DRUGS ACTING ON THE PERIPHERAL NERVOUS SYSTEM
PREPARED BY MR. ABHIJIT DAS
NEUROHUMORAL TRANSMISSION
Neurohumoral transmission refers to the
communication that occurs between nerve cells and other cells in the body
through the use of chemicals called neurotransmitters and hormones.
STEPS INVOLVED IN NEUROHUMORAL
TRANSMISSION
1.
Action potential generation: When a
nerve cell receives a stimulus, it generates an electrical signal called an
action potential.
2.
Neurotransmitter synthesis: Within the
nerve cell, neurotransmitters are synthesized from precursor molecules.
3.
Neurotransmitter release: Calcium ions
enter the presynaptic neuron, triggering the release of neurotransmitters. Neurotransmitters are released into the
synaptic cleft (the small gap between the presynaptic neuron and the
postsynaptic neuron).
4.
Neurotransmitter binding: The
neurotransmitters released into the synapse bind to specific receptors on the
surface of the receiving cell.
5.
Signal transduction: The binding of
neurotransmitters to receptors on the receiving cell triggers a series of
intracellular signaling events that lead to a response within the cell.
6. Neurotransmitter inactivation: To terminate the signal, neurotransmitters are either taken back up into the nerve cell or broken down by enzymes in the synapse.
NEUROMUSCULAR BLOCKING AGENTS
Neuromuscular blocking agents (NMBAs) are drugs that
block the transmission of nerve impulses at the neuromuscular junction, leading
to skeletal muscle relaxation. They are used to induce muscle paralysis in
surgical procedures, facilitate mechanical ventilation in critically ill
patients, and reduce muscle spasms in certain medical conditions.
The degree and duration of muscle paralysis depend
on the pharmacokinetic properties of the specific NMBA used. Some NMBAs have a
short duration of action and are rapidly metabolized, while others have a
longer duration of action and require excretion by the liver or kidneys.
NONDEPOLARIZING (COMPETITIVE) AGENTS
These medications are commonly used in anesthesia to
induce muscle relaxation, which can help with surgical procedures or mechanical
ventilation.
Nondepolarising neuromuscular blocking agents work
by blocking the action of acetylcholine at the neuromuscular junction,
preventing muscle contraction.
Some examples of these medications include tubocurarine,
atracurium, vecuronium, rocuronium etc.
MECHANISM OF ACTION OF TUBOCURARINE
It binds to NM nicotinic receptors on the motor end plate and block the actions of acetylcholine by competitive blockade.
PHAMACOLOGICAL ACTIONS OF TUBOCURARINE
SKELETAL MUSCLE
- It
works by blocking the action of acetylcholine at the neuromuscular
junction, which prevents muscle contraction.
- This
results in a decrease in muscle tone, muscle strength, and reflexes.
- The
onset of action is slow, typically taking 3-5 minutes to take effect, and
the duration of action is prolonged, lasting up to 60 minutes or more
RESPIRATORY SYSTEM
Tubocurarine can cause respiratory depression, so it
should be used with caution in patients with respiratory problems.
ADVERSE EFFECTS OF TUBOCURARINE
- Tubocurarine
can cause respiratory depression, which can
be dangerous, especially in patients with pre-existing respiratory
problems or those who are sensitive to the drug.
- It
can also cause hypotension, or low blood
pressure, by causing vasodilation (widening of blood vessels).
- The
medication can cause histamine release,
which can lead to allergic reactions, such as skin rashes, itching, and
bronchospasm.
- Tubocurarine
may also cause muscle fasciculations, or
involuntary muscle twitches, during administration.
- Prolonged
use of the drug can result in muscle weakness and
paralysis, which can last for several hours.
THERAPEUTICAL USES OF TUBOCURARINE
- Tubocurarine is primarily used to produce
muscle relaxation during surgical procedures that require general
anesthesia.
- It
can also be used to facilitate mechanical ventilation in patients who require
assistance with breathing.
- It
may be used in some cases as a treatment for hypertonicity (muscle
stiffness) caused by conditions such as spinal cord injury or multiple
sclerosis.
DEPOLARIZING AGENTS
Depolarizing neuromuscular blocking agents are drugs
that temporarily paralyze muscles by blocking the signals between nerves and
muscles. They work by binding to and activating a receptor called the nicotinic acetylcholine receptor. This causes a brief
depolarization, or change in electrical charge, which results in muscle
paralysis. Examples of depolarizing neuromuscular blocking agents include
succinylcholine and decamethonium.
MECHANISM OF ACTION OF SUCCINYLCHOLINE
Succinylcholine is a depolarizing neuromuscular
blocking agent that works by binding to the nicotinic
acetylcholine receptor at the neuromuscular junction. This causes a
depolarization of the muscle cell membrane, which results in muscle contraction
followed by paralysis. Unlike non-depolarizing neuromuscular blocking agents,
which compete with acetylcholine for binding to the receptor, succinylcholine
mimics the action of acetylcholine by causing a persistent
depolarization of the muscle cell. This sustained depolarization
prevents the muscle from receiving any further signals and results in muscle
relaxation.
ADVERSE EFFECTS OF SUCCINYLCHOLINE
- It
can cause muscle twitching, which can sometimes be mistaken for seizure
activity.
- Succinylcholine
can also cause an increase in heart rate and blood pressure.
- Succinylcholine
can also cause hyperkalemia, or high potassium levels in the blood, which
can be life-threatening.
THERAPEUTIC USES OF SUCCINYLCHOLINE
·
It is useful for achieving rapid and
complete muscle paralysis, allowing for easier intubation and ventilation.
·
Succinylcholine can also be used to
prevent muscle movement during electroconvulsive therapy (ECT) for certain
psychiatric conditions.
DRUGS USED IN MYASTHENIA GRAVIS
MYASTHENIA GRAVIS
Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction, causing muscle weakness
and fatigue. It is caused by the body's immune system mistakenly attacking the
nicotinic acetylcholine receptors at the neuromuscular junction, leading to a
decrease in the number of functional receptors available for acetylcholine
binding. This results in muscle weakness and fatigue, which can affect various
parts of the body, including the eyes, face, throat, limbs, and respiratory
muscles.
CLASSIFICATION OF DRUGS USED IN
MYASTHENIA GRAVIS
·
Acetylcholinesterase inhibitors:
Pyridostigmine and Neostigmine.
·
Immunosuppressants: Azathioprine,
Mycophenolate mofetil, and Cyclosporine
·
Immunomodulatory drugs: Rituximab and Eculizumab
·
Corticosteroids: These drugs have
anti-inflammatory properties and can be used to suppress the immune response in
myasthenia gravis. Examples include prednisone and dexamethasone.
·
Intravenous immunoglobulin (IVIG) and
plasmapheresis: These therapies are used in severe cases of myasthenia gravis
to remove harmful antibodies from the blood and replace them with normal
antibodies or plasma. IVIG involves the infusion of immunoglobulin G (IgG)
antibodies obtained from donated blood, while plasmapheresis involves the
removal of plasma from the blood and replacement with a substitute fluid.
MECHANISM OF ACTION OF NEOSTIGMINE
The mechanism of action of neostigmine involves
inhibition of the enzyme acetylcholinesterase, which is responsible for
breaking down acetylcholine at the neuromuscular junction. By blocking
acetylcholinesterase, neostigmine increases the concentration of acetylcholine
in the synaptic cleft, enhancing its binding to nicotinic acetylcholine
receptors on the muscle fibers. This results in increased muscle contraction
and improved muscle strength in patients with myasthenia gravis.
ADVERSE EFFECTS OF NEOSTIGMINE
- Nausea
and vomiting
- Diarrhea
and abdominal cramps
- Increased
saliva production
- Sweating
and flushing
- Muscle
twitching and cramps
- Headache
and dizziness
- Blurred
vision and changes in color vision
- Difficulty
breathing and wheezing
- Irregular
heartbeat and palpitations
THERAPEUTIC USES OF NEOSTIGMINE
- Neostigmine
is a medication that is primarily used for the treatment of myasthenia
gravis. However, it also has several other therapeutic uses. Here are some
of the therapeutic uses of neostigmine:
- Reversal
of neuromuscular blockade after surgery
- Management
of severe constipation
LOCAL ANAESTHETICS
QUESTION: WRITEDOWN THE
DEFINITION, CLASSIFICATION, MECHANISM OF ACTION, PHARMACOLOGICAL ACTIONS
AND USES OF LOCAL
ANAESTHETICS.
DEFINITION
Local anesthetics are drugs that block nerve signals
in a specific area of the body, numbing the region and temporarily preventing
pain sensation without causing unconsciousness.
CLASSIFICATION OF DRUGS
INJECTABLE ANAESTHETICS
LOW POTENCY, SHORT DURATION: Procaine,
Chloroprocaine
INTERMEDIATE POTENCY: Lidocaine (Lignocaine),
Prilocaine
HIGH POTENCY, LONG DURATION: Tetracaine,
Bupivacaine, Ropivacaine,
Dibucaine
SURFACE ANAESTHETICS
SOLUBLE: Cocaine, Lidocaine, Tetracaine, Benoxinate
INSOLUBLE: Benzocaine, Oxethazaine,
Butylaminobenzoate
MECHANISM OF ACTION
Local anaesthetics reversibly inhibit nerve transmission
by binding to voltage-gated sodium channels in the nerve plasma membrane (by
preventing
depolarization).
Therefore they prevent the development of action
potential in the nerve fibre.
PHARMACOLOGICAL ACTIONS:
EFFECT OF SENSATION
They block the sensation of pain, then they block
the sensation for touch and
pressure.They produce blockade of both small and
large nerve fibres.
CNS
They produce stimulation of CNS. That’s why they
produce euphoria.
Cocaine is a powerful CNS stimulant which also
causes euphoria, excitement,
mental confusion, restlessness and tremor.
Procaine and other synthetic LAs are much less
potent. At higher doses they
produce CNS stimulation followed by depression.
CARDIOVASCULAR SYSTEM
They produce vasodilation(Hypotension) but cocaine
produce
vasoconstriction(Hypertension).
They produce depressant effect on the myocardium.
LAs tend to fall in blood pressure.
SMOOTH MUSCLE
They produce relaxant effect on smooth muscles.
ADVERSE EFFECTS:
1. Dizziness
2. Headaches
3. Blurred vision
4. Twitching muscles
5. Weakness
6. Continuing numbness
7. Allergic reaction
THERAPEUTIC USES:
1. Surface anaesthesia for pain.
2. Used as local infiltration anaesthesia
3. Used as antiarrhythmic agents
4. LAs are used for procedures such as performing a
skin biopsy, repairing a
broken bone, stiching a deep cut etc.
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
Ø Non-steroidal
anti-inflammatory drugs (NSAIDs) are drugs that are
commonly used to bring down a high temperature,
relieve pain, and reduce
inflammation.
Ø They
are used to relieve symptoms of headaches, colds and flu, arthritis, and
other causes of long-term pain.
Ø They
are not steroids (steroids, also called as corticosteroids, are man- made
version of chemicals used to treat inflammation).
CLASSIFICATION
A. Nonselective COX inhibitors
1. Salicylates: Aspirin.
2. Propionic acid derivatives: Ibuprofen, Naproxen,
Ketoprofen,
Flurbiprofen.
3. Anthranilic acid derivative: Mephenamic acid.
4. Aryl-acetic acid derivatives: Diclofenac,
Aceclofenac.
5. Oxicam derivatives: Piroxicam, Tenoxicam.
6. Pyrrolo-pyrrole derivative: Kitorolac.
7. Indole derivative: Indomethacin.
8. Pyrazolone derivatives: Phenylbutazone, oxyphenbutazone.
B. Selective COX-2 inhibitors
Celecoxib, Parecoxib, Etoricoxib.
C. Analgesic-antipyretics with poor
anti-inflammatory action
1. Paraaminophenol derivative: Paracetamol
(Acetaminophen).
2. Pyrazolone derivatives: Metamizol (Dipyrone),
Propiphenazone.
3. Benzoxazocine: Nefopam
MECHANISM OF ACTION OF NSAIDS
The mechanism of action of NSAIDs is the inhibition
of the enzyme
cyclooxygenase (COX). Cyclooxygenase is required to
convert arachidonic acid into
thromboxanes (TXA2), Prostacyclins (PGI2), and
Prostaglandins (PGE2).
Thromboxane is responsible for platelet aggregation,
prostacyclin is responsible for
gastric protection and prostaglandin is responsible
for pain, fever and inflammation.
So NSAIDs inhibit production of prostaglandins, a
group of compounds that
contribute to inflammatory response and are
responsible for signs such as fever and
pain.
ASPIRIN
Aspirin is acetylsalicylic acid. It is rapidly
converted in the body to salicylic acid
which is responsible for most of the actions.
MECHANISM OF ACTION
Aspirin non-selectively inhibits COX enzyme that
means aspirin inhibits both
COX-1 and COX-2. So ultimately PGE2 biosynthesis is
inhibited, which was
responsible for pain, fever, and inflammation.
PHARMACOLOGICAL ACTIONS
1. Metabolic effects
Cellular metabolism is increased in skeletal
muscles. So increased utilization
of glucose is observed and blood sugar may decrease
and liver glycogen is
depleted.
2. Respiration
At anti-inflammatory doses, respiration is
stimulated. Further rise in salicylate
level causes respiratory depression which may lead
to death due to respiratory
failure.
3. CVS (Cardio Vascular System)
Larger doses of aspirin increase cardiac output to
meet increased peripheral
oxygen demand and cause direct vasodilation so Blood
pressure may fall.
4. GIT (Gastro Intestinal Tract)
Aspirin irritates gastric mucosa, causes nausea and
vomiting.
Aspirin also causes acute ulcer and erosive
gastritis.
5. Blood
Aspirin, even in small doses, irreversibly inhibits
TXA2. So aspirin interferes
with platelet aggregation and bleeding time is
prolonged to nearly twice the
normal value.
6. Immunological effect
Aspirin inhibits antigen-antibody reaction.
ADVERSE EFFECTS
1. At analgesic dose aspirin causes nausea,
vomiting, blood loss in stools, peptic
ulcer etc.
2. Skin rashes of various types.
3. Bone marrow depression leading to anaemia.
4. Hypersensitivity reactions such as angioedema
(painless swelling under the
skin), asthma, and anaphylaxis (severe
life-threatening allergic reaction).
5. Dizziness, tinnitus (ringing or buzzing noise in
one or both ears).
THERAPEUTIC USES
1. As analgesic for headache, backache, joint pain,
tooth ache etc.
2. As antipyretic against fever of any origin.
Paracetamol, being safer, is
generally preferred.
3. Used in acute rheumatic fever.
4. Used in Rheumatoid arthritis.
5. Used in Osteoartthritis.
6. Used in postmyocardial infraction patients by
inhibiting platelet aggregation.