
produce orthostatic hypotension, unlike the
other α1-blockers
– Due to its selective effect on α1A receptors
92

93. Selective α2-antagonists
 Yohimbine
– It is an alkaloid obtained from plants
– Readily enters to CNS
– It is competitive α2-selective antagonist
• Increases sympathetic outflow
• Increases blood pressure & heart rate
• Produces opposite effects to clonidine
• Therapeutic uses
– The treatment of male erectile dysfunction (ED)
• Not widely used due to availability of effective agents
93

94. 94
 -Blockers
A. Non selective -Blockers
– Are also called 1st generation -blockers
– Propranolol, Timolol
– Nadolol, Pindolol
B. Cardio selectives [1Blockers ]
– Are called 2nd generation -blockers
– Atenolol, Acebutolol, Bisoprolol
– Esmolol, Metoprolol
C. Non-selective adrenergic blockers( &  Blockers)
– Carvedilol, Labetalol, Bucindolol, Nebivolol
– Are also called 3rd generation -blockers
Longest half life: Nadolol, Cartelol (24 hrs)
Shortest half life: Esmolol (10 min)

95. • Some of the β-blockers have some intrinsic
activity & membrane stabilizing activity
– May be considered as partial antagonists
– Examples
• Pindolol
• Acebutolol
• Bucindolol
95

96. 96
 Pharmacological actions of -blockers
A. Heart (1 receptors)
•  myocardial contraction
•  HR
•  AV-conduction & automaticity
B. CNS/Neurological
– Sedation ( with Propranolol, Carvedilol)
C. Respiratory system
– Bronchoconstriction
• Little effect on pulmonary functions of normal individuals
• Can cause life-threatening bronchospasm in patients with
COPD
• 1 selective blockers or those with intrinsic
sympathomimetic activity are less likely than propranolol to
cause severe bronchoconstriction

97. D. EYE:
–  IOP by reducing production of aqueous humor
E. Liver
– Decrease glycogenolysis & lipolysis
– Can aggravate hypoglycemia in diabetic patients treated with
insulin or oral hypoglycemic agents
– 1 selective blockers are less likely to produce hypoglycemic
effects
F. Adipose tissue
– Non selective -blockers reduce lipolysis
– Reduce HDL, increase LDL & increase triglycerides
F. Kidney
– Reduce renin release
97

98. 98
 Therapeutic uses of β-blockers
1. Hypertension
2. Coronary heart disease
 Angina Pectoris
 Myocardial infarction
3. Cardiac arrhythmias
4. Anxiety : to  sympathetic manifestations
5. Hyperthyroidism: to  sympathetic manifestations
6. Migraine headache
– Blockade of cranial beta receptors reduce vasodilation
7. Glaucoma
– Reduce the production of aqueous humor
– Timolol is applied topically to treat glaucoma

99. – Advantages of Timolol over miotics in the treatment of glaucom are :
 no pupil constriction
 no effect on accommodation
 no ocular discomfort
 no retinal detachment
 no shallowing of anterior chamber
 no cataract formation and no iridocyclitis
– The advantages over epinephrine :
 are no pupil dilatation
 no maculopathy in aphakics
 no conjunctival hyperaemia
 no adrenochrome deposits and no ocular irritation
– The advantages over carbonic anhydrase inhibitors are
 effective topically
 no CNS effects
 no GI effects
 no kidney stones
 no parasthesias
 no acidosis
 no weight loss
– Thus Timolol has come out to be an important weapon in "therapeutic
arsenal" of the ophthalmologists in their fight against glaucoma
99

100. 100
 Adverse effects of β-blockers
1. CVS
– Bradycardia
– hypotension
– AV block
2. Bronchoconstriction
3. Hypoglycemic effect
4. Affect lipid profile
5. Muscle pain & fatigue
6. Sleep disturbances, nightmares
More pronounced with 1 selectives
Produced by non-selective blockers

101. 101
 Contraindications to β-blockers
1. Heart failure
2. Slow AV-node conduction
3. Asthma & COPD
4. Diabetes mellitus
5. Hypothyroidism
6. Combination with Ca-channel blockers

102. Non selective  &  antagonists
– Includes: Labetalol, Carvedilol, Bucindolol
– Are called 3rd generation, vasodilatory β-blockers
Labetalol
• Possess both  &  blocking activity
•  blocking activity is more potent than  blocking
activity
• Non selective b/n 1 & 2 receptors
• Have some intrinsic activity at 2 receptors
• Responsible for vasodilatory effect of the drug
• At  receptors, labetalol
– Is more selective to  1 receptors
• Causes vasodilation (another mechanism for vasodilation)
102

103. • So, labetalol causes vasodilation by:
– Blocking vasoconstrictive effects of  1 receptors
– Activating 2 receptors
• Therapeutic use
– Labetalol is used in the treatment of hypertension
• Reduces both CO & TPR
• Side effects
– Postural hypotension
– GI distress
– Tiredness
– Sexual dysfunction
– Skin rashes
103