Chapter two

1
Introduction
 The nervous system is divided into two parts:

üCentral nervous system (CNS)

üPeripheral nervous system (PNS)

 The CNS consists of the brain and spinal cord

 The PNS consists of

üAfferent (sensory) neurons

üEfferent (motor) neurons

2
 The peripheral efferent system is further
divided into
 Somatic nervous system
üEffector cells are skeletal muscle cells
üControls voluntary movement of skeletal
muscles
• Respiration, body movements
 Autonomic nervous system
üThe effector cells are
• Smooth muscle cells, cardiac cells &
exocrine glands
üMainly controls involuntary body functions
• Cardiac functions, visceral organ functions
3
Ø ANS is autonomic

◦ Its actions are involuntary, unconscious &

automatic by their nature

Ø Autonomic nerves are composed of two neurons

ØThe preganglionic neurons (myelinated)

ØThe postganglionic neurons (not myelinated)

4
 ANS is further classified as:

◦ Cell bodies of the preganglionic neurons arise

from thoracic and lumbar areas of spinal cord
◦ Also called as thoracolumbar division of ANS

◦ Cell bodies of the preganglionic neurons arise

from cranial and sacral regions of the spinal cord
◦ Also called as craniosacral division of ANS
5
Enteric nervous system
Ø is sometimes considered a third division of the ANS.

Ø is a collection of nerve fibers that innervate the

gastrointestinal tract, pancreas, and gallbladder,

Ø constitutes the brain of the gut.

Ø Functions independently of the CNS and controls the

motility, exocrine and endocrine secretions and
microcirculation of the gastrointestinal tract.

Ø is modulated by both the sympathetic and

parasympathetic nervous systems.

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Sympathetic ganglia

§ is found near to vertebral column

 preganglionic fibers are generally short
 post ganglionic fibers are generally long
Exceptions: few sympathetic ganglia lie near the organs
innervated e.g. urinary bladder & rectum

Parasympathetic ganglia

§ lie very close to the effector/organs innervated

 preganglionic neurons are long
 post ganglionic neurons are short
7
Sympathetic nervous system functions
1) Regulating the cardiovascular system
§ Increase cardiac output
§ Causes vasoconstriction
2) Regulate body temperature
§ By regulating blood flow to the skin
§ By promoting secretion of sweat, thereby
helping the body to cool
§ By inducing piloerection (erection of hair) can
promote heat conservation

8
3. Implementing the “ fight – or – flight” reaction
which consists
§ Increasing heart rate and blood pressure
§ Shunting blood away from the skin and
viscera into skeletal muscles
§ Dilating the bronchi to improve oxygenation
§ Dilating the pupil to enhance visual acuity
§ Mobilizing stored energy
§ thereby providing glucose for the brain and
fatty acids for muscles

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10
ü maintains essential bodily functions

• such as digestive processes, elimination of wastes

and is required for life

ü usually acts to oppose or balance the actions of the

sympathetic division

◦ Is dominant over the sympathetic in “rest and digest”

situations

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  Slowing the heart rate
 Increase gastric secretion
 Emptying of the bladder
 Emptying of the bowel
 Focusing the eye for near vision
 Constricting the pupil
 Contracting bronchial smooth muscle
ü So that, the PsNS is concerned primarily with what might be called
◦ “ the housekeeping” chores of the body (digestion of food and
excretion of wastes)
ü In addition, the system helps, control vision & conserve energy (by
reducing cardiac work)

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13
Dual innervations
I. Opposite action

II. Complementary actions

Single innervation

14
ü Neurotransmission in the peripheral NS occurs at 3 major
sites:

1. Preganglionic synapses in both PsNS & SNS

2. Postganglionic neuroeffector junctions of PsNS & SNS

3. All somatic motor end plates on skeletal muscles

 Most PsNS postganglionic neurons are cholinergics

◦ Significant number of PsNS postganglionic neurons

utilize NO or peptides for transmission

 All preganglionic efferent autonomic fibers are cholinergic

15
 O n ly a fe w o f S N S p o s tga n g l i o n i c n e u ro n s a re
cholinergic (i.e. those innervate sweat gland)

 All efferent somatic fibers are cholinergic

 Most of the postganglionic SNS fibers are adrenergic

16
Ø Cholinergic neurons

◦ are neurons which synthesis, store & release Ach

Ø Cholinomimetics

◦ are those agents which mimic the activity of Ach

◦ Are also called parasympathomimetics
Ø Chlinoreceptors

◦ are binding site for Ach & cholinomimetics

Ø Cholinoreceptor antagonists

◦ are agents which antagonize the actions of Ach

17
Ø Adrenergic neurons

◦ are neurons which synthesis, store & release NE

Ø Adrenomimetics

◦ are agents which mimic the activities of NE

◦ Are also called sympathomimetics
Ø Adrenoceptors

◦ are binding sites for NE, EP & adrenomimetics

Ø Adrenoceptor antagonists

◦ are agents which antagonize the activities of NE

◦ are also called sympatholytics/sympathoplegics
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19
 Re g a r d l e s s o f t h e t y p e o f n e u r o n u n d e r
consideration
Øthe fundamental steps in chemical transmission are the
same

ØE a c h o f t h e s e s t e p s i s a p o t e n t i a l s i t e f o r
pharmacological intervention in the normal
transmission process

20
Cholinergic neurotransmission

Synthesis of Acetylcholine (Ach)

 Ach is synthesized in cholinergic neurons from Acetyl CoA & Choline

by the enzyme Choline acetyltransferase (ChAT)

◦ Acetyl-coA is synthesized in the mitochondria

◦ Choline is found in the extracellular fluid

 Transported into the neuron by sodium-dependent carrier

protein (Carrier A)

 Can be inhibited by drugs called Hemicholiniums

Acetyl CoA + Choline Choline acetyl transferase (ChAT) Ach

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23
 After release, Ach binds & activates
cholinoceptors
 Eve n t u a l ly, a l l o f A c h m o l e c u l e s w i l l b e
degraded by AchE (Acetyl cholinesterase)

Ach AchE Choline + acetate

 Choline is recycled

24
Cholinesterase
 Rapidly metabolizes Ach into Choline & acetate

 Highly accumulated in the neuron & effector cells

 Two types

Ø Found in the neurons & effectors

Ø Specifically metabolizes Ach

Ø Found in the plasma, liver, glia & other tissues

Ø Also called butyrylcholinesterase

Ø Non specific (also metabolizes other ester compounds)

25
Adrenergic neurotransmission
 Tra n s m i s s i o n i n n o ra d re n e r g i c n e u ro n s i s
somewhat more complex
◦ steps of synthesis and removal mechanisms
 Synthesis of norepinephrine (NE) begins with the
amino acid tyrosine
◦ Enters the neuron by Na+/tyrosine symporter
 In the neuronal cytosol, tyrosine is changed into
dihydroxyphenylalanine (DOPA)
◦ by tyrosine hydroxylase (rate limiting step)
◦ Inhibited by tyrosine analog, metyrosine
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27
Ø For terminating the actions of NE/EP, there are three
mechanisms

I. Neuronal reuptake

II. Diffusion into the circulation

. Metabolized by liver & kidney enzymes

ü C a t e c h o l - O - m e t hy l t ra n s f e ra s e ( CO M T ) &
monoamine oxidase (MAO)

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29
 Includes cholinergic and adrenergic receptors

Two types: muscarinic & nicotinic

cholinoceptors
Muscarinic receptors
• All are GPCRs
• Are activated by muscarine (plant alkaloid)
• Found in many visceral organs such as smooth muscle
cells, cardiac cells, exocrine glands, CNS, Autonomic
ganglia
• Further classified into M1, M2, M3, M4 & M5
• M1, M3 & M5
 Activate the IP3 & DAG pathway
 Activate adenylcyclase pathway
30
 So, the M1, 3 & 5 receptors are involved in

◦ Increasing glandular secretion

◦ Smooth muscle contraction

 M2 & M4

◦ Are coupled to Gi/Go

◦ So inhibit the activity of adenylyl cyclase

31
Nicotinic receptors

• Are ligand – gated ion channels

• Activated by nicotine (tobacco alkaloid)

◦ Formed by five subunits arranged around a central

pore

 The pore becomes permeable to Na+ and Ca+2 when

the receptor is activated by Ach

 Resulting in depolarization and excitation of the cell

32
 Based on their location nicotinic Ach receptors are
grouped into two types

◦ Nn (at ganglia)

◦ Nm (at neuromuscular junction)

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34
Adrenoceptors
◦ Interact with NE, EP & other related drugs
◦ Two types based on agonist selectivity
1. α-adrenoceptors (α-1, α-2)
2. β-adrenoceptors (β-1, β-2)
 α-affinity:
 Norepinephrine ≥ epinephrine >> isoproteranol
 β-affinity:
 Isoproteranol >epinephrine >> norepinephrine
§ Isoproteranol is synthetic adrenomimetic agent
35
§ α-1 are found on post junctional or post
synaptic neurons

§ α-2 are mostly found presynaptically involved in

feedback inhibition of

 β-1 are mainly found in heart & fat cells

 β-2 are mainly found in

◦ Bronchial smooth muscles, brain, liver
◦ Skeletal muscle blood vessels

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37
• Similar effects to acetylcholine (Ach)
• Elicit all or some of the effects of Ach
• Classified as
1. Direct acting
ü Cholinergic receptor agonists
2. Indirect acting
ü acetyl cholinesterase enzyme inhibitors
(AchEIs) also called anticholinesterase

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39
ü Activate either muscarnic or nicotinic receptors or
both
ü Are Polar compounds and poorly cross GIT and BBB

ü Differ in duration of action

• Ultra short action ……Ach

• Intermediate action……methacholine
• Long action……Bethanecole and carbacol

40
§ Includes methacholine, Carbachol & Bethanechol

§ Are derivatives of acetylcholine

 These drugs have the following advantages over

acetylcholine:

ülonger duration of action

üeffective orally as well as parenterally, and

ürelatively more selective in their actions

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Heart:

 negative chronotropic effect

 negative dromotrpic effect

 negative inotropic effect

42
Gastrointestinal System:
 Choline esters causes:

◦ Increase in amplitude of contractions

◦ Increase peristaltic activity of the stomach and

intestine

◦ Enhanced secretory activity of GIT

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Genitourinary tract:

 Cholinesters can cause:

◦ Increase urethral peristalsis

◦ Contraction of detruser muscle of the urinary bladder

◦ increase voluntary voiding pressure

◦ Decrease capacity of the bladder

◦ Relaxation of trigone and sphincters

 Carbachol and Bethanechol stimulate GIT and urinary

tract selectively, unlike Ach and methacholine.

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Respiratory system

 Muscarinic stimulants:

◦ Contract smooth muscles of the bronchial tree

◦ Increase secretion of the glands of the

trachiobronchial mucosa.

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Eye:

 The iris has two types of muscles

◦ Circular papillary constrictor smooth muscle( has
M3 receptor)
 At the papillary margin, the sphincter smooth muscle is
organized in a circular band with parasympathetic innervations,
which when stimulated causes miosis (constriction).

◦ Radial papillary dilator smooth muscle( α-1

receptor)
 Anterior to the pigmented epithelium, the dilator smooth muscle
is oriented radially and is innervated by the sympathetic
nervous system which causes mydriasis (dilation).
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 The eye has also ciliary body which has two main parts :

◦ Ciliary process secretion of aqueous humor by the

epithelial bilayer( has B- 2 receptor)

◦ Ciliary muscles: has only M3 receptor

 The pharmacological effects of cholinomometic drugs

on the eye include

◦ Miosis due to stimulation of papillary constrictor

smooth muscle ………M3 receptor

◦ Accommodation to near objects due to constriction

of ciliary muscles ……………M3 receptors
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48
 Includes
……use externally
◦ muscarine
◦ arecoline not clinically used
◦ nicotine

49
§ Alkaloid obtained from pilocarpus microphyllus and
pilocarpus japorandi.
§ A tertiary amine compound
§ Can cross the cornea of the eye & BBB more easily &
faster
§ Pure muscarinic agonist
§ A natural alkaloid
§ Not affected by cholinesterase

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Pharmacologic effects

Ø Increase in GIT smooth muscle tone & peristalsis

Ø Dilates blood vessels
Ø Decreases heart activity
Ø Miosis, accommodation for near vision
Ø Decrease intraocular pressure

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§ Pilocarpine is mainly used for

§ Used in the treatment of

◦ To reverse mydriatic (dilating) effects of atropine

◦ Xerostomia

◦ Fever

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 accumulation of fluid in the eye & increased intraocular
pressure
 Could be
Open angle glaucoma
üTreated with pilocarpine, Carbachol
Angle closure glaucoma
üTreated with pilocarpine or by surgical removal
of part of the iris (iridectomy).

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Ø Contraindication to cholinomimetics

◦ Bronchial asthma

◦ GIT hyper-motility

◦ Peptic ulcer disease

◦ Coronary artery disease

◦ Hypotension

◦ Bradycardia

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Ø Adverse effects
 Choline esters can cause:
◦ Nausea
◦ Abdominal cramps
◦ Salivation
◦ Diarrhea
◦ Hypotension
◦ Reflex tachycardia
◦ Bronchoconstriction
◦ Sweating
◦ Flushing

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 Reversible inhibitors of AchE

 Irreversible inhibitors of AchE

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 Noncovalent Carbamate
Inhibitors Inhibitors
♦ Edrophonium ♦ Physostigmine

♦ Tacrine ♦ Neostigmine

♦ Donepezil ♦ Pyridostigmine

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 Diisofluorophosphate (DFP)
 Insecticides
Malathione
Parathion
 Nerve gases
Sarin
Tabun
Soman
 Echothiophate iodide

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Tacrine/Donepezil
♦synthetic tertiary ammonium compound
♦higher affinity to AchE
♦readily cross the blood brain barrier to inhibit
AChE in the CNS
♦longer duration of action
♦useful in patients with Alzheimer’s disease

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Carbamate Esters
♦covalent binding
♦bind reversibly with the esteratic site
♦increase relative conc. of Ach
♦does not alter enzyme function

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Physostigmine
♦a n a l k a l o i d o b t a i n e d f ro m P hy s o s t i g m a
venenosum
♦tertiary amine
♦activates both muscarinic and nicotinic receptor
♦can easily enter the CNS
♦2-4 hours duration of action

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Neostigmine
♦synthetic quaternary ammonium compound

♦more polar – do not pass through the BBB

♦directly stimulates Nicotinic Receptor at the motor end

plate

♦2-4 hrs duration of action

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Neo…..
♦dual action

•reversible Achase inhibitor

•direct activation of nicotinic receptor at the motor end

plate

♦beneficial in Myasthenia Gravis

♦Antidote for toxicity to Non-depolarizing Neuromuscular

blocker

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Pyridostigmine
♦synthetic quaternary ammonium compound

♦used for long term treatment of

Myasthenia gravis

♦longer duration of action (4-6 hrs)

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Irreversible Acetylcholinesterase
Inhibitors Organophosphates

♦covalent binding

♦cause inhibition of physiologic function of enzyme

♦Phosphorylate enzyme complex undergo “aging”

65
 LOSS OF AN ALKYL GROUP FROM
PHOSPHORYLATED AChE “AGES” THE ENZYME

AChE,
phosphorylated “Aged”
and inhibited by AChE 66
Pharmacological Properties
Organophosphates
♦highly lipid soluble except Echothiophate

♦effectively absorbed from all routes

♦endogenous Ach stimulates all cholinergic receptors

(peripheral and CNS)

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Parathion/Malathion
♦low volatility and stability in aqueous solutions widely

used as insecticides

♦employed for home, garden and agricultural use

♦also use in suicide attempts or deliberate poisoning

♦also used topically in the treatment of Pediculosis (lice

infestations )

♦converted to active metabolites by CYPs

68
Nerve Gases

♦most potent synthetic toxins known

♦used in warfare and terrorism attacks

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70
Victims of the Sarin attack
taken from the Tokyo subways on 71
 Glaucoma-
◦ Physostigmine
 Myasthenia gravis-
◦ Neostigmine, Pyridostigmine
◦ Edrophonium is used for diagnosis.
 Post operative paralytic ileus-atony or paralysis
of the stomach or bowel following surgical
manipulation.
◦ neostigmine

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 The drugs which reactivate acetyl cholinesterase are
oximes like

◦ pyridone-2-aldoxime(2- PAM)-SC, IM, PO

◦ diacetyle monoxime, obidoxime (more potent than 2-

PAM)-cross BBB

 especially useful in reversing neuromuscular effects of

organophosphorous compounds which cannot be

inhibited by atropine (muscarnic antagonist)

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74
1. Naturally occurring alkaloids: a. Ganglionic
◦ atropine & scopolamine antagonists:
2. Semisynthetic derivatives of ◦ Trimethaphane
the alkaloids: differ in PKs ◦ mecamylamine
◦ Homatropine, ipratropium,
b. Neuromuscular
◦ tropicamide, methylatropine blockers:
& tiotropine
◦ gallamine
3. Synthetic antagonists: receptor
◦ tubocurarine
selectivity
◦ pancuronium
◦ Pirenzepine, tolterodine &
oxybutinin, Clidinium ◦ vecuronium
◦ succinyl choline

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 Muscarinic receptor antagonists
 Prevent the effects of Ach on muscarinic receptors of
◦ Smooth muscles
◦ Cardiac muscle & gland cells
◦ In the CNS
 No antagonist, including pirenzepine, is completely
selective

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 Muscarinic antagonists have no intrinsic activity
 The magnitude of the response produced by
muscarinic antagonists depends on
◦ The existing level of cholinergic activity or
◦ on the presence of muscarinic agonists
◦ The organ’s pattern of innervations

E.g. some organs receive dual innervation from

adrenergic and cholinergic pathways
 At these locations, block of muscarinic receptors can
increase the activity of the adrenergic input

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Heart

v Higher doses produce tachycardia

üdue to direct inhibitory effect on the parasympathetic

input to SA node

Gastrointestinal tract

Ø↓amplitude & frequency of peristaltic contraction,

↓gastric acid secretion, ↓salivation, dry mouth

ØHigher doses are needed to inhibit acid production

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Eye
◦ dilation of the pupil (mydriasis) and paralysis of
accommodation (cycloplegia) responses

üCauses photophobia & inability to focus on nearby

objects

79
§ Urinary bladder
• Inhibit cholinergic activity on the detrusor muscle &
cause urinary retention

§ Lung
◦ Muscarinic antagonists inhibit secretions and relax
smooth muscle in the respiratory system

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Clinical uses of antimuscarinic drugs
Cardiovascular Uses
can be useful in
1. Carotid sinus syncope
 Results from excessive activity of afferent neurons
whose stretch receptors are in the carotid sinus
 By reflex mechanisms, this excessive afferent input to
the medulla oblongata causes pronounced bradycardia
which is reversible by atropine
2. S-A node dysfunction
 If sinus bradycardia is due to extracardiac causes,
atropine can generally elicit a tachycardic response
 Whereas it cannot elicit tachycardia if the bradycardia
results from intrinsic causes
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Uses in Anesthesiology
◦ To block excessive salivary and respiratory
secretions induced by certain inhalation
anesthetics (e.g. diethyl ether)
E.g. atropine and scopolamine

Use With Cholinesterase Inhibitors

◦ Atropine or another muscarinic antagonist
should be given to prevent the stimulation of
mus c ar i n i c rec eptor s th at ac c om pan i es
excessive inhibition of AchE in two cases
 During reversal of competitive NM blockade by using
AchEIs
 When managing myasthenia gravis with AchEIs
82
Uses in Ophthalmology
◦ widely used to produce mydriasis &
cycloplegia
üpermit an accurate determination of the
refractive state of the eye
ü have aesthetic value

83
◦ are also useful in treating specific ocular diseases

◦ the antimuscarnic drugs used in ophthalmology

include

üAtropine
üscopolamine long duration of action

ücyclopentolate
ü tropicamide short duration of action

84
Uses in Digestive system disorders
 For the therapy of peptic ulcers
◦ Pirenzipine 100-150 mg/day

 as adjunctive therapy in the treatment of

irritable bowel syndrome (IBS)
◦ Decrease pain associated with spasm of intestinal
smooth muscles, by blocking contractile responses
to Ach

85
Genitourinary Tract
 Overactive urinary bladder disease can be successfully
treated with antimuscarinics
ülower intravesicular pressure, increase capacity &
reduce the frequency of contractions
üAre also useful in treating urinary incontinence,
enuresis
Uses in cholinomimetic poisoning
◦ Atropine is used as an antidote in poisoning by an
overdose of a cholinesterase inhibitor

86
Uses in respiratory disorders
 For a long time, muscarinic receptor blocking drugs occupied a
major place in the therapy of asthma
 But they have been largely replaced by the adrenergic drugs
◦ Have low therapeutic index
◦ Cause impaired expectoration
 Consequence of their inhibition of mucous secretion, ciliary
activity & mucous transport
 Ipratropium bromide
◦ Is a synthetic quaternary muscarinic blocking drug
◦ Gained widespread use in recent years for the
treatment of respiratory disorders
◦ It is applied topically to the airways through the use
of a metered-dose inhaler
◦ Has minimal systemic side effects

87
Uses in Parkinsonism
◦ Antimuscarinic agents have beneficial effects in the
treatment of parkinsonism Especially, drug induced
parkinsonism
◦ Benztropine mesylate, biperiden, procyclidine and
trihexyphenidyl hydrochloride
Uses in Motion Sickness
◦ Scopolamine is useful for prevention of motion sickness
when the motion is very stressful and of short duration
◦ When the motion is less stressful & lasts for longer
period of time, antihistamines are used than
antimuscarinics
 Promethazine, meclizine, dimenhydrinate
◦ A transdermal preparation with a 72-hour duration of
action has been marketed for this purpose
◦ Blockade of cholinergic sites in the vestibular nuclei
& re t i c u l a r f o r m a t i o n m ay a cco u n t f o r t h e
effectiveness of this agent
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Adverse effects
◦ Constipation
◦ Abdominal distension
◦ Retention of urine
◦ Photophobia as result of mydriasis
◦ Glaucoma
◦ Near vision blurred
◦ Flushed skin
◦ Dry mouth
◦ CNS side effects

89
ü Contraindications
 Muscarinic blockers are
contraindicated in
◦ Glaucoma
◦ Cardiac diseases
◦ Hyperthyroidism
◦ Reflux esophagitis
◦ Prosthete hypertrophy

90
1. Ganglionic blocking drugs

2. Neuromuscular junction blockers (NMBs)

91
 Depolarizing ganglion blockers
◦ These blocking agents are actually ganglionic
stimulants

◦ Thus, for nicotine, small doses give an action similar

to that of the neutral neuroeffector ACh, an action
known as the “Nicotinic effect of ACh”

92
 However larger amounts of the nicotine bring
about a ganglion block characterized initially
by depolarization, followed by a typical
competitive antagonism.
 This depolarization of the membrane of the
muscle end plate is quite similar to that
produced by Ach itself at ganglia and NMJ.
 Chemicals that cause this type of ganglionic
block are not of therapeutic significance

93
◦ Compounds in this class possess the necessary
affinity to attach to the nicotinic receptor sites that
are specific for Ach but lack the intrinsic activity
necessary for impulse transmission.

N+
N+
N+

tetraethylammonium hexamethonium

94
 Non-depolarizing non-competitive ganglionic
Blocking agents
◦ These blocking agents produce their effect, not at the
specific Ach receptor site, but at some point further
along the chain of events that is necessary for
transmission of the nerve impulse.

95
 When the block has been imposed, increase of the
concentration of Ach has no effect: thus apparently,
Ach does not act competitively with the blocking
agent at the same receptor.
O
N CH2
CH2 N

S+

Trimethaphane camsylate

96
Neuromuscular junction blockers (NMBs)

 Based on their MOA, NMBs are grouped into two

E.g. Succinylcholine

 d-tubocurarine
 Atracurium
 Mivacurium
 Pancuronium
 Vecuronium
 Rocuronium
 Rapacuronium

97
98
Depolarizing NMBs (Leptocurares)
Succinylcholine
◦ Structurally, equivalent to two Ach molecules attached
to each other back to back

99
MOA
 Produces NMB by overstimulation of nicotinic
acetylcholine receptors in the NMJ
 Neuromuscular blockade occurs in two sequential events
Phase I (depolarization block)
üInitial depolarization of the motor end plate producing
muscle action potentials & fasciculation

üAs result of maintained depolarization, Na+ channels

become inactivated

§ Muscle action potentials can’t be generated

100
Phase II (desensitization block)
 In continued presence of Succinylcholine, membrane
potential becomes repolarised

üNa+ channels inactivation is reversed

üMuscle membrane excitability is restored

 But NMB persists b/s of desensitization of nicotinic

acetylcholine receptors

101
Pharmacokinetics of Succinylcholine
 Is positively charged & highly polar drug, given parentrally
 Metabolized by plasma cholinesterase to succinyl
monocholine
 Pharmacologically inactive
 The response to Succinylcholine may be prolonged in
üPatients with renal or liver diseases (the enzyme
synthesis decreases in such patients)
üIn individuals with a genetic defect
§ Atypical plasma cholinesterase is produced
§ This enzyme has reduced affinity for substrates like
succinylcholine
 About 10% of the active drug is excreted unchanged in the
urine

102
Pharmacological actions
Succinylcholine
◦ Primarily acts at nicotinic Ach receptors of the skeletal
NMJ
◦ Has little effect on nicotinic Ach receptors of the
autonomic ganglia
◦ Has no direct effect on the uterus or other smooth
muscles
◦ Doesn’t enter to the CNS & doesn’t cross the placental
barrier
◦ Increases histamine release from mast cells
 The effect of Succinylcholine is not reversible by AchEIs,
and may prolong the block

103
Clinical uses
 Succinylcholine is used to produce paralysis of the
skeletal muscles for surgical procedures
 It has fast onset & short duration of action
◦ Makes it suitable for short term surgical procedures,
like
 Endotracheal intubation
 Setting of fractures
 Prevention of injury during electroconvulsive
therapy
Adverse effects
◦ Results in fasciculation & myoglobinuria
◦ Postoperative pain, transient elevation of intraocular
pressure
◦ Hyperkalemia
 Cardiac arrhythmias 104
 Curare (1516) and tubocurarine

 Curare was first identified when Spanish soldiers in South

America found themselves the unwilling victims of
poisoned arrows.

 It was discovered that the Indians were putting a poison

on to the tips of their arrows.

 This poison was a crude, dried extract from a plant called

Chondrodendron tomentosum and caused paralysis as well
as stopping the heart.

105
 curare is a mixture of compounds.

 The active principle, however, is an antagonist of

acetylcholine which blocks nerve transmissions
from nerve to muscle.

 Can be used medically if they are taken at the

right dose levels and under proper control.

106
 T h e m a i n a p p l i c a t i o n i s i n t h e re l a xa t i o n o f
abdominal muscles in preparation for surgery. (This
allows the surgeon to use lower levels of general
anesthetic)

 Curare, as mentioned above, is actually a mixture of

compounds, and it was not until 1935 that the active
principle (Tubocurarine) was isolated.

107
 Classification according to duration of action
Short Intermediate Long
Mivacurium Vecuronium Pancuronium
Atracurium
Rocuronium
 Classification based on structure

Aminosteroids Benzylisoquinolines
• Pancuronium • Atracurium
• Vecuronium • Mivacurium
• Rocuronium • d-Tubocurarine
• Rapacuronium • Doxacurium
• Piperacuronium • Metocurine
108
MOA
 These agents work by acting as reversible competitive
inhibitors to Ach at nicotinic Ach receptors in the NMJ

 Their effect can be reversed by AchEIs, since the

blockade is competitive

109
d-tubocurarine

◦ Is has a quaternary ammonium group, poorly crosses

cells
◦ Doesn’t cross BBB
◦ Has moderate onset of action (3-4 minutes), followed
by progressive flaccid paralysis
◦ Different muscles have differential sensitivity
Head & neck muscles---->limb muscles---->muscles of
respiration
• Recovery from blockade occurs in the reverse order

110
 Sensitive individuals
◦ Newborns
◦ Patients with myasthenia gravis
 but resistant to depolarizing agents
◦ These altered responsiveness is probably due to fewer
functional nicotinic Ach receptors at the muscle end
plate

111
 Drug interactions
◦ Certain inhalational anesthetics like isoflurane,
enflurane, halothane & nitrous oxide potentiate the
action of non depolarizing blockers
 Modifying end plate responsiveness
 Alteration of local blood flow
◦ So, doses of these muscle relaxants should be reduced
when used with these anesthetics
◦ Some antibiotics such as aminoglycosides, macrolides,
polymyxins & lincomycin enhances NMB
 Decreasing Ach release
 Blocking postjunctional response
◦ Procainamide & phenytoin also increases the effects of
non depolarizing NMBs
 Dose of the NMBs should be adjusted accordingly

112
113
 Adrenomimetics
 Drugs which mimic the effects of adrenergic SN
stimulation

 Also called sympathomimetics

 Have a wide range of effects

 Can be classified into different groups, based on

◦ Chemical structure

◦ Mechanism of action

◦ Receptor selectivity

114
Ø Based on chemical structure
◦ Adrenomimetics can be divided into two:
 Catecholamines
 Have catechol ring in their structure
E .g. NE, EP, DA, Isoproternol, Dobutamine,
Colterol, ethyl NE, Metaproternol
 Non Catecholamines
 Don’t have catechol ring
E.g. ephedrine, phenylephrine, albuterol,
metaraminole, tyramine, amphetamine,
terbutalin, methamphetamine, ritodrine,
salmiterol, methoxamine

115
116
117
Ø Based on mechanism of action
◦ Adrenomimetics can be classified into three groups

1. Direct acting adrenomimetics

◦ Directly interact & stimulate adrenoceptors

◦ Exhibit receptor selectivity

Examples: NE, EP, DA, IP, Dobutamine, phenylephrine,

albuterol, salmiterol, metaraminole, terbutalin,
clonidine, oxymethazoline

118
2. Indirect acting adrenomimetics
◦ Don’t interact with the adrenoceptors
◦ Increase availability of NE/EP to stimulate the
adrenoceptors
◦ Their action emanates from one of the following
 Displace stored neurotransmitters from the vesicles
E.g. amphetamine, tyramine, methamphetamine
 Inhibit reuptake of neurotransmitters into the neuron
E.g. cocaine, TCAs
 Inhibit the metabolizing enzymes (MAO & COMT)
E.g. pargyline, entacapone
119
3. Mixed acting adrenomimetics
◦ Work by both direct & indirect mechanisms

◦ Increase release of NE & also activate adrenoceptors

E.g. ephedrine

120
Ø Based on selectivity to adrenoceptors
◦ Grouped into many classes
a. Non selective b/n α & β adrenoceptors
 NE, EP
b. α1 selective adrenomimetics
 Phenylephrine, methoxamine, metaraminole,
midodrine, mephentermine
c. α2 selective adrenomimetics
 clonidine, methyldopa, guanfacine, guanbenz
d. non selective α1 & α2 adrenomimetics
 oxymethazoline, xylomethazoline, naphazoline
e. β1 selective adrenomimetics
 Dobutamine
121
f . β2 selective adrenoceptor agonists

◦ Albuterol, terbutalin, salmeterol, metaproternol,

bitolterol, ritodrine, isoetharine

g. β1β2 nonselective adrenoceptor agonists

◦ Isoproternol, EP

122
◦ vasoconstriction(BLOOD VESSEL)
◦ GUT→ contraction of the sphincter tone of the bladder
→contraction of uterus in non pregnant women
◦ ↓salivary secretion(SALIVARY GLANDS)
◦ increase force of contraction of heart (HEART)
◦ contraction of pupillary dilator muscle (EYE)
◦ Hepatic glycogenolysis and gluconeogenesis (liver)
◦ Sweat glands→ sweat secretion

123
II.

On pre-synaptic:
 Inhibition of transmitter release (auto receptor)

Post-synaptic
 platelet aggregation (platelates)

 decrease sympathetic outflow in CNS

 Inhibition of insulin release (B-cell of pancreas)

 Decrease aqueous humor secretion

124
III. B1-
◦ Increased cardiac rate and force
◦ Increased rennin secretion in kidney juxtaglomerular
cells
III. Β2-
◦ Bronchodilation and vasodilatation
◦ Relaxation of visceral smooth muscle of GIT
◦ GUT :
 Bladder relaxes
 Uterus (in pregnant women) relaxes
◦ hepatic glycogenolysis
◦ mast cell decrease histamine secretion
◦ ↑ed secretion of aqueous humour (ciliary
epithelium)
IV. β3- Lipolysis (fat cell)
125
Pharmacologic responses of NE, EP & Isoproternol

Ø Blood vessels of skin & Mucus membranes

◦ Predominantly contain α-adrenoceptors
◦ So, both NE & EP can produce potent constriction
 b/s both NE & EP are non selective adrenomimetics
◦ IP has very low affinity for α-adrenoceptors & so produce no effect
on these vessels

Ø Blood vessels of visceral organs

◦ Predominantly contains α-adrenoceptors & some β-adrenoceptors
◦ NE & EP produce vasoconstriction
◦ Isoproternol produces minor vasodilation
126
Ø Blood vessels of skeletal organs

◦ Contain both α & β adrenoceptors

◦ So, NE produces vasoconstriction through its effect on

α-adrenoceptors

◦ IP dilates the vessels by its effect on β adrenoceptors

◦ EP has complex effect depending on its dose

127
2.
◦ 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

128
3.
 Postjunctional α1 & α2 adrenoceptors mediate
constriction of vascular smooth muscles

 Prejunctional & endothelial α2 adrenoceptors

mediate vasodilation

129
4.

§ Bronchial smooth muscles

◦ Predominantly β2 receptors are found
◦ Bronchodilation by EP & IP due to β2 action
◦ 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
130
§ Eye
◦ Radial muscle of the iris contain a1 adrenoceptors
 NE/EP cause contraction of this muscle & lead to
mydriasis
◦ The epithelium of ciliary muscle contains β2
adrenoceptors
 So, EP & IP ↑ed secretion of aqueous humour
◦ α-2--------?????
§ Urinary system
◦ Detrusor muscle contains β2 adrenoceptors

 So, EP & IP relax the detrusor muscle

◦ Trigon & sphincter muscles contain α1 adrenoceptors

 Contracted by NE & EP, w/h inhibits the voiding of urine

131
§ Uterine muscle
◦ Contains both α1 & β2 adrenoceptors

 NE causes uterine contraction

 EP/IP cause uterine relaxation

◦ Though catecholamines minimally cross the

BBB, they cause CNS stimulation (mechanism
not well known)

 Apprehension, restlessness & increased

respiration 132
Ø Increases skeletal muscle glycogenolysis
 IP>EP>NE
 Mediated by β-adrenoceptors
 Increases blood lactic acid level than blood
glucose level
 b/s skeletal muscle lacks glucose-6-
phosphatase enzyme which converts G-6-P to
glucose
Ø Increased lipolysis
◦ Increases blood free fatty acid levels
◦ Mediated by β3 adrenoceptors
 IP>EP>NE

133
Ø K+ homeostasis
◦ Catecholamines play an important role in the short
term regulation of plasma K+ levels

 Stimulation of hepatic α- 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

134
Clinical uses of catecholamines
 Is based on their actions on bronchial smooth
muscles, blood vessels & the heart
ü Allergic reactions

◦ EP is mainly used in allergic reactions which are

due to histamine release
◦ So, EP is used in the treatment of
 Anaphylactic shock
 Urticaria
 Angioneuretic edema
 Serum sickness
135
ü Open-angle glaucoma

◦ EP has been used to lower IOP in open-angle

glaucoma
 Works by increasing outflow of aqueous humor

◦ EP is C/I in closed-angle glaucoma

 b/s it reduces the filtration angle further & hinders outflow
of fluid in this case

ü Used with local anesthetics

◦ NE/EP is coadministered with LAs, to

 Prolong duration of action of the LAs
 Prevent systemic absorption & toxicity of the LAs
136
ü Control of bleeding

◦ EP is used as topical hemostatic agent for the

control of local hemorrhage
ü Management of hypotension

◦ NE is infused IV to combat systemic hypotension

during spinal anesthesia
◦ NE is also useful in controlling hypotension in
which TPR is low
 But NE is not used to combat hypotension due to most
types of shock
137
 Side effects of Catecholamines
◦ Tachycardia
◦ Reflex bradycardia
 By NE, but not with EP or IP
◦ Headache & tremor
◦ Anxiety, fear & nervousness
◦ Tissue sloughing & necrosis
◦ Arrhythmia
◦ Hypertension
◦ Pulmonary edema

138
 Other adrenomimetic agents
◦ A number of adrenomimetics aren’t catecholamines
 Resistant to enzymatic degradation(COMT)
 have longer action
 Are orally active
v α1-selective adrenomimetic agents
◦ Phenylephrine, metaraminole & methoxamine

◦ Are all directly acting adrenomimetics

 Exert their effect primarily by α1-adrenoceptor activity

 Has no/little direct effect on the heart

◦ They have vasoconstrictor effect

 Increase both the systolic & diastolic blood pressure

◦ They don’t precipitate cardiac arrhythmias &

don’t stimulate CNS
139
 Their vasoconstrictor effect is
accompanied by
◦ Reflex increment in the vagal input to the
heart

 Reflex bradycardia

 No change in the contractile forces

◦ Have considerably longer duration of action

than NE

 Phenylephrine resistant to COMT metabolism

 Metaraminole & methoxamine are resistant

140
 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

141
vα2 selective adrenomimetics
 Includes: methyldopa, clonidine, guanfacine
§ Methyldopa
 Is a centrally acting adrenomimetic agent
 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 preferred drug for treatment of HTN
during pregnancy
 b/s it is safe for both the mother & infant 142
 Adverse effects
◦ Sedation

◦ Occasional depression

◦ Dryness of mouth

◦ Reduction in libido

◦ Hyperprolactinemia
 Gynacomasteia, galactorrhea

◦ Serious but rare hepatotoxicity

 C/I in patients with hepatic disease

◦ Can also cause hemolytic anemia

143
§ Clonidine, guanbenze & guanfacine
◦ 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 CO &
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 144
 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

145
vβ1-selective adrenomimetics
◦ Dobutamine
 Acts directly on β1-adrenoceptors in the
heart
 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
 Has a fast onset & short half life (2mins)
 Therapeutic uses
 Indicated for short term treatment of
cardiac decompensation that may occur
 After surgery
 In patients with CHF
146
 Dobutamine increases the SV & CO in such
patients, usually without marked increase
in the heart rate
 It is also useful in the treatment of
cardiogenic shock
Ø Adverse effects
◦ May increase the size of myocardial infarct
 By further increasing the O2 demand
◦ Increased risk of atrial fibrillation

147
v β2-selective adrenomimetic agents
◦ Are agents used in the management of asthma
◦ 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
◦ Recent studies suggest that β2
adrenomimetics may
 Suppress release of leukotrenes & histamine in
lung tissue
 Enhance mucociliary function
 Decrease microvascular permeability 148
Ø Terbutaline
◦ Is β2 selective
◦ Belongs to resorcinol bronchodilators class
 Resistant to COMT
◦ Effective when given by oral, Sc or inhalational
routes
 Onset of action is rapid from inhalational & Sc
routes
◦ Uses: terbutaline is used for
 Long term treatment of obstructive airway
disease
 Treatment of acute bronchospasm
 Emergency treatment of status asthmaticus
Ø Albuterol
◦ β2 selective, given by inhalational or oral 149
Ø Salmeterol
◦ Is a β2 selective agent with the longest duration
of action (>12hours)
◦ At least 50 times more β2 selective than
albuterol
◦ Highly lipophilic & has sustained action
◦ Metabolized by CYP3A4 to α-OH-salmeterol
 Excreted by faces

◦ Has slow onset of action

 Not suitable monotherapy for acute attacks of asthma

◦ Due to its sustained duration of action,

salmeterol
 Is drug of choice for treatment of nocturnal asthma
150
Ø Formoterol
◦ 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
Ø 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 IV in selected patients to
arrest premature labor 151
 Adverse effects of β2 selective
adrenomimetics
◦ Tremor
◦ Feeling of restlessness, apprehension &
anxiety
◦ Tachycardia, which may result from
 β1 stimulation
 β2 receptor stimulation in the heart
 Reflex response to peripheral vasodilation
◦ Cardiac arrhythmias or myocardial ischemia
 Less likely to in patients without pre-existing
cardiac disease
 High risk of occurrence in patients with
underlying coronary artery disease or pre-
existing arrhythmia
◦ Pulmonary edema 152
 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

153
 • Includes: amphetamine, methamphetamine,
cocaine, methylphenidate, TCAs
Ø 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
 L-isomer of amphetamine is more potent than
the d-isomer in producing CVS effects 154
 CNS effects
◦ It is one of the most potent sympathomimetic
amines in stimulating the CNS
◦ The d-isomer is more potent than the l-isomer
in producing CNS stimulant effects
◦ Amphetamine:
 Stimulates medullary respiratory centres
 Lessens degree of central depression caused
by various drugs
 Alters psyche of individuals

155
 Therapeutic uses
◦ Amphetamine is used chiefly for its CNS
effects
◦ Dextroamphetamine, with more CNS
actions than peripheral actions

 Was used for reducing obesity

 Is approved by FDA for treatment of

 Narcolepsy

 Attention deficient hyperactivity disorder

156
 Toxic & adverse effects of
amphetamines
◦ Are extensions of pharmacological actions of
amphetamine
◦ 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
◦ CVS effects
 Pallor or flushing, palpitations, cardiac 157
 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

158
v Mixed acting adrenomimetic drugs
Ø Ephedrine
◦ 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
◦ Has longer duration of action than NE
 Very resistant to both COMT & MAO
◦ Unlike NE/EP, ephedrine is effective when taken orally
 Less potent compared to NE/EP
◦ Tachyphylaxis develops after repeated use
159
 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
ØRelieving bronchoconstriction & mucosal
congestion associated with bronchial asthma
Øprevention of asthmatic attacks
ØNasal decongestion
ØProducing mydriasis
◦ Terbutaline & albuterol are replacing
ephedrine for treatment of asthma
 Less side effects, effective bronchodilation 160
 Adverse effects
◦ Tachycardia
◦ Insomnia
◦ Nervousness, nausea, vomiting
◦ Emotional disturbances

161
162
§ Are drugs that inhibit responses mediated by
adrenoceptor activation
§ 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
 Don’t prevent release of NE/EP from adrenergic
neurons
 Are not catecholamine depleting agents 163
Ø Classification of 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

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
164
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
165
v Non-selective α-blockers
◦ Block both α1 & α2 adrenoceptors
◦ E.g. Phenoxybenzamine, Phentolamine, Tolazoline

Ø 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
166
 Therapeutic uses
◦ Treatment of pheochromocytoma
ØTumors of the adrenal medulla & sympathetic
neurons
üS e c r e t e e n o r m o u s a m o u n t s o f N E / E P , w / h l e a d s t o
hypertension

ØPhenoxybenzamine, 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 167
Ø 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↑

168
 Therapeutic uses
Ø Benign prostetic hyperplasia
Ø Hypertensive emergencies
Ø Local vasoconstrictor excess
Ø Pheochromocytoma
Ø Side effects
• Postural hypotension
• Reflex tachycardia
• GI stimulation
 Abdominal pain
 Nausea
 Exacerbation of peptic ulcer
169
v Selective α1-antagonists
◦ Includes: prazosin, terazosin, doxazosin,
tamsulosin

◦ 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

170
 Therapeutic uses
◦ Treatment of essential hypertension
◦ Congestive heart failure
 b/s reduce both preload & afterload

◦ 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
171
 Side effects

◦ Major adverse effect is 1st dose phenomenon

 Can be minimized by limiting initial dose &

gradually increasing the dose

◦ Headache, dizziness

◦ Asthenia (abnormal loss of strength)

172
Ø Selective α2-antagonists
üYohimbine
 Is an alkaloid obtained from plants
 Readily enters to CNS
 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
173
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

174
 Some of the β-blockers have some intrinsic activity &
membrane stabilizing activity

◦ May be considered as partial antagonists

Examples

 Pindolol

 Acebutolol

 Bucindolol

175
Ø 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
176
D. EYE:
◦  IOP by reducing production of aqueous humor

E. Liver
◦ Decrease glycogenolysis & lipolysis

F. Adipose tissue
◦ Non selective -blockers reduce lipolysis
◦ Reduce HDL, increase LDL & increase
triglycerides

F. Kidney
◦ Reduce renin release 177
Therapeutic uses of β-blockers
1. Hypertension
2. Coronary heart disease
 Angina Pectoris
 Myocardial infarction

3. Cardiac arrhythmias
4. Anxiety :
5. Hyperthyroidism:
6. Migraine headache
7. Glaucoma
◦ Timolol is applied topically to treat glaucoma

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1. CVS
◦ Bradycardia
◦ hypotension More pronounced with 1
◦ AV block selectives

2. Bronchoconstriction
3. Hypoglycemic effect Produced by non-
selective blockers
4. Affect lipid profile
5. Muscle pain & fatigue
6. Sleep disturbances, nightmares

179
Ø 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

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v Non selective  &  antagonists
◦ Includes: Labetalol, Carvedilol, Bucindolol
◦ Are called 3rd generation, vasodilatory β-blockers

Ø 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)

181