Drugs Acting on the

Peripheral Nervous System

Drugs Acting on the Peripheral
Nervous System

The peripheral nervous system consists of the nerves that branch out from the
brain and spinal cord. These nerves form the communication network between the
CNS and the body parts.
The peripheral nervous system is further subdivided into the somatic nervous
system and the autonomic nervous system. The somatic nervous system consists
of nerves that go to the skin andmuscles and is involved in conscious activities.
The autonomic nervous system consists of nervesthat connect the CNS to the
visceral organs such as the heart, stomach, and intestines.

NEURO-HUMORAL TRANSMISSION - Neurohumoral transmission implies

that nerves transmittheir message across synapses and neuro-effector junctions
by the release of humoral chemical messengers.

Steps in neurohumoral transmission:

1. lmpulse conduction :
The resting transmembrane potential (-70 mV) is established by high K*
permeability of axonal membrane and high axoplasmic concentration of this ion
coupled with low Na* permeability and its active extrusion from the neuron
stimulation or arrival of an electrical impulse causes a suddenincrease in Na*
conductance depolarization and overshoot (reverse polarization, inside becoming 20
mV positive); K* ions then move out in the direction of their concentration
gradient & repolarization occurs. Ionic distribution is normalized during the
refractory period
by the activation of Na* K* pump.
The action potential (AP) thus generated sets up local circuit currents which
activate ionic channels at the next excitable part of the membrane (next node
of
Ranvier in myelinated nerve)and the AP is propagated without decrement.
 2. Transmitter release:
The transmitter (excitory or inhibitory) is stored in prejunctional nerve
endings within sympathetic vesicles. Nerve impulse promotes fusion of
vesicular and neuronal membranes through Ca+2 entry which fluidizes
membranes.
All contents of the vesicle transmitter, enzymes and other proteins are
extruded
(exocytosis) inthe junctional cleft. The release process can be modulated by the
transmitter itself and by other agents through activation of specific receptors
located on the prejunctional membrane.

Example : Noradrenaline (NA) release is inhibited by NA (receptor), dopamine,

adenosine, prostaglandins and enkephalins while isoprenaline (B2 receptor)
and angiotensin AT1 receptor)increase NA release.

3. Transmitter action on post junctional membrane:

The released transmitter combines with specific receptors on the postjunctional
membrane anddepending on its nature induces an excitatory
postsynaptic potential (EPSP) or an inhibitory postsynaptic potential
(IPSP).
A) EPSP: Increase in permeability to all cations -> Na* or Ca2* influx
(through fast or slow channels) causes depolarization followed by K*
efflux. These ionic movements are passive as theflow is down the
concentration gradients.
B) IPSP: Increase in permeability to smaller ions, i.e. K* and Cl- (hydrated
K+ ion is smaller thanhydrated Na* ion) only, so that K* moves out and
Cl- moves in (in the direction of their concentration gradients) resulting
in hyperpolarization.
4.Post junctional activity:
suprathreshold EPSP generates a propagated postjunctional AP which results in
nerve impulse (in neuron), contraction (in muscle) or secretion (in gland). An IPSP
stabilizes the postjunctionalmembrane and resists depolarizing stimuli.

5. Termination of transmitter action : Following its combination with the

receptor, the transmitter iseither locally degraded (e.g. ACh) or is taken back
into the prejunctional neuron by active uptake or diffuses away (e.g.
NA,GABA).
 Cholinergic drugs
(Cholinomimetics)
These are the drugs which produces actions similar to that of ACh, either by
directly or indirectly interacting with cholinergic receptors or by increasing
availability of Ach at these sites ( anticholinesterases ).
Classification of Cholinergic drugs

Pharmacological actions of Cholinergic drugs:

A. Muscarinic actions:
a. Heart
 ACh hyperpolarizes the SA nodal cells and decreases their rate of
diastolic depolarization. As aresult, rate of impulse generation is reduced-
bradycardia or even cardiac arrest may occur.

b. Smooth muscle
 Smooth muscle in most organs is contracted. Tone and peristalsis in
the
gastrointestinal tract is increased and sphincters relax →abdominal
cramps and evacuationof bowel.
 Peristalsis in ureter is increased.
 Bronchial muscles constrict, asthmatics are highly sensitive →
bronchospasm, dyspnoea, precipitation of an attack of
bronchial asthma.
 c. Glands

 Secretion from all parasympathetically innervated glands is increased,

sweating, salivation, lacrimation, increased tracheobronchial and gastric
secretion.
 The effect on pancreatic and intestinal glands is not marked. Secretion of
milk and bile is not affected.

d. Eye
 Contraction of circular muscle of iris resulting in miosis.
 Contraction of ciliary muscle causing spasm of
accommodation,
increased aqueous outflow facility, reduction in intraocular tension
(especially in glaucomatous patients).

B. Nicotinic actions
1. Autonomic ganglia Both sympathetic and parasympathetic ganglia are
stimulated. High dose of ACh given after atropine causes tachycardia and rise
in BP dueto stimulation of sympathetic ganglia and release of
catecholamines.

2. Skeletal muscles Iontophoretic application of ACh to muscle endplate

causes contraction of the fibre.

3. CNS actions
ACh injected i.v. does not penetrate blood-brain barrier and no central effects
are
seen. However, direct injection into the brain produces arousal response followed
by depression.

Uses -
Indirect-acting cholinergic agonists are indicated for the following
medical conditions:
a. Treatment of myasthenia gravis, antidote for nondepolarizing
neuromuscular junction blockers,increased survival after exposure
to nerve gas
b. Treatment of mild to moderate Alzheimer’s disease.

Contraindications and Cautions

The following are contraindications and cautions for the use of indirect-
acting cholinergic agonists:
 a. Allergy
b. Bradycardia, intestinal/urinary tract obstruction.
c. Pregnancy
d. Asthma, coronary disease, peptic ulcer, arrhythmias, epilepsy,
parkinsonism.
e. Hepatic or renal dysfunction

Anti-Cholinergic drugs
(Cholinolytics)
The Anti-Cholinergic drugs is restricted to those which block actions of
ACh on automatic effectors and in the CNS exerted through muscarinic
receptors.
Classification of Anti-Cholinergic drugs
1. Natural alkaloids:- Atropine, Hyoscine (Scopolamine).

2.Semisyntheticderivatives:- Homatropine, Atropine methonitrate,

Hyoscine butyl bromide,Ipratropium bromide, Tiotropium bromide.

3. Synthetic compounds
(a) Mydriatics: Cyclopentolate, Tropicamide.
Quaternary
(b) Antisecretory
(i) compounds: Propantheline, Oxyphenonium,
- antispasmodics:
Clidinium, Pipenzolatemethyl bromide, Isopropamide,
Glycopyrrolate
(ii) Tertiary amines: Dicyclomine, Valethamate, Pirenzepine
(iii) Vasicoselective: Oxybutynin, Flavoxate, Tolterodine
(iv) Antiparkinsonian: Trihexyphenidyl (Benzhexol), Procyclidine,
Biperiden
Atropine

Atropine is a prescription medicine used to treat the symptoms of low heart rate
(bradycardia), reducesalivation and bronchial secretions before surgery or as an
antidote for overdose of cholinergic drugs.

Pharmacological actions of atropine :

1. CNS
 Atropine has an overall CNS stimulant action. However, these effects
are
 not appreciable at lowdoses which produce only peripheral effects because
of restricted entry into the brain. Hyoscine produces central effects
(depressant) even at low doses.
 Atropine stimulates many medullary centres -vagal, respiratory, vasomotor.
 It depresses vestibular excitation and has antimotion sickness property.

2. Eye:

 The autonomic control of iris muscles and the action of mydriatics as

well as miotics is illustrated.
 Topical instillation of atropine causes mydriasis, abolition of light reflex
and cycloplegia lasting7-10 days. This results in photophobia and
blurring of near vision.
 The intraocular tension tends to rise, especially in narrow
angle glaucoma.

3. CVS: -
 Most prominent effect is to cause tachycardia.

4. Smooth muscles :-
 All visceral smooth muscles that receive parasympathetic motor
innervation are relaxed by atropine.

5. Glands :-
Atropine markedly decreases sweat, salivary, tracheobronchial and lacrimal
secretion.

6. Body temperature :-
Rise in body temperature occurs at higher doses. It is due to both inhibition
of sweating as well as stimulation of temperature regulating centre in the
hypothalamus.

7. Localanaesthetic :-
Atropine has a mild anaesthetic action on the cornea.

Uses -
Atropine is used for the treatment of poisoning by susceptible
organophosphorus
nerve agents havinganticholinesterase activity as well as organophosphorus
or carbamate insecticides in adults and pediatric patients.
Contraindications
 Fast heartrate
 High pressure in the eye (glaucoma)
 Abdominal blockage (pyloric obstruction)
 Dry mouth
 Blurred vision
 Sensitivity to light
 Lack of sweating
 Dizziness
 Nausea

Adrenergic Drugs
(Sympathomimetics)
These are drugs with actions similar to that of Adrenaline or of
sympathetic stimulation.

Classification Of Adrenergic Drugs

1. Direct sympathomimetics: They act directly as agonists on α and/or β
adrenoceptors— Adrenaline, NA, isoprenaline (Iso), phenylephrine,
methoxamine, xylometazoline, salbutamol and many others.

2. Indirect sympathomimetics: They act on adrenergic neuron to release

NA, which then acts onthe adrenoceptors—tyramine, amphetamine.

3. Mixed action sympathomimetics: They act directly as well as indirectly—

ephedrine, dopamine, mephentermine.

Pharmacological Action -
4. Heart – Adrenaline increases heart rate by enhancing the pacemaker
activity of SA node. Force of cardiac contraction is increased.
Noradrenaline injected i.v. usually elicits bradycardia.

2. Blood vessels - Both vasoconstriction (α) and vasodilatation (β2 ) can occur
 depending on the drug, its dose and the vascular bed. Constriction
predominates in cutaneous, mucous membrane and renal beds. Vasodilatation
predominates in skeletal muscles, liver and coronaries.

3. BP - NA causes rise in systolic, diastolic and mean BP; it does not cause
vasodilatation (no β2 action), peripheral resistance increases consistently
due to α action.
Adrenaline given by slow i.v. infusion or s.c. injection causes rise in systolic
but fall in diastolic BP; peripheral resistance decreases because vascular β2
receptors are more sensitive than α receptors. Mean BP generally rises.
Pulse
pressure is increased.

4. Respiration - Adrenaline and isoprenaline, but not NA are

potent bronchodilators (β2 ).
5. Eye - Mydriasis occurs due to contraction of radial muscles of iris (α1 ),
but overall, aqueous formation is reduced and outflow is facilitated.

6. GIT - In isolated preparations of gut, activation of both α and β receptors

produces relaxation. In intact animals and man peristalsis is reduced and
sphincters are constricted.

7. Bladder, prostate, vas deferens Detrusor is relaxed (β2 , β3 ) and trigone is

constricted (α1 ): both actions tend to oppose bladder voiding. The tone
of prostatic muscle is increased by activation of α1 receptors. Rhythmic
contractions of vas deferens and seminal vesicles which participate in
ejaculation are also mediated through α1 receptors.

8. Uterus - Adrenaline can both contract and relax uterine muscle,

respectively through α and β receptors.

9. Skeletal muscle - Neuromuscular transmission is facilitated.

10.CNS – Adrenaline does not produce any marked CNS effects because of
poor penetration in brain, but restlessness, apprehension and tremor may
occur.
Activation of α2 receptors in the brainstem results in decreased sympathetic
outflow → fall in BP and bradycardia.

11.Metabolic - Adrenaline causes glycogenolysis → hyperglycaemia,

hyperlactacidaemia (β2 ), as well as lipolysis → rise in plasma free fatty
acid (FFA) and calorigenesis (β2 + β3 ). These are due to direct action on
liver, muscle and adipose tissue cells. In addition metabolic effects result
from
 reduction of insulin (α2 ) and augmentation of glucagon (β2 ) secretion.

Salbutamol
Salbutamol is a beta-2 adrenergic receptor agonist used to treat asthma,
bronchitis, COPD, as well asprevent exercise induced bronchospasms.

Mechanism of action:
 Salbutamol stimulate β2 adrenergic receptors which are predominant
receptors in bronchial smooth muscle.
 Stimulation of β2 receptors leads to the activation of enzyme adenyl
cyclase that form cyclic AMP (adenosine-mono-phosphate) from ATP
(adenosine-tri-phosphate).

USES -
 Shock/acute hypotension - Shock may be due to haemorrhage, volume
depletion (severe diarrhoea, vomiting, burn, etc.), cardiogenic (myocardial
infarction, arrhythmias, etc.), anaphylactic, neurogenic (in trauma, drug
overdose, etc.) or septic (gram negative bacteraemia, severe infection).
 Along with local anaesthetics – Duration of anaesthesia is prolonged
and systemic toxicity of the local anaesthetic is reduced.
 Control of local bleeding - Local bleeding is minimised.
 Nasal decongestant - In colds, rhinitis, sinusitis, blocked
nose or eustachian tube, α-agonists is used as nasal drops.
 Cardiac uses - Cardiac arrest Adrenaline may be used to stimulate the
heart in case of cardiac arrest due to drowning, electrocution,
Stokes-
Adams syndrome, and other causes.
 Bronchial asthma and COPD - Adrenergic β2 stimulants are the primary
drugs for relief of reversible airway obstruction.
 Allergic disorders - Adrenaline is a physiological antagonist of
histamine which is an important mediator of many acute
hypersensitivity reactions.
It affords quick relief in urticaria, angioedema and is life saving
in laryngeal edema or anaphylaxis.
 Ocular uses - Phenylephrine dilates the pupil, and is used to
facilitate
fundus examination, since cycloplegia is not required for this
purpose.
  Uterine relaxant - Selective β2 stimulants, especially ritodrine, infused i.v.
has been successfully used to postpone labour but maternal morbidity and
mortality may be increased due to its cardiac and metabolic actions
and incidents of pulmonary edema.
 Insulin hypoglycaemia - By its hyperglycaemic action, Adrenaline can
rapidly reverse insulin hypoglycaemia.

Adverse effect / Indication:

 The most common adverse reactions associated with use of
salbutamol
inhalation aerosol arepalpitations, anxiety, tremors, and increased blood
pressure, occasionally resulting in hypertension.

Contraindication:
• Caution when used during pregnancy.

Antiadrenergic Drugs
(Sympatholytics)
These are drugs which antagonize the receptor action of adrenaline and related
drugs. They are competitive antagonists at α or β or both α and β adrenergic
receptors and differ from the “adrenergic neurons blocking agents”, which act
by interfering with the release of adrenergictransmitter on nerve stimulation.
Classification of Antiadrenergic Drugs
I. Nonequilibrium type
(i) β-Haloalkylamines—Phenoxybenzamine.

II. Equilibrium type (competitive)

A. Nonselective
(i) Ergot alkaloids—Ergotamine, Ergotoxine
(ii) Hydrogenated ergot alkaloids—Dihydroergotamine (DHE),
Dihydroergotoxine
(iii) Imidazoline—Phentolamine
(iv) Miscellaneous–Chlorpromazine
B. α1 selective—Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin
C. α2 selective—Yohimbine

α Adrenergic blocking drugs - These drugs inhibit adrenergic responses

mediated through the α adrenergic receptors without affecting those mediated
through β receptors.

General effects of α blockers

1. Blockade of vasoconstrictor –
α1 (also α2 ) receptors reduces peripheral resistance and causes pooling of blood
in capacitance vessels → venous return and cardiac output are reduced → fall in
BP. Postural reflex is interfered with → marked hypotension occurs on standing
→ dizziness and syncope.
2. Reflex tachycardia occurs due to fall in mean arterial pressure and increased
release of NA from cardiac sympathetic neurons due to blockade of
presynaptic α2 receptors.
3. Nasal stuffiness and miosis result from blockade of α receptors in nasal blood
vessels and in radial muscles of iris respectively.
4. Intestinal motility is increased due to partial inhibition of relaxant
sympathetic
influences— loose motion may occur.
5. Hypotension produced by α blockers can reduce renal blood flow → g.f.r. is
reduced and more complete reabsorption of Na+ and water occurs in the
tubules
→ Na+ retention and expansion of blood volume. This is reinforced by reflex
increase in renin release mediated through β1 receptors.
6. Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by
blockade of α1 receptors (mostly of the α1A subtype) → urine flow in patients
with benign hypertrophy of prostate (BHP) is improved.
7. Contractions of vas deferens and seminal vesicles which result in ejaculation
are coordinated through α receptors. As such, α blockers can inhibit
ejaculation; this may manifest as impotence.

Uses -
8. Pheochromocytoma - It is a tumour of adrenal medullary cells. Excess CAs are
secreted which can cause intermittent or persistent hypertension.
Phenoxybenzamine is indicated for the control of episodes of hypertension
and sweating that occur witha disease called pheochromocytoma.

2. Hypertension - Phentolamine/phenoxybenzamine are of great value in

controlling episodes of rise in BP during clonidine withdrawal and that due
to cheese reaction in patients on MAO inhibitors.
2. Benign hypertrophy of prostate (BHP) - The urinary obstruction caused by
BHP has a static component due to increased size of prostate and a dynamic
component due to increased tone of bladder neck/prostate smooth muscle.
3. activation of α1 adrenoceptors in bladder trigone, prostate and prostatic urethra
increases smooth muscle tone, their blockade relaxes these structures, reducing
dynamic obstruction, increasing urinary flow rate and causing more complete
emptying of bladder in many patients of BHP.
4. Peripheral vascular diseases - α blockers do increase skin and to some extent
muscle blood flow in normal individuals, good symptomatic relief is afforded
by prazosin or phenoxybenzamine.
5. Papaverine/Phentolamine Induced Penile Erection (PIPE) therapy for
impotence - In patients unable to achieve erection, injection of papaverine
with or without phentolamine in the corpus cavernosum has been found to
produce penile tumescence to permit intercourse. Oral sildenafil is the
preferred drug now.

Contraindication:
Nasal congestion
Dizziness
Upset stomach
Sexual dysfunction (difficulty ejaculating)
Dizziness
Ear term pregnancy, breast feeding
mothers etc.

Neuromuscular blocking agents

Neuromuscular blocking agents are potent muscle relaxants typically only used
during surgery to prevent muscle movement. They are structurally related to
acetylcholine (the main neurotransmitter in the body) and they cause muscle
relaxation by binding to acetylcholine receptors postsynaptically (which
prevents acetylcholine from binding). This blocks neuromuscular transmission
and causes paralysis of the muscle.
 Classification:

Pharmacological Action –
1.Skeletal muscles - Intravenous injection of nondepolarizing blockers rapidly
produces muscle weakness followed by flaccid paralysis.

2.Autonomic ganglia - The cholinergic receptors in autonomic ganglia are nicotinic,

competitive neuromuscular blockers produce some degree of ganglionic blockade. d-
TC has the maximum propensity, while the newer drugs (vecuronium, etc.) are
practically devoid of it. SCh may cause ganglionic stimulation by its agonistic action
on ganglionic nicotinic receptors.

3.Histamine release - d-TC releases histamine from mast cells. Histamine release
contributes to the hypotension produced by d-TC. Flushing, bronchospasm and
increased respiratory secretions are the other effects.
 4. C.V.S. - d-Tubocurarine produces significant fall in BP.
This is due to—
(a) ganglionic blockade
(b) histamine release and
(c) reduced venous return—a result of paralysis of limb and respiratory muscles.
Heart rate may increase due to vagal ganglionic blockade.

5.G.I.T. - The ganglion blocking activity of competitive blockers may enhance

postoperative paralytic ileus after abdominal operations.

6.C.N.S. - All neuromuscular blockers are quaternary compounds—do not cross

blood-brain barrier. Thus, on i.v. administration no central effects follow.

Uses –
7. The most important use of neuromuscular blockers is as adjuvants to
general anaesthesia.
8. Assisted ventilation: Critically ill patients in intensive care units often need
ventilatory support. This can be facilitated by continuous infusion of
subparalysing doses of a competitive neuromuscular blocker which reduces
the
chest wall resistance to inflation. Vecuronium is most commonly used.
3. 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.
4. Tetanus and status epilepticus, who are not controlled by diazepam or other
drugs, may be paralysed by a neuromuscular blocker.
 Myasthenia Gravis
It is an autoimmune disorder affecting about 1 in 10,000 population, due to
development of antibodies directed to the nicotinic receptors (NR) at the
muscle endplate. The number of free Nm cholinoceptors may be reduced to 1/3
of normal or less and structural damage to the neuromuscular junction.

Symptoms - weakness and easy fatigability on repeated activity, with recovery after
rest. The eyelid, external ocular, facial and pharyngeal muscles are generally
involved first. Later, limb and respiratory muscles get affected.

Drugs used in Myasthenia gravis

 Neostigmine
 Pyridostigmine
 Ambenonium
 Azathioprine
 Edrophonium Injection

Neostigmine:
Neostigmine is a cholinesterase inhibitor, prescribed for Myasthenia Gravis.
Neostigmine and its congeners are the first line drugs used to restore
muscle strength. They improve muscle contraction by allowing ACh
released from prejunctional endings to accumulate and act on the receptors
over a larger area, as well as by directly depolarizing the endplate.
Treatment is usually started with neostigmine 15 mg orally 6 hourly; dose
and frequency is then adjusted to obtain optimum relief from weakness.

Treatment –
 Thymectomy is now generally advised for patients with generalized
weakness, particularly for those with a thymoma and for younger patients.
Thymus may contain modified muscle cells with NRs on their surface,
which may be the source of the antigen for production of anti-NR antibodies
in myasthenic patients.
 Corticosteroids afford improvement in myasthenia gravis by their
immunosuppressant action. They inhibit production of antibodies to NR,
and
 may increase synthesis of new NRs.
 Immunosuppressants like azathioprine and cyclosporine are also
beneficial. Both inhibit NR-antibody synthesis by affecting T-cells.
 Removal of antibodies by plasmapheresis (plasma exchange) is another
approach. It may produce dramatic but often short-lived improvement
in myasthenic crisis.

Local anesthetics
 Local anaesthetics (LAS) are drugs which upon topical application or
local injection cause reversible loss of sensory perception, especially of
pain, in a restricted area of thebody.

Classification:

Mechanism of Action - The LAs block nerve conduction by decreasing the entry
of Na+ ions during upstroke of action potential (AP). As the concentration of the
LA is increased, the rate of rise of AP and maximum depolarization decreases
causing slowing of conduction. Finally, local depolarization fails to reach the
threshold potential and conduction block ensues.
 Local Actions - The clinically used LAs have no/minimal local irritant action and
block sensory nerve endings, nerve trunks, neuromuscular junction, ganglionic
synapse and receptors (non-selectively), i.e. those structures which function
through increased Na+ permeability. They also reduce release of acetylcholine
from motor nerve endings. Injected around a mixed nerve they cause anaesthesia
of skin and paralysis of the voluntary muscle supplied by that nerve.
Uses:
 Local anesthesia is given to reduce the stress associated with surgery, and to
provide pain relief after surgery.
 More commonly, it is used for pain caused by hemorrhoids, fissures,
insect bites, andminor burns.
 It is applied topically for these conditions. It is also indicated
for vaginal, rectal and otological examinations, cystoscopy, and
catheterization.

Systemic Action –
1. C.N.S. - All LAs are capable of producing a sequence of stimulation
followed by depression. Cocaine is a powerful CNS stimulant causing
in sequence euphoria—excitement—mental confusion—restlessness—
tremor and twitching of muscles— convulsions—unconsciousness—
respiratory depression—death, in a dose-dependent manner.
 2. C.V.S. –
Heart - LAs are cardiac depressants, but no significant effects are
observed at conventional doses. At high doses or on inadvertent i.v. injection,
they decrease automaticity, excitability, contractility, conductivity and prolong
effective refractory period (ERP).
Blood vessels - LAs tend to produce fall in BP. At high concentrations,
locally at the site of injection, do cause direct relaxation of arteriolar smooth
muscle.

Uses –
1. Surface anaesthesia - This is produced by topical application of a
surface anaesthetic to mucous membranes or abraded skin. Only the
superficial layer is anaesthetised and there is no loss of motor
function.
2. Infiltration anaesthesia - Infiltration is used for minor operations,
e.g. incisions, excisions, hydrocele, herniorrhaphy, etc.
3. Conduction block - The LA is injected around nerve trunks so that
the area distal to injection is anaesthetised and paralysed.
4. Spinal anaesthesia - Lower abdomen and hind limbs are anaesthetised
and paralysed.
5. Epidural anaesthesia - The spinal dural space is filled with semiliquid
fat through which nerve roots travel. The LA injected in this space acts
primarily on the nerve roots (in the epidural as well as subarachnoid
spaces to which it diffuses) and small amount permeates through
intervertebral foramina to produce multiple paravertebral
blocks.
6. Intravenous regional anaesthesia (Intravascular infiltration anaesthesia,
or Bier’s block) - It is mainly used for the upper limb and for
orthopaedic procedures.

Contraindications:

 Convulsions, tremors, dizziness, blurred vision, nervousness, nausea

 Cardiovascular collapse and cardiac arrest may also occur in some
cases
 Paralysis of the injected area.
 Non-steroidal anti-inflammatory drugs
(NSAIDs)
The nonsteroidal anti inflammatory drugs (NSAIDs) and antipyretic
analgesics are a class of drugs that have analgesic, antipyretic and anti
inflammatory actions in different measures. Incontrast to morphine they do not
depress CNS.

They are also called non-narcotic, non-opioid or aspirin-like analgesics.

Classification:

Aspirin
Aspirin is acetylsalicylic acid. It is rapidly converted in the body to
salicylic acid which isresponsible for most of the action.
It used to treat pain, fever, inflammation, migraines, and reducing the risk of
major adversecardiovascular events.

Mechanism of Action:

Pharmacological Actions -
1. Analgesic, antipyretic, anti-inflammatory actions - Aspirin is a weaker
analgesic (has lower maximal efficacy) than morphine type drugs. However, it
effectively relieves inflammatory, tissue injury related, connective tissue and
integumental pain, but is relatively ineffective in severe visceral and
ischaemic pain.
Aspirin resets the hypothalamic thermostat and rapidly reduces fever by
promoting heat loss (sweating, cutaneous vasodilatation), but does not
decrease heat production.
Anti-inflammatory action is exerted at high doses. Signs of inflammation like
pain, tenderness, swelling, vasodilatation and leucocyte infiltration are
 suppressed.
2. GIT - Aspirin, as well as salicylic acid released from it irritate gastric
mucosa, cause epigastric distress, nausea and vomiting. At high doses, it
stimulates CTZ. Vomiting caused by aspirin has a central component as well.
3. Blood - Aspirin, even in small doses, irreversibly inhibits TXA2 synthesis
by platelets. Thus, it interferes with platelet aggregation and bleeding time
is prolonged to nearly twice the normal value.
4. Cellular metabolism is enhanced, especially in skeletal muscles, due
to uncoupling of oxidative phosphorylation.
5. Glucose utilization is increased resulting in fall in blood glucose
level (especially in diabetics); liver glycogen is depleted.
6. Respiration is stimulated by direct action on respiratory centre as well as due
to increased CO2 production.
7. Respiratory stimulation tends to washout CO2 and produce
respiratory alkalosis.
8. This is compensated by enhanced HCO3 – excretion by kidney. Most adults
receiving 3–5 g/day stay in a state of compensated respiratory alkalosis. Still
higher doses depress respiration while excess CO2 production continues to
cause respiratory acidosis. Increased production of metabolic acids (lactic,
pyruvic, acetoacetic) and dissociated salicylic acid may contribute to
uncompensated metabolic acidosis, since plasma HCO3 – is already low.
Dehydration occurs due to excess water loss in urine, sweating and
hyperventilation. Most children menifest this phase during salicylate
poisoning, while in adults it is seen only in late stages of poisoning. • Aspirin
has no direct effect on heart or circulation, but doses which enhance metabolic
rate, increase cardiac output indirectly. Toxic doses depress vasomotor centre,
so that blood pressure may fall. CHF may be precipitated if cardiac reserve is
low. SECTION 3 214 AUTACOIDS AND RELATED DRUGS • Aspirin
interferes with urate excretion and antagonises the uricosuric effect of
probenecid. However, at high doses (≥ 5 g/day) it may block urate
reabsorption and increase its excretion, but aspirin is not a reliable uricosuria

Uses :

Pain, fever, and inflammation cold, neck and back pain, dysmenorrhea,
headache, tooth pain,sprains, fractures, myositis, neuralgia, synovitis,
arthritis, bursitis, burns, and various injuries.

Contraindication:
 Sensitive Persons
 Children with viral diseases
 Peptic ulcer disease and bleeding disorders
 Chronic liver diseases
 Diabetes, CHF and juvenile Rh. Arthritis
 G-6-PD deficient persons
 Stop prior to surgery