DRUGS ACTING ON

AUTONOMIC NERVOUS SYSTEM

Dr. Suja Rani. S., Ph.D.

Assistant Professor
Dept of Pharmacology and Toxicology
College of Veterinary and Animal Sciences
Mannuthy,Thrissur
COMPONENTS OF NERVOUS SYSTEM
 Somatic nervous system
◦ The effector cells are skeletal muscle cells
◦ Somatic motor neurons regulate the action of
skeletal muscle.

 Autonomic nervous system

◦ innervates three types of effector cells:
 smooth muscle
 cardiac muscle
 exocrine glands
◦ Autonomic motor neurons control the
functioning of all visceral organs except skeletal
muscle like activities of smooth muscle, cardiac
muscle, glands and other internal body systems.
General Organization of ANS
 Autonomic nervous system
◦ Greek words autos=self, nomos= governing
◦ Visceral/ vegetative/ involuntary NS
◦ In the periphery, it consists of nerves, ganglia, and
plexuses
◦ organized to modulate the involuntary activity of
secretary glands, smooth muscles and visceral organs
◦ most important components of ANS are outflow
(efferent) nerve tracts.
◦ The efferent segments of ANS is divided into
sympathetic and parasympathetic outflow
tracts
 ANS requires a sequential two-neuron efferent
pathway
◦ Preganglionic and postganglionic neurons
◦ PreG.fibre synapses with postG.fibre which in turn form a
junction with the receptors of the organs supplied by it.
◦ The cell body of a PreG.neuron is located within CNS
(begin at the outflow).
◦ The synapse (junction) of a preG.axon with a ganglionic
neuronal body occurs outside the CNS within an
autonomic ganglion.
◦ An axon of a ganglionic cell passes peripherally and
innervates its effector organ substructure.
◦ The junction of a postG.axonal terminal with its effector
cell is termed a neuroeffector junction
ANS consists of two major subdivisions (depending
upon emergence of pre G fibres from CNS):
i. Sympathetic nervous system
◦ thoracolumbar outflow: the neurons begin at the
thoracic and lumbar (T1–L2) portions of the spinal cord
ii. Parasympathetic nervous system
◦ craniosacral outflow: the neurons begin at the cranial
nerves (CN3, CN7, CN9, CN10) and sacral (S2–S4) spinal
cord

Some prefer to classify Enteric Nervous System as a

third anatomic division of ANS
◦ Semi-autonomous part of ANS; organized collection of
different neurons located on the wall of GIT controlling its
functions.
Differences between sympathetic and
parasympathetic divisions of ANS
 Sympathetic Nervous System
 The cells that gives rise to the preganglionic fibres of this
division lie mainly in the intermedio-lateral columns of spinal
cord and extent from T1 to L2/L3 segment. : Thoracolumbar
outflow
 The sympathetic ganglia are three in number –
◦ Para vertebral
◦ Prevertebral
◦ Terminal.
 Adrenal medulla is the only exception to the two-neuron
arrangement is the innervation
◦ Adrenal medulla and other chromaffin tissue are
embryologically and anatomically similar to sympathetic
ganglia.
 Sympathetic Neurotransmitters
 Neurotransmitter at symp.ganglia: Ach
 All post G symp. Fibres (few exceptions) release NE
at neuroeffector junction
 Exceptions are
◦ Post G symp fibres to sweat glands (cholinergic)
◦ Some postG fibres supplying to arterioles of skeletal
muscle (cholinergic)
◦ Some postG sympathetic neurons at splanchnic and renal
blood vessels (dopaminergic)
◦ Chromaffin cells of adrenal medulla innervated by preG
sympathetic nerves fibres that release Ach; on stimulation,
these cells secrete epinephrine directly into the blood
stream along with small amount of NE.
 Adrenergic Receptors
 α adrenergic receptors
◦ α1: postsynaptic; excitatory effects in most of the
organs except in intestine; subtypes such as α1A,
α1B, α1C, α1D
◦ α2: presynaptic; decrease release of NE; subtypes
such as α2A, α2B, α2C

 β adrenergic receptors
◦ β1: postsynaptic; excitatory effects; positive
inotropic and chronotropic
◦ β2: postsynaptic; inhibitory effects; s.m. relaxation
◦ β3: on adipocytes; promotes lipolysis
 Parasympathetic System
 PreG fibres originate from brain stem (midbrain and
medulla oblongata) and sacral spinal cord of CNS: cranio
sacral outflow.
 The midbrain, or tectal, outflow consists of fibers arising
from the Edinger-Westphal nucleus of the third cranial
nerve (occulomotor nerve) and going to the ciliary
ganglion in the orbit.
 The medullary outflow consists of the parasympathetic
components of the VII (facial nerve), IX (glossopharyngeal
nerve), and X (vagus)cranial nerves
 The vagus nerve is considered to be the most important
parasympathetic nerve trunk.
 The parasympathetic sacral outflow consists of
axons that arise from cells in the second, third, and
fourth segments of the sacral cord and proceed as
preganglionic fibers to form the pelvic nerves
 Parasympathetic G: terminal G
◦ Ciliary G
◦ Sphenopalatine and submandibular G
◦ Otic G
◦ Pelvic G
 Parasympathetic neurotransmitters

 Ach is the neurotransmitter at all the autonomic

(symp & parasymp) ganglionic synapse
 Cholinergic fibres means all such fibres releasing
Ach as a neurotransmitter
◦ All somatic motor neurons to skeletal muscles
◦ All preG parasymp. or symp. Fibres, including adrenal
medulla
◦ All postG parasymp fibres to neuroeffector junction
◦ PostG symp fibres to sweat glands
 Acetylcholine receptors
 Nicotinic R
◦ On NMJ and at all autonomic ganglia including adrenal
medulla
◦ NM (muscle type) and neuronal type (NN) receptors
 Muscarinic Receptor
◦ At parasymp. NEJ at all s.m. and glands
◦ M1 to M5 subtypes
◦ M1 (neuronal and gastric):increase gastric acid secretion
◦ M2 (cardiac): decrease heart rate and conductivity
◦ M3 (glandular and visceral s.m.): increase in sweating,
bronchial and salivary secretions; contraction of visceral
s.m.
◦ M4 and M5: confined to CNS
Comparison of Symp., Parasymp. &
Somatic Motor Nerves

 The principal neurotransmitters are ACh and NE.

The main receptors for these transmitters are
◦ nicotinic (N) and muscarinic (M) cholinergic receptors
◦ α and β adrenergic receptors.
 Somatic nerves innervate skeletal muscle directly at
a specialized synaptic junction, the motor end plate,
where
◦ ACh activates Nm receptors.
 Autonomic nerves innervate smooth muscles,
cardiac tissue, and glands.
 Both parasympathetic and sympathetic systems have ganglia,
where ACh is released by the preganglionic fibers; ACh acts
on Nn receptors on the postganglionic nerves.

 ACh is also the neurotransmitter at cells of the adrenal

medulla, where it acts on Nn receptors to cause release of
EPI and NE into the circulation.

 ACh is the dominant neurotransmitter released by

postganglionic parasympathetic nerves and acts on muscarinic
receptors.

 NE is the principal neurotransmitter of postganglionic

sympathetic nerves, acting on α or β adrenergic receptors.
 Autonomic nerves form a diffuse pattern with
multiple synaptic sites.
◦ Parasympathetic System:
 The ganglia are near or within the organ being innervated;
Post ganglionic fibres short
 generally a one-to-one relationship between pre- and
postganglionic fibers.
◦ Sympathetic system:
 The ganglia are generally far from the effector cells (e.g.,
within the sympathetic chain ganglia); Post ganglionic
fibres long
 Preganglionic sympathetic fibers may make contact with a
large number of postganglionic fibers.
 Enteric nervous system
 The processes of mixing, propulsion, and absorption of
nutrients in the GI tract are controlled locally through a
restricted part of the peripheral nervous system called
the ENS.
 The ENS comprises components of the sympathetic and
parasympathetic nervous systems and has sensory nerve
connections
 ENS is involved in sensorimotor control and thus
consists of both afferent sensory neurons and a number
of motor nerves and interneurons that are organized
principally into two nerve plexuses:
◦ myenteric (Auerbach) plexus
◦ submucosal (Meissner) plexus.
NEUROHUMORAL TRANSMISSION

 First definitive evidence of chemical neurotransmission

obtained by Loewi (1921) and coworkers

 Loewi electrically stimulated the vagus nerve of an

isolated perfused frog heart.

 The perfusate leaving this preparation was perfused

through another frog heart.

 Upon stimulation of vagus, the first heart was

immediately depressed within a few seconds, the second
heart was also depressed.
 The study indicated that vagus nerve liberated a
chemical “myocardial inhibitory substance”, referred
to as vagus stoff (vagus substance) which was
later identified as Acetylcholine (Ach)

 Ach was found to be the chemical released from

◦ all (parasympathetic and sympathetic) autonomic
preganglionic fibres

◦ post ganglionic parasympathetic fibres.

 NE is the neurotransmitter released at

◦ majority of sympathetic neuro effector junctions.
Events involved in neurohumoral
transmission

 Axonal conduction
 Neurotransmitter release
 Receptor events and initiation of post
synaptic activity
 Catabolism of neurotransmitter.
 Axonal Conduction
 Refers to passage of impulse along a nerve fibre.
 Dependent upon selective permeability changes of
axonal membrane to electrolytes.
 At rest, the interior mammalian axon is
approximately -70 mV.
◦ 40 times higher concentration of K+ in the axoplasm as
compared with the extracellular fluid and the relatively high
permeability of the resting axonal membrane to K+.
◦ Na+ and Cl- are present in higher concentrations in the
extracellular fluid than in the axoplasm, but the axonal
membrane at rest is considerably less permeable to these
ions.
 During depolarization (supratheshold stimulus) , an
action potential or nerve impulse is initiated at a
local region of the membrane.
 The action potential consists of two phases:
◦ Phase I: rapid increase in the permeability of Na+ through
voltage-sensitive Na+ channels
◦ Phase II: rapid inactivation of the Na+ channel and the
delayed opening of a K+ channel, which further permits
the outward movement of K+ to terminate the
depolarization
◦ Ionic distribution is normalized during the refractory
period by the activation of Na+ K+ pump
 As a result of such localized changes in membrane
potential, adjacent resting channels in the axon are
activated and excitation of an adjacent portion of the
axonal membrane occur

 brings about propagation of the AP along the axon

 In myelinated fibres, permeability changes occur only

at the node of Ranvier, thus causing a rapidly
progressing type of jumping or saltatory conduction.
Drugs that modify axonal conduction:
 Tetrodotoxin (Puffer fish toxin) and Saxitoxin (shell
fish toxin)
◦ block axonal conduction causing paralysis.
◦ by blocking voltage-sensitive Na+ channel
◦ prevent the increase in Na+ permeability associated
with the rising phase of the action potential.
 Batrachotoxin (frog toxin)
◦ produces paralysis
◦ through a selective increase in permeability of the Na+
channel, which induces persistent depolarization.
 Scorpion toxin
◦ causes persistent depolarization
◦ by inhibiting the inactivation process
 Neurotransmitter Release
 The transmitter ( excitatory or inhibitory) is
stored in prejunctional nerve endings within
'synaptic vesicles
 Arrival of the axonal action potential at the nerve
terminal trigger release of NT
 Nerve impulse promotes fusion of vesicular and
axonal membranes through Ca2+ entry which
fluidizes membranes.
 Ca2+ influx triggers synaptobrevin-syntaxin
complex formation leading to the exocytotic
discharge of NT from the vesicles into the
junctional cleft. (These proteins can be targets of drug
action to modify junctional transmission).
Receptor events and initiation of
post synaptic activity
 After rapid migration of NT across the cleft, it
binds with receptive areas on the postsynaptic
membrane.
 Receptor activation triggers change in the
permeability of the post synaptic membrane to all
ions
 Receptor events may be of two types:
◦ Excitatory : induces an excitatory postsynaptic
potential (EPSP)
◦ Inhibitory: induces an inhibitory postsynaptic
potential (IPSP).
 EPSP
◦ Increase in permeability to all cations
◦ N a+or Ca2+ influx (through fast or slow channels)
causes depolarization followed by K+ efflux.
◦ These ionic movements are passive as the flow is down
the concentration gradients.
◦ Electrically these changes are characterized as an
excitatory post synaptic potential (EPSP) and further
propagated
IPSP
◦ Increase in permeability to smaller ions, i.e. K+ and Cl-
only, so that K+ moves out and Cl- moves in (in the
direction of their concentration gradients) resulting in
hyperpolarization.
◦ Hyper polarization of the membrane increases threshold
to stimuli and elicit an inhibitory response in the cell
 Postjunctional activity
◦ A suprathreshold EPSP generates a propagated
postjunctional AP which results in nerve impulse
(in neurone), contraction (in muscle) or
secretion (in gland).

◦ An IPSP stabilizes the postjunctional membrane

and resists depolarizing stimuli.
 Catabolism of Neurotransmitter
 Termination of action of released neurotransmitter
involves different mechanisms.
◦ 1. Metabolic degradation: by enzymes in the synaptic
cleft or pre-synaptic nerve terminals Eg: Ach – acetyl
choline esterase
◦ 2. Reuptake mechanism: taken back into the pre-
synaptic nerve terminal by specific carrier systems Eg:
Adrenergic neurotransmitters (simple diffusion and
reuptake)
◦ 3. Active transport into neurons and surrounding glia
Eg: termination of action of amino acid transmitters
◦ 4. Diffusion: peptide neurotransmitters hydrolysed by
peptidases and dissipated by diffusion
 Definition and terms
 Neurotransmitter
◦ chemical released in the synapse/junction and
carries out the propagation of nerve impulse.
◦ It excites or inhibits post synaptic neuron or
effector organ
◦ Eg: acetylcholine and noradrenaline
 Neuromediator
◦ Substance that participates in the elicitation of
the post-synaptic response to a
neurotransmitter
◦ Eg: cyclic AMP, cyclic GMP, diacylglycerol
 Neuromodulator
◦ Any chemical substance which modulates or
control the function of autonomic nervous system
by affecting the synthesis, storage, release and
action of neurotransmitter
◦ through elaborate cascade of intracellular
messengers.
◦ Does not participate directly in neurotransmission
◦ The phenomenon of neuromodulation involves
slower processes (taking seconds to days) when
compared with neurotransmission (milliseconds)
◦ Eg: prostaglandins, adenosine, neuropeptides
 Co-transmitter
◦ Neuron releases more than one transmitters or
modulators, each of which interacts with specific
receptors and produces effect that cannot be
achieved by a single transmitter.

◦ In the ANS, besides the primary transmitters ACh

and NA, neurones have been found to elaborate
cotransmitters like
 Purines (ATP, adenosine)
 Peptides (vasoactive intestinal peptide or VIP,
neuropeptide-Y or NPY, substance P, enkephalins,
somatostatin, etc.)
 nitric oxide and prostaglandins
◦ VIP is associated with ACh, while A TP is
associated with both Ach and NA.
◦ Vascular adrenergic nerves contain NPY which
causes long lasting vasoconstriction
◦ cotransmitter is stored in the same neurone but
in distinct synaptic vesicles or locations or in the
same vesicle along with primary neurotransmitter.
◦ may serve to regulate the presynaptic release of
the primary transmitter and/or postsynaptic
sensitivity to it (neuromodulator role)
◦ These are also generally called as non-adrenergic
non-cholinergic (NANC) transmitters
Cotransmission
 CHOLINERGIC PHARMACOLOGY

 Acetyl choline act as neurotransmitter in

◦ 1. Post ganglionic parasympathetic nerve endings
◦ 2. Post ganglionic sympathetic nerve endings to
sweat glands
◦ 3. Pre ganglionic fibres to autonomic ganglia (both
sympathetic and parasympathetic)
◦ 4. Somatic nerves to skeletal muscles
◦ 5. Central nervous system
 Cholinergic neurotransmission
 Neurons that release Ach are called cholinergic
neurons and the neurotransmission is called as
cholinergic neurotransmission
 Synthesis and Storage
◦ ACh is synthesized within the cholinergic nerves by
combination of acetyl CoA from mitochondria present
in the nerve terminals and choline from the
extracellular fluid with the help of enzyme choline
acetyltransferase (choline acetylase).

CAT
◦ Acetyl CoA + choline ACh
 Choline obtained from diet and reaching the
extracellular fluid is transported into the nerve terminal
by Na+Choline transporter.
 This choline uptake is the rate limiting step in ACh
synthesis
 inside the nerve terminal, free choline is acetylated by
choline acetyltransferase to Ach.
 ACh synthesized is stored into synaptic vesicles by ACh
proton antiport mechanism.
 The storage vesicles, in addition to ACh, contains ATP
and heparan sulphate, a glycoprotein
 Hemicholinium
◦ blocks choline uptake
 Vesamicol
◦ blocks the transport of ACh into synaptic vesicles
 Release
◦ nerve impulse when arrives at nerve terminal,
voltage sensitive Ca channels open, causing an
increase in the i/c Ca concentration.
◦ This promote the fusion of synaptobrevin-syntaxin
(vesicular proteins) complex and releases ACh by
transient pore formation and or by exocytosis into
the junctional cleft.
◦ A small amount of ACh is released during resting
phase also, but it is not sufficient to evoke any
response.
◦ Botulinum toxin
 causes lysis of vesicular proteins and inhibits the release
of ACh
◦ Black widow spider toxin, latrotoxin,
 causes massive release and depletion of ACh.
Action
 After release, ACh diffuses the junctional cleft and
binds either
◦ post junctional receptors on the target cells or
◦ pre-junctional receptors on the cholinergic neurons.
 Binding of ACh to the receptor leads to a biological
response within the effector cell.
 Two classes of receptors for ACh are recognised
◦ Muscarinic R
 G protein coupled receptor
◦ Nicotinic R
 ligand gated cation channel
 Historical Perspective
 Sir Henry Dale noted that the various esters of
choline elicited responses that were similar to those
of either nicotine or muscarine depending on the
pharmacological preparation
 Dale suggested that
◦ ACh or another ester of choline was a neurotransmitter
in the autonomic nervous system
◦ Ach had dual actions, which he termed a “nicotine
action” (nicotinic) and a “muscarine action”
(muscarinic).
 The capacities of tubocurarine and atropine to block
nicotinic and muscarinic effects of ACh, respectively,
provided further support for the proposal of two
distinct types of cholinergic receptors.
 Nicotinic Receptors
 Nicotinic (term derived from nicotine) receptors
are present in
◦ autonomic ganglia
◦ CNS
◦ neuromuscular junction of somatic nervous system.
 Accordingly the receptors at these sites are called
nicotinic cholinergic sites.
 Two subtypes are present
◦ NN (Nicotinic receptor – neuronal)
◦ NM(Nicotinic receptor – muscle).
 These receptors are linked to ion channels and
mediate fast excitatory synaptic transmission.
PTMA: phenyl trimethyl ammonium
DMPP: Dimethyl Phenyl Piperazinium
 Muscarinic Receptors
 Muscarinic (term derived from muscarine, a toxic
mushroom (Amanita muscaria) alkaloid
 All muscarinic receptors belong to 7trans
membrane G protein coupled receptors
 5 subtypes- M1, M2, M3, M4 and M5.
◦ CNS contains all types of muscarinic receptors
including M4 and M5.
◦ M1 is present in CNS and autonomic ganglia,
◦ M2 is present in myocardium.
◦ M3 is present in smooth muscles and secretory
glands.
 M1, M3 and M5 are excitatory
 Gq protein -activate membrane bound
phospholipase C (PLc)-inositol trisphosphate (IP3)
and diacylglycerol (DAG)-release Ca2+ intracellularly
 cause depolarization, glandular secretion, and raise
smooth muscle tone.
 activate phospholipase A2- enhanced synthesis and
release of prostaglandins and leucotrienes in certain
tissues.
 M2 and M4 are inhibitory
◦ opens K+ channels (through βγ subunits of Gi) -
inhibits Adenylyl Cyclase (through α subunit of Gi)
◦ resulting in hyperpolarization, reduced pacemaker
activity, slowing of conduction and decreased force
of contraction in the heart
 Autoreceptors
◦ Muscarinic autoreceptors are present
prejunctionally on postganglionic cholinergic nerve
endings
◦ ACh released from parasympathetic neurons may
interact with M2 and M4 receptors prejunctionally
to inhibit further release of acetylcholine.
 These receptors present prejunctionally are called as
auto inhibitory receptors.
◦ Prejunctional post ganglionic membrane also
contains M1 and nicotinic receptors which can
cause the release of ACh.
 These receptors are called as auto stimulatory
receptors.
 Heteroreceptors
◦ Heteroreceptors are receptors that respond to
neurotransmitters released from adjacent
neurons or cells
◦ they are opposite to autoreceptors.
◦ For Eg: NE can influence the release of ACh from
parasympathetic neurons by acting on α2
adrenergic (α2A, α2B, and α2C) heteroreceptors
on parasympathetic neurons.
◦ Similarly ACh can influence the release of NE
from sympathetic neurons by acting on M2 and
M4 receptors heteroreceptors on sympathetic
neurons.
 Fate of Ach
◦ ACh released into the junctional cleft after its
action on the receptors is rapidly hydrolysed into
choline and acetate by acetylcholinesterase
enzyme.
◦ Two different types of cholinesterase enzymes
 acetyl cholinesterase (specific or true cholinesterase)
 butryl cholinesterase (non-specific or
pseudocholinesterase).
◦ AChE is present in
 cholinergic neurons (in the tissues) pre junctionally and
post junctionally
 highly concentrated in the vicinity of cholinergic
synapses.
 Butryl cholinesterases are present in plasma.
 After hydrolysis, choline may be recaptured by
sodium choline transporter mechanism that
transports choline into the neuron.
 CHOLINERGIC DRUGS
(Cholinomimetic, Parasympathomimetic)

 Cholinomimetic/ Cholinergic indicates an

acetylcholine like effect at all cholinergic sites in
the body including parasympathetic nerves,
somatic nerves, CNS and autonomic ganglia
 Parasympathomimetics denotes the action of ACh
in the organs innervated by parasympathetic
nervous system (smooth muscle, heart and glands)
 However, both the terms are used interchangeably
 These drugs which produce actions similar to that
of ACh, act either by
◦ directly interacting with cholinergic receptors
(cholinergic agonists)
or
◦ increasing availability of ACh at these sites
(anticholinesterases).

 Thus the drugs that cause parasympathomimetic

effect can be divided two major groups.
 Directly acting drugs (Cholinergic agonists)
 Choline esters: Acetylcholine and its synthetic
derivatives (Methacholine, Carbachol,
Bethanechol )
 Cholinomimetic Alkaloids: Muscarine, Pilocarpine,
Arecoline, Nicotine
 Indirectly acting drugs (Anticholinesterases)
 Reversible inhibitors of cholinesterase:
Physostigmine, Neostigmine, Edrophonium
 Irreversible inhibitors of cholinesterase: OP
compounds: Di-isopropyl flurophosphate,Tetra
ethylpyrophosphate, Parathion, Malathion, Sarin
 Direct acting agents
 These drugs act directly on cholinergic R
 Produce the effects like Ach
 ACh as such has no therapeutic value
because of lack of specificity and its rapid
hydrolysis by choline esterase enzyme
 ACh is the prototypical cholinergic agent
 Pharmacological effects of ACh
I) Muscarinic Actions
Heart:
 Parasympathetic system has inhibitory effect on
the heart (M2) and is responsible for the negative
chronotropic (decreased heart rate) and
dromotropic (decreased conduction) effects.

 Anticholinergic drugs stimulate the heart by

decreasing the inhibitory effect of ACh on heart.
Blood vessels:
 In small doses, ACh produces a rapid fall of systolic
and diastolic BP due to decrease in peripheral
resistance.
 Vascular smooth muscle relaxation and dilatation
of blood vessels is noticed.
 Muscarinic receptors (M3) of blood vessels are
located in the endothelium rather than the
smooth muscle.
 Endothelial receptor activation releases EDRF
(nitric oxide), which is also responsible for
vasodilatation and decrease in peripheral
resistance
 Larger doses produce prolonged muscarinic effects and
therefore a pronounced decrease in peripheral
resistance and blood pressure.

 Stimulation of vagus cause negative chronotropic ,

dromotropic and inotropic effects

 Different arrhythmias include sinus arrest, severe

bardycardia, heart block, momentary ventricular
asystole, atrial fibrillation and flutter

 However, if endothelium is damaged, ACh can stimulate

M3 receptors in the vascular smooth muscle leading to
vasoconstriction
Eye:
 Cholinergic system stimulates sphincter
pupillae (circular muscle of eye) and thus
results in miosis (M3).
 ACh also causes contraction of ciliary muscle
of the eye and thus accommodation is
possible.
 ACh helps in the drainage of intraocular fluids
and reduction of intraocular pressure.
 Anticholinergic drugs result in mydriasis and
loss of accommodation (blurred vision).
Glands:
 Cholinergic system stimulates the secretion
of glands and results in the increased
salivation, lacrimation as well as sweating
(M3).
 On the other hand anticholinergic drugs will
result in dry mouth, dry eyes and difficulty in
swallowing (due to decreased saliva).

Adrenal medulla
 Release of norepinephrine and epinephrine
Urinary bladder:
 Cholinergic drugs stimulate detrussor and relax the
trigone (sphincter)of urinary bladder resulting in
increased micturition (M3).
 Anticholinergic drugs may result in urinary
retention.

Bronchus:
 Cholinergic system causes bronchoconstriction (M3)
 Anticholinergic drugs lead to bronchodilation.

Male sex organs:

 Due to vasodilation, cholinergic system is
responsible for erection of the male organ.
Gastro-intestinal tract:
 GI motility and secretions are enhanced by
ACh.
 Hydrochloric acid secretion in the stomach
(M1 and M3) is stimulated by
parasympathetic system
 thus increases the risk of peptic ulcer disease.
 Peristalsis of GIT is increased and sphincters are
relaxed by the cholinergic drugs.
 Anticholinergic drugs can be used as
spasmolytic agents for intestinal colic.
 Nicotinic Actions
Autonomic ganglia:
 Both sympathetic and parasympathetic ganglia are
stimulated by ACh through the stimulation of NN
receptors.

Neuromuscular junction:
 ACh stimulates skeletal muscle contraction by its
action on NMJ (NM receptors).
 Prolonged exposure and high doses cause tremors
and fasciculations which terminate in depolarising
paralysis due to inactivation of sodium channels and
desensitisation of nicotinic receptors.
Central Nervous System
 Because of highly charged quaternary nitrogen
group, Ach is lipophobic and poorly penetrates
cell membrane and BBB.

 Intra-arterial injection of large amounts of ACh

into cerebral arteries produces increased
electrical activity, excitation and convulsion.
 Effect of large doses Ach
 With high doses (50-100mg/kg) of ACh muscarinic
effect will be accentuated.
 Profound hypotenion due to extensive vasodilation is
produced.
 GI tract and visceral smooth muscles are markedly
activated, defecation, urination and vomiting occurs.
 Large doses cause stimulation of nicotinic receptors
of autonomic ganglia.
 The effects are evident when muscarinic receptors
are blocked by atropine
 Differences between various choline esters
Methacholine Carbachol Bethanechol
Structure Substitution of Acetic moiety is Acetic moiety is
beta carbon of substituted with substituted with
choline with carbamyl group carbamyl and choline is
methyl group methylated
Activation of R Muscarinic Muscarinic & Muscarinic
Nicotinic

Degradation Slowly Resistant to AChE; Resistant to AChE;

metabolised by hence duration of hence duration of
AChE, resistant to action more action more
BuChE; hence
duration of action
more
Site of Action More active at More active at GIT More active at GIT and
CVS and urinary bladder urinary bladder
 Differences between various choline esters

Methacholine Carbachol Bethanechol

Action on More active Less potent No effect
CVS
Action on large doses req. More active More active
GIT
Action on Uterine Contraction of Contraction of
other contractions urinary bladder urinary bladder
smooth during later period
muscles of gestation
Skeletal No action (no Fasiculations and No action (no
muscles nicotinic effect) paralysis nicotinic effect)
Other - Releases -
effects epinephrine from
adrenal medulla
CHOLINOMIMETIC ALKALOIDS
 Plant alkaloids that exert
parasympathomimetic effect with activity
primarily at muscarinic receptors and
minimum on nicotinic sites are
◦ Pilocarpine
◦ Muscarine
◦ Arecoline
 Parasympathomimetic plant alkaloid that
exert effect primarily on nicotinic sites
◦ Nicotine
 Pilocarpine Arecoline Muscarine Nicotine

Source P. jaborandi, P. A. catechu Amanita Nicotiana

microphyllus muscaria tobaccum

MOA Muscarinic, Muscarinic Muscarinic Nicotinic

stimulates
autonomic
ganglia
Parasymp less potent toxic toxic
athomim
etic
potency
 PHARMACOLOGICAL EFFECTS

Pilocarpine Arecoline Muscarine Nicotine

Exocrine Stimulates Stimulates Stimulates Stimulates
glands secretion of secretion of secretion of secretion of
digestive, resp. digestive, digestive, digestive,
and salivary resp. and resp. and resp. and
glands salivary salivary salivary
glands glands glands

Eye Miosis - - -
CVS BP (low Decrease Slowing of BP (low
doses) heart rate heart rate doses)
BP (high and BP and BP (high
doses) hypotension doses)
 Pilocarpine Arecoline Muscarine Nicotine
Other Augment GI Augment GI Augment GI Augment GI
effects motility and motility and motility and motility and
increases tone increases increases increases
and motility of tone and tone and tone and
uterus, urinary motility of motility of motility of
bladder, gall uterus, uterus, uterus,
bladder and urinary urinary urinary
biliary ducts bladder, gall bladder, gall bladder, gall
bladder and bladder and bladder and
biliary ducts biliary ducts biliary ducts
 Clinical Uses
Pilocarpine
◦ primarily used in the treatment of glaucoma.
◦ drug of choice in emergency lowering of intraocular
pressure of both narrow angled (closed angled) and
wide-angled (open angled) glaucoma.
◦ used to control mydriasis and cycloplegia produced by
atropine and ganglionic blockers.
◦ used to improve tear secretions in patients that have
lachrymal gland dysfunction.
◦ used as a sialogogue and diaphoretic agent.

Arecoline
◦ An anticestodal agent.
◦ At one time arecoline was in veterinary medicine as a
purgative in horses
 Indirectly acting agents
(Cholinesterase Inhibitors)
 AChE terminate the action of endogenous Ach at
cholinergic synapses and NEJ.

 ChE inhibitors inactivate or inhibit AChE and

psuedoChE and thereby intensify activity of
endogenous ACh.

 Prolong the action of drugs that are

biotransformed by ChE (eg: succinyl choline)
 Classification
 Based on stability of complexes formed with AChE
enzyme, antiChE agents are divided into two groups.

1. Reversible anticholinesterase agents

Eg. Physostigmine, Neostigmine, Pyridostigmine,
Edrophonium, Tacrine

2. Irreversible anticholinesterase agents

Eg: Diisopropyl fluoro phosphate (DFP),
Ecothiophate, Dichloros, Parathion, Malathion,
nerve gases like Soman, Sarin and Tabun, Carbamate
insecticide like carbaryl, propoxur
 Chemistry
 Anti-ChEs are either esters of carbamic acid or
derivatives of phosphoric acid.

 In carbamates R1 may have a nonpolar tertiary

amino N, e.g. in physostigmine, rendering the
compound lipid soluble.
 In others, e.g. neostigmine, R1 has a quaternary N+-
rendering it lipid insoluble.
 All organophosphates are highly lipid soluble except
echothiophate which is water soluble .
Mechanism of Action
 Cholinesterase inhibitors produce
characteristic inhibitory action on AChE.
 This results in decreased hydrolysis of
neuronally released ACh and intensification
of its action at cholinergic receptors.
 The anti-ChEs react with the enzyme essentially
in the same way as ACh.
 The carbamates and phosphates respectively
carbamylate and phosphorylate the esteratic
site of the enzyme.
 AChE has an Anionic and Esteratic site
◦ Anionic site: electrostatic binding with cationic
nitrogen
◦ Esteratic site: covalent binding with carboxyl part of
acetyl esters
◦ After ACh-AChE interaction, choline splits off leaving
acetylated enzyme (acetylated esteratic site)
◦ Acetic acid is rapidly formed as water react with
acetyl group and enzyme is reactivated
Hydrolysis of Ach by AChE
 Neostigmine and Physostigmine and other
carbamate derivatives interact with anionic and
estertic sites of the enzyme, thereby preventing
ACh from affixing to the enzyme.
 Neostigmine and Physostigmine are hydrolyzed in
a similar manner but much slower than ACh.
 Therefore Neostigmine and related drugs are
reversible cholinesterase inhibitors.
 Endrophonium is a complex compound that
interacts with anionic site of cholinesterase.They
are not hydrolyzed but act as simple competitive
reversible inhibitors.
 Organophosphate interacts with ACh at the
esteratic site and forms an extremely stable
enzyme inhibitor complex that does not undergo
spontaneous dissociation.
 The esteratic site is persistently phosphorylated
and recovery of cholinesterase activity is
dependent upon synthesis of new enzyme.
 Some organophosphate compounds eg.
Ecothiophate interact with both anionic and
esteratic sites.
 Since cholinesterase synthesis requires days, OP
cause irreversible inhibition.
 Pharmacological effects

Digestive tract: contraction of smooth muscles

Ocular effects: pupillary constriction
Skeletal muscles: twitching observed in high
doses
Other effects
Ganglionic stimulation and cause muscarinic
effects
 REVERSIBLE INHIBITORS

Physostigmine (Eserine)
 A tertiary amine alkaloid obtained from the
dried ripe seeds of Physostigma venenosum
 Absorbed orally, from conjunctiva and
crosses the BBB
 Used in ruminal atony and in treatment of
atropine poisoning
 Physostigmine effectively antagonizes the
effects of atropine both centrally and
peripherally
Neostigmine
 Synthetic quaternary ammonium compound with rigid
onset of action
 Can also directly stimulates the nicotinic receptors -
powerful anticurare effect
 Not absorbed orally and is not able to penetrate the
BBB

Edrophonium
 Primarily binds with the anionic site of AChE
 Duration of edrophonium is very shortened and is less
potent
 Primarily used in the diagnosis of myasthenia gravis
Pyridostigmine
 Similar to neostigmine, but has slower onset of
action
Ambenonium
 Slightly more potent and longer acting than
neostigmine
Tacrine
 Lipophilic acridine compound, able to cross blood
brain barrier
 Used in the symptomatic treatment of Alzemier’s
disease
Carbamates
 Insecticides in agriculture and in control of
ectoparasites in animals
 Non polar, highly lipid soluble, easily
absorbed from the site of exposure
 Potent poisons, poisoning is of shorter
duration than OP
 IRREVERSIBLE INHIBITORS

 Covalently bind to AChE and cause its inhibition

irreversibly
 Unlike carbamate and other reversible
cholinesterase inhibitors, these do not posses
cation group and thus react only with the
esteratic site of ChE enzyme
 The enzyme-substrate complex thus formed is
highly stable and does not undergo spontaneous
hydrolysis
Eg: Organophosphorus compounds
Soman, Sarin and Tabun – Nerve gas
Dichlorvos - anthelmintic
MECHANISM OF ACTION
 Irreversibly phosphorylate the esteratic site of both
AChE and pseudo cholinesterase throughout the
body.
 Endogenous ACh is not inactivated resulting in
effects due to accumulation of ACh.
 Esteratic site persistently phosphorylated – dialkyl
phosphoryl enzyme formed
 Organophosphate poisoning produce diffuse
cholinomimetic effects, muscarinic and nicotinic
effects
 SYMPTOMS OF OP POISONING

 Muscarinic effects
 Profuse salivation, miosis, vomiting, defecation,
hypermotility of GIT, urination, bradycardia,
hypotension, severe bronchoconstriction and
excess bronchial secretions
 Nicotinic effects
 Skeletal muscle fasciculations, twitching and
paralysis, ataxia and confusion, life threatening
bronchoconstriction and convulsions, Death due
to respiratory failure
 Delayed neurotoxicity
 peripheral nerve demyelination leading to
slowly developing weakness and sensory
loss

TREATMENT
 ANTAGONIST
 Atropine – competitive antagonist
 ANTIDOTE
 Cholinesterase reactivators
Atropine
 Atropine blocks the muscarinic effects
produced by organophosphate compounds.
 Atropine is a competitive antagonist to
ACh and large doses are effective.
 Dose: Dogs and Cats: 0.2-2 mg/kg
 LA: 0.2-0.5 mg/kg
 Cholinesterase Reactivators
 Organophosphates
◦ cause phosphorylation of the esteratic site of
cholinesterase leading to formation irreversible complex.
 Pralidoxime (Pyridine – 2 aldoxime methiodide, 2
PAM) : a selective antidote to organophosphate –
cholinesterase interaction.
 This compound causes an effective removal of
phosphate group from the enzyme, so the enzyme
is reactivated.
 Main drawback to use oximes as an antidote to
OP poisoning
◦ Within few hours the phosphorylated enzyme
undergoes ‘ageing’ that it renders it no longer
susceptible to reactivation

◦ Ageing is due to the loss of on alkoxy group leaving

a much more stable monoalkyl or monoalkoxy
phosphoryl –AchE).

◦ So the treatment should not be delayed.

 Oxime combines with free anionic site of the
phosphorylated AChE enzyme by electrostatic
attraction of its quaternary N atom.
 This orients the nucleophilic oxime group to react
with electrophilic P atom; the oxime phosphonate is
split off leaving a regenerated enzyme.
 Oxime reactivitors are probably ineffective in
antagonizing the carbamate cholinesterase inhibitors.
◦ because in carbamylated enzyme both the anionic and
esteratic sites are occupied by the enzyme, so oxime does
not get binding site on the inhibited enzyme.
 If atropine given along with 2-PAM, lethal dose is
increased many times
 Dose of PAM in dogs: 10-20 mg/kg slow IV. Dose
may be repeated
 Horse: 20 mg/kg
 Cattle: 10-40 mg/kg
 Other reactivator oximes are
◦ Pyridine 2- aldoxime dodeca iodide
◦ Monoiso nitroso acetone (MINA)
◦ Diacetyl monoxamine (DAM)
 Parasympatholytic Agents/
Anticholinergic Drugs
 Drugs that prevent ACh from producing its
characteristic effects in structures innervated by
postganglionic parasympathetic nerves.
 These drugs block or inhibit muscarinic actions
of ACh and related cholinergic agonists.
 Anticholinergic are more precisely termed as
antimuscarinic or muscarinic receptor antagonists
 Hence the term ‘antimuscarinic’ is more suitable
than parasympatholytic.
 This group include atropine and related alkaloids
and synthetic compounds
 Classification
1. Non-selective muscarinic receptor antagonist/
Non-selective antimuscarinic drugs
i. Natural alkaloids
eg: Atropine and Scopolamine (hyoscine)
ii. Semi-synthetic and synthetic antimuscarinic drugs
• Mydriatics
• Homatropine, Cyclopentolate, Tropicamide, Eucatropine
• Antisecretory-antispasmodics
i) Quaternary compounds:
• Propantheline, glycopyronium, Ipratropium, Tiotropium
ii) Tertiary amines:
• Oxybutynin, Dicyclomine
iii) Antiparkinsonians:
• Benzhexol, Benztropine, Procyclidine
II. Selective muscarinic receptor
antagonists/ selective antimuscarinic
drugs
• Selective M1 receptor antagonist:
• Eg. Pirenzepine,Telenzepine
• Selective M2 receptor antagonist:
• Eg. Tripitramine, Methoctramine
• Selective M3 receptor antagonist:
• Eg. Darifenacin
 Natural antimuscarinic drugs

 Atropine
◦ Prototypical muscarinic blocking agent.
◦ Alkaloid extracted from belladonna plants
belongs to Solanaceac family
◦ It include
 Atropa belladona (Deadly night shade)
 Datura stramonium (Thorn apple or Jimson
weed).
◦ Alkaloids obtained from belladonna are
atropine and scopolamine.
 Mechanism of action
 Competitively antagonize Ach and other
muscarinic agonist at all the muscarinic receptors
 High doses, block the nicotinic receptors at
autonomic ganglia and neuromuscular junction
 Blockade of muscarinic receptors involve
competitive antagonism
 Binding action is reversible as it can be overcome
by high conc. of ACh
 More effective in blocking responses to
exogenously administered cholinergic agonists
than those produced by stimulation of cholinergic
nervous system
 Pharmacological effects
 Due to the heterogeneity of muscarinic receptors, the
pharmacological effects of atropine are dose related

Cardiovascular systems
Heart
 Tachycardia is the dominant effect.
 Large doses of atropine produce increased heart
rate.
 Small doses show slowing of heart rate due to
stimulation of prejunctional M1 receptors prior to
its block
 Atropine blocks transmission of vagal impulses to
the heart. Hence animals with pre existing high
vagal tone show relatively greater tachycardia
Blood pressure
 CO increase because of increased heart rate.
 In animals exposed to ACh or cholinomimetics,
atropine cause increase in blood pressure
 Since atropine blocks cardiac vagus, it abolishes
cardiac inhibitory effects of drugs acting through
vagal mechanism
 Potentiates the pressor effect of adrenergic and
nor adrenergic by blocking the cardio inhibiting
effects of vagus
Gastrointestinal tract
 Relaxes the GI smooth muscles by inhibiting the
contractile responses produced by endogenous
Ach
 Reduces tone and motility of gut resulting in
increased gastric emptying time and causes closure
of sphincter
 Reduces the amplitude and frequency of peristalsis
resulting in antispasmodic or spasmolytic effect
 Secretions of GI tract are also blocked by
atropine.
Respiratory System :
 Relaxes the bronchioles and decrease secretions
 Symptomatic relief from dyspnea of “Heaves” in
horses

Smooth muscles
 Relaxation due to blockade of M3 muscarinic
receptors

Ocular effects
 Atropine produce mydriasis and cycloplegia after
topical or systemic administration.
Urinary tract :
 Relaxes smooth muscle of urinary tract.
 The spasmolytic effect on the ureters may be of
some benefit in the treatment of renal colic.
 Atropine cause urine retention because it inhibit
smooth muscle tone.

Exocrine glands
 Markedly decreases sweat, salivary, tracheo
bronchial and lachrymal secretions due to M3
receptor blockade
 Atropine does not affect sweating in horses
(adrenergic).
Body temperature :
 Raises the body temperature

Central Nervous System

 Therapeutic doses have minimal effect on CNS
but larger doses have stimulant effect
 Very high doses : mania and excitement in
domestic animals, which is later followed by
depression and coma
 Toxicology
Interspecies variation:
 Dogs, cats and Humans – highly susceptible
 Herbivores are comparatively resistant
 Horses, cattle and goats are relatively resistant to
belladonna when administered orally but are
susceptible to atropine when given parenterally
 Rabbits – resistant to belladonna leaves because
atropine esterase (atropinase) of liver hydrolyses
and inactivate atropine
Signs of atropine poisoning:
 Similar in all mammals
 Dry mouth, thirst, dysphagia, constipation,
 Mydriasis, tachycardia, hyperpnoea,
 restlessness, delirium, ataxia, muscle trembling,
convulsions,
 respiratory depression, respiratory failure
 A drop of urine obtained from patient suspected of
atropine toxicosis cause mydriasis when placed in
the eye of a cat. Also, the tested pupil will not
constrict when exposed to light
 Clinical Uses

 As pre-anaesthetic to prevent or reduce

secretions of salivary glands and respiratory
tract
◦ The pre-anesthetic dose: 0.045 mg/Kg s/c in
dogs, cats;
◦ 0.07-0.09 mg/Kg i/m in pigs and 0.2 mg/Kg i/v
for 15 minutes in Goats and Sheep
 As antispasmodic to relax spasms of
smooth muscles of intestinal, urinary or
biliary duct
 As bronchodilator in bronchial asthma and other
bronchoconstrictive diseases.

 As cardiac stimulant to treat sinus bradycardia,

sinoatrial arrest or incomplete AV block

 As antidote to anticholinesterase agents (eg:

Carbamate and OP poisoning)

 As a mydriatic, for the measurement of refractive

errors and other diagnostic procedure
 Scopolamine
 Scopolamine (Hyoscine) obtained from
Hyoscyamus niger (henbane)
 Hyoscine is a competitive muscarinic
receptor antagonist
 produces peripheral effects similar to
atropine.
 It has greater action on CNS.
 It is primarily a depressant of CNS
producing drowsiness, euphoria, fatigue and
sleep in therapeutic doses.
 Clinical uses
 As an antispasmodic in GI disorders
 As a pre-anesthetic to decrease salivary and
bronchial secretions.
:The sedative effect calms the patient
before operations
 As antiemetic in motion sickness – more
effective prophylactically
 In humans, hyoscine is used along with
morphine in obstetrics to produce amnesia
and sedation
 SYNTHETIC ANTIMUSCARINIC DRUGS

Mydriatics
 Tertiary amines instilled into the conjunctival sac to
produce mydriasis and or cycloplegia
 Rapid onset and shorter duration of action; devoid
of systemic effects
Homatropine
 Semisynthetic drug produced from atropine, 10
times less potent than atropine
 Eucatropine
 Produces mydriasis without cycloplegia

 The duration of action of mydriatic agents

is as follows:
◦ Atropine>Homatropine>Cyclopentolate>Tropi
camide> Eucatropine
 Antisecretory Antispasmodics
Quaternary compounds
 Being quaternary compounds, they are not
absorbed from gut and do not cross BBB and
conjunctival barrier

 These drugs have some ganglionic blocking

activity, which partly contribute to their
antispasmodic effects
Propantheline
 Antisecretory, antispasmodic in GI disorders
 Indicated in urinary inconsistency
Isopropamide
 Antiemetic, antidiarrrhoeal, anticholinergic effects
 Often used in fixed – dose combination with
prochlorperazine

Glycopyrronium (Glycopyrrolate)
 preanaesthetic in veterinary medicine
 reduce gastric secretion and reduce intestinal motility
 Tachycardia is a not a greater problem with
glycopyrrolate

Ipratropium
 Used as bronchodilator in treating chronic obstructive
pulmonary disease
Tertiary Amines
 Antimuscarinic and non- specific direct relaxant effect
on smooth muscles
 Reduce spasm of the GI tract, biliary tract, ureter and
uterus
Oxybutynin
 Antispasmodic (urinary bladder) and antisecretory
effects
Dicyclomine
 Direct smooth muscle relaxant effect in addition to
antispasmodic action without producing atropine
like effects on the heart, eyes, salivary and sweat
glands
Antiparkinsonian Drugs
 Cross BBB and act on basal ganglion and extra
pyramidal system to reduce the involuntary
movements and rigidity of parkinson’s disease
 Also used to treat the extra pyramidal side
effects of antipsychotic drugs
 Feeble peripheral effects and hence are more
selective for central effects
Eg. Benzhexol, Benztropine, Procylidine etc.
SELECTIVE MUSCARINIC ANTAGONISTS
Selective M1 Muscarinic Receptor Antagonists
Pirenzepine : Inhibit gastric acid secretions
Telenzepine : Analogue of pirenzepine, more potent
than pirenzepine , Used in the treatment of peptic
ulcer
Selective M2- Muscarinic Receptor Antagonists
Tripitramine : block cholinergic bradycardia
Selective M3- Muscarinic Receptor Antagonists
Darifenacin : block smooth muscle activity or
epithelial secretions
 AUTONOMIC GANGLIONIC
BLOCKING DRUGS

 Nicotinic receptors represents primary

ganglionic transmission pathway in all autonomic
ganglia
 A secondary excitatory cholinergic pathway in
autonomic ganglia
◦ muscarinic mediated through M1
◦ an inhibitory mechanism by M2 receptors
 Muscarinic receptors facilitates impulse
transmission.
 The adrenergic component may act as a
modulator to prevent excessive impulse traffic
 CLASSIFICATION

 Autonomic ganglionic stimulating drugs

 Autonomic ganglionic blocking drugs
 Autonomic Ganglionic Stimulating Drugs
I. Nicotinic receptor stimulants
 Natural alkaloids
Eg. Nicotine, Lobeline
 Synthetic drugs
Eg.Tetramethyl ammonium (TMA),
Dimethyl Phenyl Piperazinium (DMPP)
II. Muscarinic receptor stimulants
Eg: Acetylcholine, muscarine, methacholine,
anticholinesterase agents

 Autonomic ganglionic blocking drugs

 depolarizing ganglionic blocking drugs
Eg. Nicotine(large doses)
 Non-depolarizing ganglionic blocking
drugs/Synthetic ganglionic blockers
1. Quaternary ammonium compounds
Eg: Hexamethonium, Pentolinium, Pentamethonium
2. Tertiary/Secondary amines
Eg: Mecamylamine (long acting), Pempidine
3. Monosulphonium compounds
Eg: Trimetaphan, Camforsulphonate
 NICOTINIC RECEPTORS
STIMULANTS

Rapid onset

Mimic fast EPSP

Blocked by non – depolarising ganglionic

blocking agents Eg: Hexamethonium
 MUSCARINIC RECEPTORS
STIMULANTS

Slow onset
Mimic slow EPSP
Blocked by atropine like drugs
PERSISTENT DEPOLARISING GANGLIONIC
BLOCKING DRUGS

Nicotine
Liquid alkaloid from Nicotiana tabacuum
First stimulates and then depresses both the
sympathetic and parasympathetic autonomic
ganglia, adrenal medulla, neuromuscular
junction and CNS due to prolonged
depolarisation of post-synaptic membranes
Lobeline
Alkaloid from Indian tobacco – Lobelia inflata
 Pharmacological effects of Nicotine
 CNS:
◦ Alkaloid nicotine is an extremely toxic substance that
transiently stimulates and then severely depresses CNS.
◦ Death in form respiratory paralysis of the diaphragm and
chest muscles.

 CVS:
◦ Both cardio accelerator and cardio inhibitor nerves are
activated by small amounts of nicotine.
◦ Effect on cardio inhibitor nerves is predominant which
cause decreased pulse rate.
◦ Small doses of nicotine cause a pressor response.
◦ After large doses causes peripheral vasodilation due to
ganglionic block
 Gastro Intestinal :
◦ Nicotine activates smooth muscles and
secretary glands.
◦ There will be excessive salivation, increased
gastric secretion, vomiting increased peristalsis
and defecation.

 Skeletal Muscles :
◦ Nicotine initially stimulates nicotinic receptors
of motor end plate
◦ large doses produce persistent depolarizing
muscle paralysis
 Acute Nicotinic Poisoning
 Accidental ingestion of 40% Nicotine solution
results in acute toxicosis characterized by
◦ excitement hyperpnoea, salivation, pulse rate
irregularities, diarrhoea and emesis.
 After stimulation, depression occurs which is
characterized by
◦ incordination, tachycardia, dyspnoea and coma.
 Death occurs from respiratory paralysis.
NON DEPOLARISING/ COMPETITIVE GANGLIONIC
BLOCKING DRUGS
Hexamethonium
First ganglionic blocker
Ganglionic blockade without initial stimulation
Hypotensive with tachycardia
Pentolinium
To treat severe hypertension when other drugs
fail
Mecamylamine
Long acting ganglionic blocker
Trimetaphan
Very short – acting ganglionic blocker
 SKELETAL MUSCLE RELAXANTS

• Drugs that act peripherally at neuromuscular

junction/ muscle fibre itself
or
• centrally in the cerebrospinal axis to reduce
muscle tone and/or cause paralysis

Based on the site of action

I. Peripheral acting muscle relaxants
II. Centrally acting muscle relaxants
I) PERIPHERALLY ACTING MUSCLE RELAXANTS
A. Neuromuscular blocking agents
a) Non.depolarizing (Competitive) blockers
 Long acting: d-Tubocurarine, Pancuronium,
Doxacurium, Pipecuronium, Gallamine
 Intermediate acting: Vecuronium, Atracurium,
Rocuronium, Rapacuronium
 Short acting: Mivacurium
b) Deolarizing (Non-Competitive) blockers
 Succinyl choline (SCh., Suxamethonium),
Decamethonium (C-10)
B. Directly acting agents
 Dantrolene sodium, Quinine
II. CENTRALLY ACTING MUSCLE RELAXANTS
A. Carbamate derivatives:
Carisoprodol, Methocarbamol.
B. Benzodiazepines:
Diazepam,chlordiazepoxide
C. GABA derivative:
Baclofen.
D. Glyceryl ethers:
Guaiphenesin, mephenesin, chlozoxazone
 NEUROMUSCULAR BLOCKING AGENTS

Neuromuscular blocking agents are agents that

• interfere with the transmission of nerve impulses
from the somatic nerve endings to the skeletal
muscle fibres.
• By acting at these sites, they produce profound
muscle relaxation
 Competitive neuromuscular blocking drugs
 Competitive antagonist of ACh at nicotinic receptors on
motor end plate
 Competitive blockers have affinity for the nicotinic (Nm)
cholinergic receptors at the muscle end plate, but have no
intrinsic activity
 Bind to the nicotinic receptors and prevent binding of
ACh competitively and prevent subsequent
depolarisation and muscular contraction
 Competitive blockers generally have have two or more
quaternary N+ atoms which provide the necessary
attraction to the Ach binding site of R and these thick bulky
molecules were termed Pachycurare by Bovet (1951).
 Competitive neuromuscular blocking drugs

 The antagonism is controllable by increasing the

concentration of ACh in vitro and by anticholinesterases
in vivo.
d-Tubocurarine/Tubocurarine
 Obtained from Styrchnos toxifera and
Chondodendron tomentosum - arrow poison
Pancuronium
 Rapidly acting muscle relaxant
 does not release histamine
 No ganglionic blockade, but has vagolytic action
Gallamine
 Used to capture exotic species (eg: crocodiles)
Vecuronium
 No histamine release
 No autonomic ganglionic blockade or vagolytic
action, hence minimal cardiovascular effect
 Good muscle relaxant with regard to cardiovascular
stability

Atracurium
 Hoffman elimination : spontaneous breakdown at
37o C and pH 7.4
 Depolarising neuromuscular blockers

 Have affinity as well as submaximal inrinsic activity at

the NM cholinoceptors
 Depolarize the muscle end plates by opening Na+
channels and initially produces twitching and
fasciculations.
 Initial phase is rapid in onset
 These drugs do not dissociate rapidly from the
receptor causing
 prolonged partial depolarization of the region
around the muscle end plate which causes the
inactivation of Na+ channels (because the
transmembrane potential drops to -50mV).
 ACh released from motor nerve endings is
unable to generate propagated muscle action
potential leading to flaccid paralysis.
 In other words a zone of inexcitability is created
around the end plate preventing the activation of
the muscle fibre.
 In birds, the area of depolarization is more
extensive and spastic paralysis occur.
 In humans, dogs, rabbits, in slow contracting
soleus muscle of cat, the depolarizing agents
produce dual mechanism of neuromuscular
blockade which can be divided into two phases
 Phase I Block:
◦ Rapid in onset
◦ Results from persistent deporization of muscle end plate
and has feature of classical depolarization blockade
◦ depolarization declines shortly afterwards and
repolarization occurs gradually despite continued
presence of drug at the receptor, but neuromuscular
transmission is not restored and Phase II block
supervenes
 Phase II Block:
◦ Slow in onset
◦ Results from desensitization of the receptors to ACh.
◦ Superificially resembles block produced by d-
tubocurarine:
◦ Membrane is nearly repolarized, recovery is slow
Suxamethonium/ Succinylcholine
 Ultra short acting muscle relaxant
 Most commonly used muscle relaxant for passing
tracheal tube.
 It induces rapid, complete and predictable
paralysis with spontaneous recovery in ᷉ 5 min.
 Pharmacological actions
 Skeletal muscles:
◦ Nondepolarizing blockers I/V:
 produces muscle weakness followed by flaccid
paralysis.
 Small fast response muscles (fingers, extraocular)
are affected first; paralysis spreads to hands,
feet-arm, leg, neck, face-trunk-intercostal
muscles-finally diaphragm: respiration stops.
◦ Depolarizing blockers
 typically produce fasciculations lasting a few
seconds before inducing flaccid paralysis
 Autonomic ganglia:

◦ competitive blockers:
 produce some degree of ganglionic blockade;

 d-TC has the maximum propensity in this regard.

◦ Depolarizing blockers
 SCh may cause ganglionic stimulation by its agonistic
action on nicotinic R
 Histamine release:
◦ d-TC releases histamine from mast cells.
◦ Increased respiratory tract secretion and bronchospasm
seen after administration of d-TC.

 C.V.S. :
◦ d-Tubocurarine produces significant fall in BP.
◦ This is due to- (i) ganglionic blockade (ii) histamine release
and (iii) reduced venous return-a result of paralysis of limb
and respiratory muscles.
◦ Exceptions are pancuronium and vecuronium which
increases BP because of increased heartrate and slight
sympathetic stimulation.
 G.I.T.:
◦ The ganglion blocking activity of competitive
blockers may enhance postoperative paralytic ileus
after abdominal operations.

 C.N.S.:
◦ All neuromuscular blockers are quaternary
compounds- do not cross blood-brain barrier.
◦ Thus, on i.v. administration no central effects
follow.
◦ However, d-TC applied to brain cortex or
injected in the cerebral ventricles produces
strychnine like effects.
 Pharmacokinetics
 All NMB are quarternary compounds; not
absorbed orally.
 Muscles with higher blood flow receive more drug
and are affected earlier.
 They do not cross placenta or penetrate brain.
 SCh is rapidly hydrolysed by plasma pseudo ChE to
succinyl monocholine and then succinic acid and
choline.
 Toxicity
i. Respiratory paralysis and prolonged apnoea

ii. Flushing is common with d-TC; fall in BP and

cardiovascular collapse can occur

iii. Cardiac arrhythmias and even arrest have

occurred, especially with SCh

iv. Post-operative muscle soreness after depolarizing

blockers
Therapeutic uses
 As an adjuvant to surgical anaesthesia, particularly of the
abdominal wall, so that operative manipulations are
facilitated
 In various orthopaedic procedures such as dislocation
and alignment of fractures
 Convulsions and trauma from electroconvulsive therapy
can be avoided by the use of muscle relaxants without
decreasing the therapeutic benefit. SCh is most
commonly used for this purpose.
 Severe cases of tetanus and status epilepticus, which are
not controlled by diazepam or other drugs may be
paralysed by a neuromuscular blocker
Clinical reversal of Neuromuscular
Paralysis
 Treatment of overdosage of NMB include
◦ immediate and continued artificial respiration
◦ withdrawal of administration of involved agent
◦ Administration of ChE inhibitors such as
neostigmine or endorphonium, if competitive
NMB was used.
◦ 4-AP antagonize curare induced neuromuscular
block.
◦ Combined therapy of low doses of 4-AP and a
ChE inhibitor has considerable potential
application
 Directly acting muscle relaxant
 Dantrolene

 Interfere with the release of Ca 2+ from sarcoplasmic

reticulum

 Interferes with the excitation-contraction coupling

causing skeletal muscle relaxation

 Drug of choice in malignant hyperthermia, a

condition due to persistent release of Ca2+ from SR
 II) CENTRALLY ACTING MUSCLE
RELAXANT

 These are drugs which reduce skeletal muscle tone

by a selective action in the cerebrospinal axis,
without altering consciousness.
 They selectively depress spinal and supraspinal
polysynaptic reflexes involved in the regulation of
muscle tone without significantly affecting
monosynaptically mediated stretch reflex.
 They have no effect on neuromuscular transmission
and on muscle fibres, but reduce rigidity, upper
motor neurone spasticity and hyperreflexia.
Mephenesin group
 Eg. Mephenesin, Carisoprodol
 It cause muscle relaxation in animals without
producing unconciousness
 Called as internuncial neurone blocking agent
because its primary site of action is the spinal
internuncial neurone which modulates reflexes
maintaining muscle tone.
 It has weak analgesia, antipyretic and
anticholinergic action in addition.
 It is not used clinically.
Benzodiazepines
 Eg. Diazepam and others
 It acts in the brain on specific receptors enhancing
GABAergic transmission.
 Muscle tone is reduced by supraspinal rather than
spinal action.

GABA derivative:
 Baclofen
 Primary site of action is spinal cord, where it
depresses both polysynaptic and monosynaptic
reflexes.
 Uses
 In acute muscle spasm (Eg. Sprain, tearing of
tendon)
 Neuralgia, backache
 Anxiety and tension
 Tetanus, spastic neurological disease
 Electroconvulsive therapy
 Orhopedic manipulations
 COMPARATIVE FEATURES

Feature Neuromuscular Central muscle

blockers relaxants
Mech. of Block Inhibit polysynaptic
action neuromuscular reflexes in CNS
transmission
On skeletal Muscle paralysis Reduced muscle
muscle tone, spasmolytic
effect
On CNS No effect Some CNS
depression/sedation

Clinical Short term muscle Chronic spastic

uses relaxation ( eg: conditions, acute
surgical operations) muscle spasms
 ADRENEGRIC NEUROHUMORAL
TRANSMISSION
 Adrenergic (more precisely Noradrenergic')
transmission is restricted to the sympathetic division of
the ANS.
 There are three closely related endogenous
catecholamines (CAs).
◦ Noradrenaline (NA)
◦ Adrenaline (Adr)
◦ Dopamine (DA)
 Catecholamines
 Noradrenaline (NA)
◦ It acts as transmitter at postganglionic sympathetic sites
(except sweat glands, hair follicles and some vasodilator
fibres) and in certain areas of brain.
 Adrenaline (Adr)
◦ It is secreted by adrenal medulla and may have a
transmitter role in the brain.
 Dopamine (DA)
◦ It is a major transmitter in basal ganglia, limbic system, CTZ,
anterior pituitary, etc. and some of the peripheral neurons
to splanchnic and renal vessels.
 Isoproterenol or isoprenaline
◦ It is a synthetic catecholamine.
 Synthesis of Catecholamines
 Noradrenaline is synthesized from the amino acid
Tyrosine in stepwise process.
◦ Tyrosine is an essential amino acid, which is present in
the diet and is also synthesized from phenylalanine.
 The aromatic ring of phenyl alanine is hydroxylated by
the action of an enzyme, phenyl alanine hydroxylase.
◦ Tyrosine is taken up from circulation by an active
transport process (Na+ linked carrier) which is
converted to dihydroxyphenyl alanine (DOPA) by
the enzyme tyrosine hydroxylase.
 This reaction is the rate limiting step in
catecholamine synthesis.
 inhibition by αmethyl- p-tyrosine results in
depletion of Cas
◦ This can be used in pheochromocytoma before surgery
and in inoperable cases.

 All enzymes of CA synthesis are rather nonspecific

and can act on closely related substrates

 DOPA is decarboxylated by enzyme L aromatic

amino acid decarboxylase (dopa decarboxylase) to
dihydroxyphenylethylamine (dopamine).
◦ Conversion of tyrosine to dopa and dopa to dopamine
occurs within the cytoplasm.
 Dopamine is taken up into the storage
granules by an active process from
cytoplasm and is converted by dopamine-β-
hydroxylase to noradrenaline.

 In the adrenal medulla

◦ noradrenaline is released from the granules of
chromaffin cells and is N-methylated within the
cytoplasm by Phenyl ethanolamine N methyl
transferase to from adrenaline.
◦ Adrenaline is localized in another type of
intracellular storage granules prior to its release
from adrenal medulla.
 Liver/blood

Na linked
carrier

Adrenergic neuron

VMAT

Synaptic vesicle

Adrenal medulla
‘VMAT: vesicular monoamine transporter'
 STORAGE, RELEASE, REUPTAKE
AND METABOLISM

 Storage of CAs
◦ Catecholamines are taken up from the cytoplasm
into granule by an active transport system that is
adenosine triphosphate (ATP) and Mg++ dependent.
◦ Storage within granular vesicles is accomplished by
complexation of the catecholamines with ATP and
specific protein chromogranin.
◦ The intra granular pool of noradrenaline is the
principal source of neuro transmitter release upon
nerve stimulation.
Release of CAs
 Excitation secretion coupling and release of
norepinephrine from adrenergic nerve terminal
◦ dependent upon an inward movement of Ca2+ from
extracellular fluid into cytoplasm of the neuron.

◦ This causes storage fusion of synaptobrevin-syntaxin

complex that causes the release of noradrenaline
along with ATP, chromogranin and peptides
into the junctional cleft by exocytosis.

◦ release is modulated by presynaptic α receptors, of

which α2 inhibitory control is dominant.
 Released noradrenaline migrate across the
synaptic cleft and interacts with specific
adrenergic receptor site on the post junctional
membrane.

 The duration of action of noradrenaline can

be terminated by
◦ active reuptake in to the nerve,
◦ diffusion from the cleft via extra cellular fluid
◦ metabolic breakdown by MAO or COMT
 Uptake of CAs
 mechanism by which NA released from the
nerve terminal is recaptured. This occurs in 2
steps
◦ Axonal uptake
 Active amine pump (NET) is present at the neuronal
membrane which transports NA by a Na+ coupled
mechanism
 It takes up NA at a higher rate than Adr and labelled as
uptake-1.
 The indirectly acting sympathomimetic amines like tyramine,
but not isoprenaline, also utilize this pump for entering the
neurone.
 most important mechanism for terminating the postunctional
action of NA.
 This pump is inhibited by cocaine, desipramine and few other
drugs
 Vesicular uptake
◦ The membrane of intracellular vesicles has
another amine pump the 'vesicular monoamine
transporter' (VMAT-2), which transports CA
from the cytoplasm to within the storage
vesicle.
◦ The VMAT-2 transports monoamines by
exchanging with H+ ions.
◦ The vesicular NA is constantly leaking out into
the axoplasm and is recaptured by this
mechanism
◦ This uptake is inhibited by reserpine, resulting in
depletion of CAs.
 Extraneuronal uptake of CAs (uptake-2)
◦ Carried out by extraneuronal amine transporter
(ENT or OCT3) and other organic cation
transporters OCTl and OCT2 into cells of
other tissues.
◦ In contrast to NET this uptake transports Adr
at a higher rate than NA
◦ Not Na+ dependent and is not inhibited by
cocaine, but inhibited by corticosterone.
◦ It is not of physiological or pharmacological
importance.
Metabolism of CAs
 Part of the NA leaking out from granules
into cytoplasm as well as that taken up by
axonal transport is first attacked by MAO

 NA that diffuses into circulation is first

acted upon by catechol-o-methyl
transferase (COMT) in liver and other
tissues.
 Metabolism of NE & E

Oxidative deamination

O-methylation

Sulphation/glucuronidation

Excreted through urine

Adrenergic Receptors/adrenoceptors

Ahlquist in 1948- two classes designated as α and β

Subtypes
α -α1and α2
β-β1,β2, and β3
α-excitatory in general except GI tract exceptions
are
β-inhibitory except heart

G protein coupled receptors

α1-Gq coupled
α2-Gi coupled
β-Gs coupled
 Second messengers
◦ α1 adrenoceptors
 activate phospholipase C, thus producing inositol
triphosphate and diacyl glycerol as second
messengers.
◦ α2 receptors
 inhibit adenylate cyclase and this decrease cAMP
production.
◦ All types of β adrenoceptor
 stimulate adenylate cyclase thereby increasing cAMP
concentration
 The main effects of receptor activation
◦ α1 adrenoceptors:
 vasoconstriction, pupillary dilation,
 increased piloerection, salivary secretion ( but
scanty and viscous)
 increased tone of intestinal urethral spincture
 hepatic glycogenolysis
◦ α2 adrenoceptors :
 inhibition of transmitter release
 platelet aggregation
 decreased lipolysis, inhibition of insulin release.
◦ β1 Adrenoceptors :
 increase cardiac rate and force of contraction
 vasoconstriction due to renin release

◦ β2 adrenoceptors :
 bronchodilation, mast cell membrane stabilization,
 vasodilation,
 relaxation of visceral smooth muscles
 hepatic gluconeogenesis

◦ β3 receptors :
 increases lypolysis
 ADRE NERGIC DRUGS
(Sympathomimetics)
 These are drugs with actions similar to that of Adr
or of sympathetic stimulation.
 Direct sympathomimetics
◦ They act directly as agonists on α and/ or β
adrenoceptors
◦ Adr, NA, isoprenaline (Iso ), phenylephrine,
methoxamine, xylometazoline, salbutamol and many
others
 Indirect sympathomimetics
◦ They act on adre,nergic neurone to release NA,
which then act on the adrenoceptors
◦ tyramine, amphetamine
 Mixed action sympathomimetics
◦ They act directly as well as indirectly
◦ ephedrine, dopamine, mephentermine.
SYMPATHOMIMETICS
 Another classification of
sympathomimtic amines
 Catecholamine
◦ These compounds have catechol nucleus
◦ direct acting sympathomimetic amines
◦ activate the receptors of effector cells, therefore
adrenergic nerves are not required for their
effects.
◦ epinephrine, nor epinephrine and Isoproterenol.
 Non catecholamines
◦ These compounds lack catechol nucleus
◦ direct or indirect acting compounds
◦ Ephedrine, amphetamines , Phenyl ephrine,
Methoxamine, meteraminol.
 Therapeutic classification of
sympathomimetic agents
 Pressor Agents:
◦ Noradrenaline, Ephedrine, Dopamine, Phenylephrine
 Cardiac Stimulants:
◦ Adrenaline, Isoprenaline, Dobutamine
 Bronchodilators:
◦ Salmeterol, Salbutamol, Terbutaline
 Nasal Decongestants:
◦ Phenylephrine, Oxymetazoline
 CNS Stimulants:
◦ Amphetamine, Dexamphetamine
 Anorectics:
◦ Fenfluramine, Sibutramine
 Uterine Relaxants & Vasodilators:
◦ Ritodrine, Isoxsuprine
 Pharmacologic effects of
Catecholamines
• Heart :
• increases the heart rate by enhancing pacemaker
activity of SA node
• Arrythmia at higher doses
• Increase Blood pressure
• Force of contraction increased
• Increased cardiac output and myocardial oxygen
consumption
• Conduction velocity enhanced
• Reduced refractory period
• When BP rises markedly reflex stimulation of
vagus nervebradycardia.
• Blood vessels :
• vasoconstriction (α) and vasodilation (β2)
• Constriction predominates in cutaneous, muc memb
and renal vasculature

• Blood Pressure :
• NE
• rise in systolic, diastolic and mean BP
• Iso
• β1(cardiac stimulation  rise in systolic pressure) β2
(vasodilation)  fall in diastolic pressure); thus mean BP
falls
• Epi
• high systolic (α) and moderate diastolic pressure (β2
vasodilation)  mean rise in BP
 Biphasic response of adrenaline
1. When adrenaline given intravenously, initially the
concentration of adrenaline is high  So it will act on α1
and β2.
But actions of α1 (vasoconstriction), will predominate over
actions of β2 (vasodilatation)  rise in blood pressure

2. Within few second level of adrenaline will decrease due to

its rapid metabolism and neuronal re- uptake  At lower
concentration only action of β2 will predominate fall in
Blood pressure

3. So initially there will be rise in blood pressure and then

after fall in blood pressure.
This is called biphasic response
 Vasomotor reversal of Dale
 If non-selective alpha blocker is administered  It
blocks the alpha receptors and hence
α1 mediated vasoconstriction is inhibited

 Upon adding adrenaline again  Only

β2 mediated action occur

 So only fall in blood presser is seen, rather than

biphasic response

 This is called vasomotor reversal of Dale

Re-reversal of Vasomotor reversal of Dale

• When non Selective Beta Blocker is given

(instead of non selective alpha blocker)  It
blocks the β2 receptors, hence β2 mediated
vasodialatation will be blocked

• When adrenaline is given  Only α1 mediated

action occur- vasoconstriction - rise in
lood pressure rather than biphasic response

• 1. If Only fall in BP- Vasomotor reversal of Dale

2. Only Rise in BP - Re-reversal of Vasomotor
reversal of Dale.
 Respiration
• Adrenaline and Isoprenaline
•  potent bronchodilators (β2)
• Adrenaline by aerosol  additionally decongest
bronchial mucosa (α1) .
• Epi directly stimulate resp centre in the brain
• Toxic doses of Epi pulmonary oedema by
shifting blood from systemic to pulmonary
circulation
 Gastro Intestinal System
◦ Adrenergic drugs inhibit GI activity.
◦ The frequency and amplitude of peristaltic
contractions in the gut are decreased due to
relaxation of smooth muscles (activation of β-R)
◦ GI spinctures are contracted by α
sympathomimetic agents.
◦ Digestive juices are decreased by α –Sympathetic
agents.
◦ Salivary glands are stimulated but saliva is scanty
and viscous.
 Uterine muscle
◦ Response is variable.
◦ In cats, epinephrine relax nongravid uterus but
contracts gravid uterus.
◦ Isoproterenol has relaxant effect in uterine muscles.
◦ Selective β2 agonist like Ritodrine is used to relax
uterus and delay premature labor.

 Spleen
◦ Smooth muscles of the splenic capsule is contracted
by epinephrine and nor epinephrine via α effects.
◦ This effect is demonstrated in dogs.

 Skeletal muscle
◦ Neuromuscular transmission is facilitated .
◦ direct effect on muscle fibres is exerted
through β2 receptors and differs according to
the type of fibre.
◦ The action on rapidly contracting fibres is to
prolong the active state and increase the
tension developed
◦ β2 agonists produce tremors
 Ocular effects
◦ Mydriasis occurs due to sympathetic
stimulation.
◦ Contraction of radial muscles of iris (α1)

 CNS
◦ Catecholamines do not cross blood brain
barrier.
◦ Certain noncatecholamines like amphetamine
readily cross blood barrier and elicit CNS
stimulation.
 Metabolic effects
◦ In mammal, overall calorigenic effect
◦ Glycogenolysis occurs in liver, skeletal muscles
and cardiac muscle.
◦ Fatty acid mobilization and lactic acid formation
occurs.
◦ Accordingly blood glucose, free fatty acid and
lactic acid increased.
◦ Insulin secretion from the pancreas decreases.
 The metabolic activities of catecholamines have been
associated with alterations in tissue concentration of
cAMP.
 In liver and muscle tissue adenyl cyclase activity is
increased by catecholamines resulting in accelerated
conversion of ATP to cAMP.
 Preparations
 Epinephrine :
◦ Free base obtained from adrenal medullary extracts of
domestic farm animals or chemically synthesized
◦ relatively insoluble in water but forms water soluble salt
epinephrine hydrochloride.
 Epinephrine Injection and Epinephrine solution
◦ aqueous solutions of epinephrine hydrochloride 1:1000
(1mg/ml).
 Sterile epinephrine suspension
◦ sterile suspension of epinephrine, usually 2 mg/ml in
sesame or peanut oil for intramuscular injection only
 Epinephrine bitartarate
◦ available as aerosol and ophthalmic solutions.
 Nor epinephrine bitartarate
◦ white crystalline powder soluble in water.
 Nor epinephrine bitartarate injection –
◦ sterile aqueous solution containing 0.2% (2mg/ml)
of the salt equivalent to 1mg/ml nor epinephrine base.
 Isoproterenol hydrochloride
◦ water soluble hydrochloride salt.
 Isoproterenol hydrochloride inj.
◦ sterile aqueous solution of Isoproternol for parenteral
injection.
 Isoproterenol hydrochloride tablet
◦ available as 10 and 15 mg tabs.
 Clinical Uses
 With local anesthetic :
◦ Epinephrine is commonly used at a concentration of
1:1,00,000 to 1:20,00,000 in local anesthetic
solutions.
◦ It produces local vasoconstriction and thereby localizes
action and delays absorption of anesthetic.
 Local hemostatic :
◦ Vasoconstrictor effect of epinephrine (1,00,000 to
1,20,000) may be used for control of superficial
bleeding.
 Hypotension :
◦ Used to maintain blood pressure during spinal surgery,
to treat hypotension associated with anaphylactic shock.
 Treatment of cardiac disorders :
◦ Indicated in the treatment of cardiac arrest,
partial or complete AV block.
 Anaphylactic and allergic reactions:
◦ Epinephrine is effective and often life saving in the
treatment of acute anaphylactic shock.
◦ It quickly reverses fall in blood pressure and
cardiac irregularities.
 Bronchial Asthma:
◦ Isoproterenol and epinephrine are useful for
providing immediate relief from bronchial asthma.
◦ These agents activate β2 receptors of the bronchial
smooth muscles and dilate air passages causing
relief from asthma.
 Adrenergic Drugs
(Sympathomimetics)
 Direct acting: NE, E, Isoprenaline
 Indirect acting
◦ Releasing agents: Tyramine, Amphetamine

◦ Uptake inhibitor: Cocaine, Imipramine

◦ MAO inhibitor: Pargyline, Clorgyline, Selegiline

◦ COMT inhibitor: Pyragallol, Entacapone

 Mixed acting: Ephedrine, metaraminol, mephentermine

• Selective α1 agonists: Phenylephrine, Methoxamine

• Selective α2 agonist: Clonidine

• Selective β1 agonist: Dobutamine

• Selective β2 agonists: Terbutaline, Salbutamol

• Non selective α agonist: Oxymetazoline
• Nonselective β agonist: Isoproterenol
• Non selective α and β agonist: Epinephrine
 Catecholamines
Catechol (2 OH groups at
positon 3 & 4 of benzene
ring) + side chain with amine
Mainly have direct action.
Few-mixed action (like
dopamine)
Have high affinity for α
and/or β receptors
Usually have shorter half life Have moderate to longer half
because of their rapid
metabolism
Non catecholamines
Lack one or both OH groups
on benzene ring
Mainly have indirect or mixed
actions and few may have
direct action (like
phenylephrine)
Have moderate to poor
affinity for adrenoceptors
life as these are degraded
slowly
Metabolised mainly by Poor substrates for MAO
MAO or COMT and resistant to COMT
Usually not effective by Most of the drugs are
oral route and are given effective orally
parenterally
Being polar drugs, poorly Easily pass blood brain
penetrate the CNS and barrier and produce
hence have minimal effect significant CNS effects
on CNS
No development of Tolerance develops
tolerance following repeated
administration
DOPAMINE (3,4 dehydroxy phenyl ethyl amine)

 It is a dopamine (Dl and D2) as well as adrenergic α

and β1 (but not β2) agonist.
 At very low IV doses (0.5-2µg/kg/min)
◦ dilates the renal, mesenteric and coronary vascular beds
causing an increase in renal blood flow( through vascular D1
receptors action).
 Higher IV doses (2-10µg/kg/min)
◦ positive inotropic and chronotropic effects on heart and
increases BP ( via stimulation of β1 receptors on heart and
releases noradrenaline).
 At high dose (10µg/kg/min)
◦ Vasoconstriction (activate vascular α1)
 Clinical uses
◦ Useful in the treatment of cardiogenic or septic
shock, renal failure and severe congestive heart
failure.
◦ Cats do not possess D1 receptors, so not effective
in acute renal failure

 Fenoldopam :
 Selective D1 receptor agonist causing
vasodilatation, clinically used in hypertension
 Ephedrine
 An alkaloid obtained from Ephedra vulgaris.
 Mainly acts indirectly but has some direct
action on α and β receptors also.
 I/V administration of ephedrine produces
hemodynamic changes similar to epinephrine.
 Systolic and diastolic pressure increases,
myocardial contractile force increases, heart
rate increases if vagal reflexes are blocked
and increase in cardiac output.
 It is resistant to MAO and Cardiac vascular
effects are observed with oral route
 Repeated injections of ephedrine evoke
progressively diminishing pressor response in
intact animals.
 This condition is called tachyphylaxis.This
may be due to the fact that ephedrine causes
◦ Repeated administration depletes the neuronal pool
of norepinephrine
◦ During stimulation of cardiovascular system, reflex
mechanisms attempt to return haemodynamic
function towards normal
◦ Repeated administration may produce less response
as adrenergic receptors are already occupied by
previously administered ephedrine
 Clinical Use
◦ Ephedrine has longer duration of action.
◦ Due to this it is used to maintain Blood pressure
in shock and spinal anaesthesia.
◦ Ephedrine 1-1.5% can be applied topically on to
congested mucosal membrane to evoke
vasoconstriction and decongestion.
◦ It is effective in allergic condition.
 It is included in cough suppressant preparation for relief
from bronchiolar congestion.
◦ Also used in urinary incontinence.
 Pseudoephedrine :
◦ Mainly used as a decongestant in upper
respiratory tract problems associated with
profuse secretion
◦ useful in cats suffering from allergic rhinitis

 Phenylpropanolamine:
◦ Pharmacologically similar to ephedrine
◦ similar in potency to ephedrine with less CNS
effects,
◦ used to treat urinary incontinence in dogs and
nasal decongestant in small animals
 Meteraminol
◦ mixed acting sympathomimetic amine
◦ action on the vascular α adrenergic receptors
◦ Their pressor effects on systolic and diastolic
blood pressure will be due to peripheral
vasoconstriction and increased peripheral
resistance.
◦ Reflex bradycardia usually results.
◦ used as pressor agents.
◦ Metaraminol is having negligible cardiac and
central action,
 Phenylephrine
◦ direct acting α1 receptor sympathomimetic
amine.
◦ causes peripheral vasoconstriction due to
direct activation of α1 receptors of blood
vessels.
◦ Systolic and diastolic blood pressure increases,
reflex bradycardia occurs.
◦ less potent pressor agent than nor epinephrine
but has longer duration of action.
◦ It is a mydriatic agent and reduces the
intraocular pressure.
◦ Also used a nasal decongestant.
 Methoxamine
◦ Directly acting sympathomimmetic with
relatively selective α1 receptor action.

◦ Unlike phenylephrine, methoxamine slightly

higher doses has some β receptor blocking
action.

◦ primarily used in the treatment of hypotensive

states in surgery involving inhalant general
anaesthetics
 Imidazoline derivatives used as nasal
decongestants:
◦ These are α1 receptor agonsits
◦ Eg: Xylometazoline, Oxymetazoline, Naphazolin
◦ Regular use of these agents for long periods
should be avoided because
 mucosal ciliary function is impaired: atrophic rhinitis
and anosmia can occur due to persistent
vasoconstriction.
 They can be absorbed from the nose and produce
systemic effects-CNS depression and rise in BP.
◦ These drugs should be used cautiously in
hypertensives and in those receiving MAO
inhibitors.
 α2 - Selective agonists

 CNS contain α2 receptors which modulate

CNS perception of pain as well as level of
sedation.
 Activation of α2 receptor by α2 agonist can
lower blood pressure.
 In veterinary medicine, α2 agonists are used
for their sedative and analgesia properties.
 Hence it is being used for the chemical
restraint of animal
 Clonidine
◦ Rapid IV injection causes a transient increase in BP
followed by a more sustained hypotensive responsive.
◦ In CNS, activates the lower brain stem α2 receptors that
suppress release of NE.
◦ Also, activates the prejunctional α2 receptors that
suppress release of NE from peripheral nerve endings.
◦ Produces bradycardia by stimulating parasympathetic
outflow
◦ Used as an Antihypertensive agent
◦ Possess central sedative and analgesic effect –
preoperative sedation & anxiolysis, drying of secretions
and analgesia
 Xylazine
◦ Structurally related to clonidine,
◦ α2- receptor agonist, central sedative- analgesic with
muscle relaxant properties
 Dobutamine
 A synthetic catecholamine (derivative of DA,)
but not a D1 or D2 receptor agonist.
 Relatively selective β1 agonist.
 CO is improved without accompanying increase
in heart rate.
 dose related increase in myocardial contractility
 It is used as an inotropic agent in pump failure
accompanying myocardial infarction, cardiac
surgery, and for short term management of
severe congestive heart failure.
 β2 Selective Stimulants
◦ Bronchodilators :
 Salbutamol, terbutaline, salmeterol,
Formoterol

◦ Uterine relaxants
 Ritodrine, Isoxsuprine (also a vasodilator)
β2 Selective Stimulants
relax smooth muscles of bronchi and uterus and
blood vessels of skeletal muscles without producing
significant cardiac stimulation
β2 selectivity is only relative; high doses-exhibit
β1 action on heart tachycardia
Also suppress release of leukotrienes & histamine
from mast cell
Widely used in vet & human practices
Primarily used in bronchial asthma
 As uterine relaxant to delay premature labour;
Ritodrine is the preferred drug
 The most important side effect is muscle tremor;
tachycardia and arrhythmias are less likely.
Clenbutarol
 Better oral absorption
 Approved bronchodilator in horses-COPD
 Also in other species-allergic respiratory
diseases,resp.infection & inflammation
 Human-bronchodilator & tocolytic
 Off label use as a weight loss drug
 Prohibited in animals intended for food
 Salbutamol(albuterol)
 has highest ratio of β2: β1action ( about 10 times)
 Properties similar to terbutaline
 But minimal cardiac stimulant action
 Used principally in dogs & cats
 Also in horses-oral,inhalation
 Human-asthma & COPD- oral & inhalation
 Iv-tocolytic in human
Orciprenaline(metaproterenol)
 Moderately selective
 Bronchodilator & tocolytic
Salmeterol
 Long acting-8 hours
 Structurally related to salbutamol
 High lipophilicity, β2 affinity , selectivity &
potency
 Available either alone or in combination
with corticosteroids
 RELEASING AGENTS
Amphetamine
◦ pharmacological profile similar to ephedrine;
◦ orally active with long duration
◦ Powerful CNS stimulant effect - include increased
alertness, decreased fatigue, elevation of mood, ability to
concentrate, euphoria, insomnia.
◦ Stimulates the respiratory centre, especially if it is
depressed.
◦ D-isomer (dextroamphetamine) is 3-4 times more potent
than L-isomer in producing CNS effects
◦ Athletic performance is improved temporarily followed by
deterioration. It is one of the drugs included in the 'dope
test' for athletes
 Peripheral effects on heart and BP are not significant at the
usual doses (which cause only slight rise in BP)
 produce marked psychological but little or no physical
dependence
 Peripheral component of toxicity includes vasomotor
effects, palpitation, arrhythmias, vomiting, abdominal cramps
and vascular collapse.
 Death is usually preceded by convulsions and coma.
 l-isomer is more potent than d-isomer to produce
peripheral effects
 In animals , it is used as analeptic.
 The central actions are largely mediated by release of NA
in the brain
 Treatment of amphetamine toxicity includes administration
of chlorpromazine which controls both central as well as
peripheral a adrenergic effects
 Methamphetamine
◦ Chemically and pharmacologically related to
amphetamine and ephedrine.
◦ At low doses, it causes CNS stimulation without
peripheral actions.
◦ At high doses, increases systolic and diastolic
pressure, cardiac output is increased, heart rate
reflexly slow down. Mainly used to get central
effects with less prominent peripheral actions.
 Methylphenidate
◦ Piperidine derivative structurally related to
amphetamine.
◦ It is a mild CNS stimulant with more prominent
effects on mental than on motor activities.
◦ Used in the treatment of narcolepsy and
attention deficit /hyperactivity disorder.
 Dexmethylphenidate & Pemoline
◦ Elicits changes in the CNS functions with
minimal effects on cardiovascular systems.
◦ Used in the treatment of narcolepsy and
attention deficit /hyperactivity disorder
 UPTAKE INHIBITORS

Tricyclic antidepressants
 Block noradrenaline and 5HT uptake by neurons
Cocaine
 Alkaloid obtained from Erythroxylum coca with local
anaesthetic action
 Also blocks Na+-K+-activated ATPase required for
transport of NE into neurons across the cell
membrane (uptake1)
 MAO INHIBITORS
Selegiline/Deprenyl
 Selective MAO-B inhibitor ; non-competitive and
long lasting inhibition
 Antidepressant and mood elevation effects.
Maintains the level of dopamine and CRH thereby
reducing the amount of ACTH – used in pituitary
dependent hyperadrenocorticism

COMT INHIBITORS

Entacapone
 Used in Parkinson disease along with
levodopa/carbidopa
 SYMPATHOLYTICS OR
ANTIADRENERGIC DRUGS

 Adrenergic antagonists
◦ interact with adrenergic receptors and by occupying
these receptors do not allow adrenergic agonist
access to the receptor
 Adrenergic neuron blocking drugs
◦ do not block the receptor but they act
presynaptically at the nerve terminal to cause a
decreased release of endogenous neurotransmitter
norepinephrine.
 Receptor blockade
 α blockade abolishes pressor response to norepinephrine.
 Epinephrine is a mixed α, β agonist.
 α blockade by phentolamine not only prevents the pressor
response to epinephrine, it actually converts it to a depressor
response.
 This is called ‘epinephrine reversal’ or Dale’s vasomotor reflex
since the α receptors are occupied by phentolamine, only the
vasodilator β2 receptors are available for interaction with
epinephrine.
 Thus epinephrine cause fall in BP.
 α blockade does not affect the β2 receptor mediated
depressor effect and cardiac stimulant effect of isoproterenol
and it does not affect.
 ADRENERGIC ANTAGONISTS
 Non selective α blocking agents
◦ Nonequilibrium type
◦ Haloalkylamine derivatives : Phenoxybenzamine,
(Nonequilibrium type)
◦ Equilibrium type
◦ Imidazoline derivatives : Phentolamine, Tolazoline
◦ Ergot derivatives: Ergotamine,
Dihydroergotamine, dihydroergotoxine

 Selective α blocking agents

◦ Selective α1 antagonists: : Prazosin, Terazozin, doxazosin
and Tamsulosin
◦ Selective α2 antagonists: Yohimbine
 General effects of α blockers
 Blockade of α1 receptors cause fall in BP.
◦ reduces peripheral resistance and CO- fall in BP-hypovolemia
accentuates hypotension.
◦ block pressor action of epinephrine which produces only fall in
BP due to β mediated vasodilation. – vasomotor reversal of
dale.
 Reflex tachycardia due to fall in mean arterial BP and increased
release of NA due to blockade of presynaptic α2 receptors
 Hypotension produced by α blockers reduces renal blood flow.
 Intestinal motility is increased – diarrhoea occurs
 Nasal stuffiness and miosis result from blockade of α receptors
in nasal blood vessels and in radial muscles of iris respectively.
 α blockers have no effect on adrenegically induced cardiac
stimulation, bronchodilation and vasodilation because these are
mediated through β receptors.
Phenoxybenzamine
 blocks both α1 and α2 adrenoceptors.
 reacts with α adrenoceptors and other biomolecules by
forming strong covalent bonds. The a blockade develops
gradually (even after i.v. injection) and lasts for 3-4 days.
 cause progressive decrease in peripheral resistance
 Cutaneous blood flow increases but little effect on skeletal
and cerebral blood flow.
 Decreased peripheral resistance provokes an increase in
cardiac output. Tachycardia may be accentuated by enhanced
release of noradrenaline due to prejunctional α blockade.
 Phenoxybenzamine causes relaxation of nictitating
membrane and blocks pupillary dilation
 Clinically used or the treatment of urinary retention and in
treatment of hypertension associated with
phaechromocytoma
Tolazoline:
 It is a weak to moderate α1 and α2 receptors blocking drug.
 It is direct vasodilator and cardiac stimulant.
 Tolazoline cause peripheral vasodilation and decrease in
peripheral resistance.
 Heart rate increases due to direct cardiac stimulant effect.
 Tolazoline stimulates GI smooth muscle and salivary,
lachrymal and sweat gland secretion will be increased.
 Also blocks 5HT receptors on intestine – Ach like action.
 Primarily used to increase blood flow in peripheral
vasospastic conditions like frost bite
Phentolamine
 It is a close congener of tolazoline.
 Its action on α adrenoceptors is more
potent than tolazoline.
 Quick and short acting α blocker for
diagnosis and intraoperative management of
phaeochromocytoma,
 used for the control of hypertension and
most suitable α blocker for local infiltration
to counteract vasoconstriction and dermal
necrosis.
Ergot alkaloids
 Ergot is a fungus (Claviceps purpurea) that
parasitizes rye and other grains.
 Ingestion of contaminated grain products
has caused outbreaks of ergotism in humans
and animals.
 Ergot is a mixture of different types of
alkaloids that have biologic effects.
 These are derivative of lysergic acid or
isolysergic acid.
There are different groups of alkaloids.
◦ 1. Ergotamine group:
 mainly adrenergic blocking action, No effect on non
vascular smooth muscles.
 Eg: Ergotamine, Ergosine
◦ 2. Ergometrine group:
 weak adrenergic blocking activity, but are powerful
stimulants of uterus (myometrium).
 Eg: Ergometrine ( Ergonovine)
◦ 3. Ergotaxine group:
 Stimulate vascular smooth muscle and uterus.
 Eg: Ergocrytpine, Ergocristine, Ergocornine
◦ 4. Dihydrogenation of lysergic acid nucleus
 increases adrenergic blocking activity, diminishes smooth
muscle contracting ability
 Eg: dihydroergotamine, dihydroergotoxine
 Ergot alkaloids
◦ adrenergic antagonists with which Dale demonstrated
the vasomotor reversal phenomenon.
◦ The amino acid alkaloids ergotamine and ergotoxine
are partial agonists and antagonists at α adrenergic,
serotonergic and doparninergic receptors.
◦ The amine alkaloid ergometrine has no α blocking
activity
 Natural ergot alkaloids
◦ produce long lasting vasoconstriction which
predominates over their α blocking action- peripheral
vascular insufficiency and gangrene of toes and fingers
occurs in ergotism.
 Ergotoxine is a more potent α blocker and
less potent vasoconstrictor than
ergotamine.
 Hydrogenation reduces vasoconstrictor and
increases α blocking activity.
 α blockade produced by clinical doses of
ergot alkaloids is low grade and short
lasting; they are not employed for this
purpose
 The principal use is in migraine
Prazosin
 It is highly selective α1 blocker.
 It blocks vasoconstriction and produce fall in BP.
 It decreases peripheral vascular resistance and
lowers BP.
 Relaxation of both arterial and venous smooth
muscle.
 Prazosin does not produce reflex tachycardia.
 Decreased sympathetic flow to the heart has been
demonstrated.
 The adverse effect of Prazosin is first dose effect
characterized by marked hypotension and syncope.
Yohimbine
 Competitive antagonist that selectively block
α2- adrenergic receptors.
 structurally resembles reserpine.
 It is obtained from Pausinystalia yohimbe and also
root of Rauwolfia.
 short acting complete blockade of α2
adrenergic receptors and blocking central α2
adrenergic receptors, it causes norepinephrine
release and increased sympathetic outflow.
 Due to vasodilator property yohimbine is used as
aphrodisiac in human beings.
 Yohimbine is used in animals to revert the
effect of xylazine over dosage.
 It is also useful as an antidote to amitraz
insecticide (α2-adrenergic receptor agents)
poisoning.
Atipamezole:
 selective α2- adrenergic receptors blocker.
 Recommended in veterinary medicine for
reversal of adverse effects of medetomidine
Uses of α blockers.
 Pheochromocytoma:
◦ It is a tumour of adrenal medullary cells.
◦ Phenoxybenzamine can be used as definite therapy.
 Hypertension:
◦ Phentolamine and Phenoxybenzamine are of great value.
 Secondary Shock:
◦ Shock due to blood or fluid loss in accompanied by reflex
vasoconstriction.
 Peripheral vascular diseases :
◦ Phentolamine, Prazosin and Phenoxy benzamine.
 Congestive heart failure :
◦ The vasodilator action of prazosin affords symptomatic
improvement in the short term.
 β Adrenergic Blocking Agents
 Dichloroisoproterenol (DCI)
◦ first drug demonstrated to cause a specific
blockade of β adrenergic receptors
◦ Show considerable agonistic property and hence
not suitable for clinical use.
 Propranolol
◦ Propranolol blocks β1 and β2 receptor
 All β blockers are competitive antagonists.
 First β1 selective agent was Practolol
◦ but it was withdrawn soon after release due to
oculo mucocutaneous syndrome.
 Classification
◦ Non selective β adrenergic receptor
antagonists:
 Propranolol, Nadolol, Pindolol, timolol,
sotalol
◦ Selective β Adrenergic receptor
antagonists.
 Selective β1 antagonists
Metoprolol, atenolol, esmolol, Acebutolol
 Selective β2 receptor antagonists
Butoxamine
Non selective β adrenergic antagonists
◦ Propranolol is taken as prototype.

◦ Propranolol

 most commonly used β adrenoceptor

antagonist.

 It interact with β1 and β2 receptors with equal

affinity.

 It lacks intrinsic sympathomimetic activity.

 Pharmacological actions
Heart:
◦ Propranolol decrease heart rate, force of contraction and
cardiac output.
◦ Cardiac work and oxygen consumption is reduced.
◦ Total coronary blood flow is reduced. Propranolol
abbreviates refractory period of myocardial fibres and
decreases automaticity.
Blood vessels
◦ Total peripheral resistance is increased initially and cardiac
output reduced.
◦ With continued treatment ,vessels gradually adapt to
chronically reduced cardiac output so that total peripheral
resistance decreases and both systolic and diastolic BP fall
 Other mechanisms are
◦ Reduced norepinephrine release from
sympathetic terminals due to blockade of β-R.
◦ Decrease renin release from the kidney
◦ Central action reduces sympathetic outflow
from CNS.
 Respiratory System
◦ Propranolol increases bronchial resistance by
blocking β2 receptors.
◦ Bronchoconstriction is more marked in patients
with chronic bronchitis and bronchial asthma.
 Other effects
◦ Propranolol produces sedation, lethargy and
depression due to central action.
◦ It is a potent local anesthetic like lidocaine but it
is not used clinically due to irritant property.
◦ Plasma triglyceride level is increased.
◦ It inhibits glycogenolysis in heart, skeletal muscle
and in liver.
◦ Prolonged therapy reduce carbohydrate
tolerance by decreasing insulin release.
 Nadolol
◦ Nadolol is a long acting adrenoceptor
antagonist .
◦ It is a polar drug and hence it appears to
produce less central effects.
◦ It is mainly used as antihypertensive
Selective β adrenergic receptor antagonists
◦ β1 adrenergic antagonists
◦ Metoprolol :
 It is the prototype of cardio selective (β1) blockers.
 Its potency to block cardiac stimulation is similar to
propranolol but 50 times higher dose is needed to
block Isoproterenol induced vasodilation.
 Produces Negative inotropic and chronotropic
effects
 reduces plasma renin activity in hypertensive patients.
 Clinically used in arrhythmias, systemic hypertension,
ventricular hypertrophy.
 Atenolol
 It is a selective β1 blocker that is devoid of
intrinsic sympathomimetic activity.
 It is one of the most commonly used β blocker
for the treatment of hypertension and angina.

 Acebutolol
 β1 blocker with significant partial agonistic and
membrane stabilizing properties.
 Acebutolol is rapidly metabolized to an active
metabolite diacetolol which is excreted through
kidney.
 It has got a longer t1/2 (8-12 hrs).
 Esmolol
◦ It is an ultra short acting β1 adrenoceptor
blocker.
◦ Esmolol is devoid of intrinsic sympathomimetic
activity.
◦ Cardiovascular effects include negative inotropic
and chronotropic effects.
◦ Useful for the investigation and immediate
therapy of tachycardia
β2 adrenergic receptor antagonists
 Butoxamine
◦ It is a selective β2 receptor antagonist.
◦ It is structurally related to α agonist
methoxamine.
◦ It blocks β2 mediated effects take vasodilation
and bronchial smooth muscle relaxation.
◦ Butoxamine has no therapeutic application.
 Use of β blockers
 Hypertension
 Angina pectoris
 Cardiac arrhythmia
 Myocardial infarction
 Congestive heart failure
 Pheochromocytoma
 Thyrotoxicosis
 Migraine
 Anxiety
 Glaucoma
 Hypertrophic cardiomyopathy
α , β adrenergic antagonists
 Labetolol
◦ It is the first adrenergic antagonists capable of
blocking both α and β receptors.
◦ However its effect on β receptors predominate.
◦ It is nonselective for β1 and β2 receptors but
selective for α1 receptors.
◦ At low doses it resemble propranolol and at
higher doses, they are like propranolol and
phenoxybenzamine.
◦ It is a potent hypotensive agent which is
specially useful in pheochromocytoma and
clonidine withdrawal hypertension.
ADRENERGIC NEURONBLOCKING AGENTS
◦ These drugs acts presynaptically at nerve
terminal and prevent release of norepinephrine.
◦ They do not block post synaptic adrenergic
receptor and hence the response of direct
acting sympathomimetric amines is not
prevented.
◦ However the effect of indirect acting
sympathomimetic amines are attenuated by
neuron blocking drugs.
 I. Drugs that affect norepinephrine
synthesis
 include α methyl p- Tyrosine, carbidopa and
methyl dopa.
 α methyl p- Tyrosine
◦ α methyl p- Tyrosine (Metyrosine) is a structural
analogues of tyrosine
◦ Instead of tyrosine, α methyl p- Tyrosine is taken
up by adrenergic neurons and block the enzyme
tyrosine hydroxylase.
◦ This result in depletion of catecholamines.
◦ It is used in the treatment of
pheochromocytoma along with
phenoxybenzamine.
Carbidopa
 It is a hydrazine derivation of DOPA which inhibits dopa
decaboxylase enzyme
 prevent formation of dopamine and noradrenaline.
 Its main use is in the treatment of parkinsonism.

α methyl dopa
 It is an analogue L-dopa, the precursor dopamine and
norepinephrine.
 α methyl Dopa is taken up into the adrenergic neurons where it
is biotransformed to α methyl norepinephrine which is stored
in granules.
 Endogenous nor epinephrine may be replaced by α methyl
norepinephrine, false neurotransmitter.
 α methyl norepinephrine is a potent α2 agonist which decrease
sympathetic outflow from CNS.
 II.Drugs that affect Norepinephrine
storage
Reserpine
 Alkaloid from the roots of Rauwolfia serpentina.
 It blocks the transport of NE and other biogenic amines into
synaptic vesicles.
 Norepinephrine accumulates in the cytoplasm and gets degraded
by MAO.
 It produce slowly developing fall in BP and bradycardia.
 The hypotensive action is primarily due to depletion of
norepinephrine from peripheral nerve endings.
 Side effects
◦ parasympathetic overactivity which causes bradycardia,
diarrhea, increased gastric acid secretion and miosis. postural
hypotension, sedation, weight gain, nasal stuffiness and
impotence.
III. Drugs that effect NE release
 Bretylium
◦ Bretylium is an adrenergic neuron blocking drug.
◦ It inhibits the release noradrenaline from
adrenergic nerve terminals.
◦ Bretylium accumulates at nerve terminal and
exert local anesthetic like effect.
◦ Only larger doses cause depletion of
catecholamines.
◦ Bretylium has effect on K+ channels in the heart
and has anti arrhythmic effect.
Guanethidine
 On administration, guanethidine is taken up
by active transport mechanism into
peripheral adrenergic neurons.
 Guanethidine acts by blocking nerve impulse
coupled release of stored norepinephrine
resulting in lowering of blood pressure
referred to as Bretylium like effect.
 Guanethidine displaces norepinephrine from
storage vesicles which decrease BP referred
to as tyramine like effect.
 Displacement of norepinephrine leads to
gradual depletion exhibiting reserpine like
effect.
 Guanethidine blocks NE uptake mechanism at
the axonal membrane.
 During chronic administration, guanethdine
acts as substitute neurotransmitter or false
neurotransmitter in that it depletes normal
transmitter and is released.
 At large doses, guanethidine causes structural
damage to adrenergic neurons.
 Guanethidine is used in antihypertensive
therapy in human.
 DRUGS THAT INHIBIT
NORADRENALINE REUPTAKE

 Tricyclic antidepressants
 Block NE and 5HT uptake into neurons

 Cocaine
 Block the Na + - K + activated ATPase across
the cell membrane of the adrenergic neuron