. Anaesthetics .

By Abdul Rehman
3rd prof.
Cadson College of Pharmacy

◾ Definition:

Anesthesia is a state characterized by

unconsciousness, skeletal muscle relaxation, loss
of reflexes and Analgesia.
Remember, no single drug can produce all these
characteristics. Because no single agent provides
all Desirable properties, several categories of
drugs are combined to produce optimal
anesthesia.
◾ General Anaesthetics:
General anesthetics are drugs which produce
reversible loss of all sensation and consciousness.

◾Stages of Anaesthesia:
General anesthesia has three stages:
1. Induction:
Induction is the period of time which begins with
the administration of an anesthetic up to the
development of Surgical anesthesia.
It is very important to avoid the stage of depth
of anesthesia.
Induction of anesthesia depends on how fast
effective concentrations of anesthetic reach the
brain.
General anesthesia in adults is normally induced
with an IV agent like propofol, thiopental,
producing unconsciousness in 30 to 40 seconds.
 2. Maintenance:
Sustaining the state of anesthesia.
After administering the anesthetic, vital signs
and response to stimuli are monitored
continuously to balance the amount of drug
inhaled and/or infused with the depth of
anesthesia.
Maintenance is commonly provided with inhaled
anesthetics e.g. Nitrous Oxide and halogenated
hydrocarbons.

3. Recovery:
For most anesthetic agents,recovery is the
reverse of induction.
Anesthesiologists at the end of Surgical
procedure withdraw the anesthetics and monitors
the return of patient to Consciousness.
◾Stages of Depth of Anesthesia:
The depth of anesthesia has four sequential
stages.

▪️Stage I—Analgesia:
Starts from beginning of anesthetic inhalation
and lasts up to the loss of consciousness.
Pain is progressively abolished during this stage.
Patient remains conscious, can hear and see, and
feels a dream like state.
Reflexes and respiration remain normal.It is
difficult to maintain it that’s why Its use is
limited to short and minor procedures.

▪️Stage II—Delirium(Excitement):
Patient appears to be delirious and
excited.Patient may shout, struggle, hold his
breath.
Muscle tone increases, jaws are tightly closed,
breathing is jerky.
Vomiting, involuntary micturition or defecation
may occur.
No stimulus or surgical procedure is carried out in
this stage.
This stage is not found with modern anesthesia-
pre anesthetic medication techniques.

▪️Stage III—Surgical anesthesia:

In this stage, patient is unconscious, with no pain
reflexes, respiration is regular and blood
pressure is maintained.
Muscle tone decreased with increased heart rate
and weak pulse.
Pupil dilated and light reflex is lost.
▪️Stage IV—Medullary depression/paralysis:
Patient may develop severe respiratory and
cardiovascular depression.
Cessation of breathing to failure of circulation
and death may occur.
Muscles are totally flabby (soft/loose), pulse
becomes imperceptible and B.P is very low.
◾General MoA:
General anesthetics (GA) mainly acts via
membrane proteins.
GA mainly act on Thalamus, Hippocampus and
spinal cord.
Major site of action is ligand gated ion channels
i.e. GABA receptors.
Many inhaled anesthetics, benzodiazepines,
barbiturates and propofol acts on these
receptors.
GABA receptor mediates the effects of gamma-
amino butyric acid (GABA), the major inhibitory
neurotransmitter in the brain.
GABA receptor found throughout the CNS.
General Anesthetics bind with these receptors
and cause opening and potentiation of these
inhibitory channels which leads to inhibition and
anesthesia.
◾Inhalational Anaesthetics:
▪️Gas: Nitrous oxide
▪️Volatile Liquids: Halothane, Desflurane,
Sevoflurane, Enflurane, Isoflurane.

🔆 Nitrous oxide:
Colorless, odorless inorganic gas with sweet taste.
Noninflammable and nonirritating, but of low
potency.
Very potent analgesic, but not potent anaesthetic.
Rapid onset of action and recovery because of its
low blood solubility.
Non toxic to liver, kidney and brain.
Removed unchanged from lungs.
Cheap and commonly used.
 Mechanism of Action:
Nitrous oxide has multiple supraspinal and spinal
targets. The anesthetic effect of nitrous oxide is
through non-competitive NMDA inhibition in the
central nervous system.
The analgesic effects occur through the release
of endogenous opioids that act on opioid
receptors; its analgesic actions are like morphine.
The anxiolytic effects are through GABA-A
activation.

Pharmacokinetics:
Nitrous oxide administration is via inhalation
utilizing a simple face mask, laryngeal mask
airway, or an endotracheal tube.
The excretion of nitrous oxide is primarily
unchanged through the lungs.
A small amount diffuses through the skin.
 Therapeutic uses:
Nitrous oxide can be used for general anesthesia,
procedural sedation, dental anesthesia, and to
treat severe pain.
It is also used as laughing gas.

Adverse effect:

▪️Respiratory Depression: When used alone,

nitrous has limited respiratory effects, but when
used in combination with other sedatives,
hypnotics, or opioids, it can potentiate the
respiratory depressant effects of these agents.

▪️Diffusion hypoxia: Following discontinuation of

nitrous oxide, the concentration gradient
between the gases in the lung and alveolar
circulation rapidly reverses.
▪️Postoperative Nausea and Vomiting: Nitrous
has an increased risk of postoperative nausea and
vomiting (PONV) compared with other agents, but
this is controllable with prophylactic anti-
emetics.

▪️ Contradictions:Critically ill patients, Severe

cardiac disease, The first trimester of pregnancy
& Severe psychiatric disorders

🔆 Halothane:
Fluorinated volatile liquid with sweet odour,non-
irritant,non-inflammable.
Prototype drug, has ability to induce anesthetic
state rapidly.
Potent anesthetic but weak analgesic.
Usually co administered with NO, opioids or local
anesthetics.
 Mechanism of Action:
Halothane causes general anaethesia due to its
actions on multiple ion channels, which ultimately
depresses nerve conduction, breathing, cardiac
contractility.
Its immobilizing effects have been attributed to
its binding to potassium channels in cholinergic
neurons.
Halothane’s effect are also likely due to binding
to NMDA and calcium channels, causing
hyperpolarization.

Pharmacokinetics:
60 to 80% eliminated unchanged.
Oxidatively metabolized in liver to produce toxic
metabolites in adults.
 Therapeutic uses:
▪️Used in obstetrics(pregnancy study).
▪️Used in induction and maintenance of general
anesthesia

Adverse effect:

▪️Cardiac effects:Bradycardia, cardiac

arrhythmias, concentration-dependent
hypotension.

▪️Malignant hyperthermia (a rare life-

threatening condition):MH causes a drastic and
uncontrolled increase in skeletal muscle oxidative
metabolism, overwhelming the body’s Capacity to
supply oxygen, remove carbon dioxide, and
regulate temperature, eventually leading To
circulatory collapse and death if not treated
immediately.
▪️Others:
Abnormal heart rhythm, decreased lung function,
decreased oxygen in the tissues or blood,
hepatitis, Kidney damage, problems with
circulation & yellowing of skin or eyes (jaundice)

◾ Intravenous Anesthetics:

▪️Barbiturates (e.g., thiopental, methohexital)

▪️Benzodiazepines (e.g., midazolam, diazepam)
▪️Propofol
▪️Ketamine
▪️Opioid analgesics (morphine, fentanyl,
sufentanil, alfentanil)
🔆 Ketamine:

Mechanism of Action:
Ketamine is a noncompetitive N-methyl-D-
aspartate (NMDA) and glutamate receptor
antagonist. It blocks HCN1 receptors. These
actions cause anaesthetics & analgesic effects.

Pharmacokinetics:
▪️Ketamine administration can be either IV or IM.
▪️the onset of action is approximately 4 minutes,
with a duration of action from 15 to 30 minutes.

Therapeutic uses:
In head and neck surgery, In asthmatics, Short
surgical procedures i.e.burn dressing, forceps
delivery, breech extraction manual removal of
placenta and dentistry.
 Adverse effect:
The most common side effects associated with
ketamine when used medically are nausea,
vomiting, dizziness, diplopia (double vision),
drowsiness.

🔆 Thiopental:

Mechanism of Action:
They bind to GABAa receptors.
The GABAa receptor is an inhibitory channel that
decreases neuronal activity, and barbiturates
enhance the inhibitory action of the GABAa
receptor.

Pharmacokinetics:
▪️ Injected intravenously
▪️Can cross BBB
 Therapeutic uses:
Thiopental is a barbiturate used to induce general
anesthesia, treat convulsions, and reduce
intracranial pressure.

Adverse effect:
Hypotension, apnea, and airway obstruction.

🔆 Morphine:

Mechanism of Action:
The analgesic properties of the opioids like
morphine are primarily mediated by the μ
receptors that modulate responses to thermal,
mechanical, and chemical nociception.
It decreases the release of Substance P, which
modulates pain perception in the spinal cord.
Morphine also appears to inhibit the release of
many excitatory transmitters from nerve
terminals carrying nociceptive (painful) stimuli.

Pharmacokinetics:
A: IV, IM & SC
D: Rapidly enters all body tissues
M: In liver
E: primarily in urine, a small amount through bile

Therapeutic uses:
▪️Analgesia
▪️Anaesthesia (preanesthetic)
▪️Treatment of diarrhea
▪️Relief of cough
▪️Treatment of acute pulmonary edema
▪️Left ventricular hypertension –IV
 Adverse effect:
Constipation, Severe respiratory depression,
Nausea, Vomiting ,Dysphoria, Dizziness, Elevation
of intracranial pressure, Energy enhance
hypotensive effect, Urinary retention, Potential
for addiction, Sedation.

◾Local Anesthetics:

Local anesthetics are drugs which upon topical

application or local injection block nerve
conducton and cause reversible loss of sensory
perception, especially of pain in a localized Area
of the body.
◾ General MoA:

Block generation and conduction of sensory nerve

impulses at a localized site of contact and in
higher concentration block motor impulses from
the periphery to the CNS without causing
structural damage to neurons resulting in loss of
sensory as well as motor impulses.
They do not cause the loss of consciousness when
administered correctly.
LA reversibly inhibit nerve transmission by
binding voltage-gated sodium channels (Nav) in
the nerve plasma membrane
Local anesthetics act on voltage sensitive sodium
channels, They block voltage activted sodium
channels and reduce Na+ influx ,so, there is no
depolarization and no Conduction of Active
Potential.
◾Techniques of local anesthesia:

1. Surfce Anesthesia( Topical ansthesia):

Local anesthetic is applied on the abraded skin
and mucous membrane of the nose, mouth, eyes,
throat, upper respiratory tract, oesophagus,
urethra. Motor function is intact.
They are available as solution, ointment, gel, jelly,
cream, spray, lozenges.e.g Tetracaine,
Benzocaine.

2. Infiltration Anesthesia:
Local anesthetic is injected directly into tissues
to be operated, it blocks sensory nerve endings.
It is suitable for only small areas. The main
disadvantage is requirement of large amount of
dose.
Contraindicted in local infection and clotting
disorders. E.g lignocaine, procaine.
 3. Conduction block:

▫️Field block anesthesia: It is achieved by

injecting a local anesthetic subcutaneously, which
anesthetizes the area distal to the injection.
▫️Nerve block anesthesia: It is injected very
close to or around the peripheral nerve plexuses.

4. Spinal Anesthesia:
It is one of the most popular forms of
anaesthesia.
LA is injected into the subarachnoid space to
anesthesize spinal roots.e.g lignocaine, tetracaine,
bupivacaine.
It should not be used in young children
hypotension and shock.
 5. Epidural Anesthesia:
It is injected into epidural space where it acts on
spinal nerve roots.
Lignocaine and bupivacaine are commonly used.
It is safer but the technique is more difficult
than spinal anesthesia & It Requires a much
larger amount of the drug.

◾Easter based Anesthetics:

▪️Long acting: Tetracaine
▪️Short acting: Procaine
▪️ Surface acting: Cocaine, Benzocaine
🔆 Cocaine:

Mechanism of Action:
Topical cocaine has an anesthetic effect similar
to local anesthetics (such as lidocaine) from
sodium channel blockade and interference with
action potential propagation.

Therapeutic uses:
Cocaine is a local anesthetic. It is applied to
certain areas of the body (for example, the nose,
mouth, or throat) to cause loss of feeling or
numbness. This allows certain kinds of procedures
or surgery to be done without causing pain.

Adverse effect:
▫️Abdominal or stomach pain.
▫️dizziness or lightheadedness.
▫️excitement, nervousness, restlessness, or any
mood or mental changes.
▫️fast or irregular heartbeat.
▫️general feeling of discomfort or illness.
▫️hallucinations or seeing, hearing, or feeling
things that are not there.
▫️headache

◾Amide based:
▪️Long acting: Ropivacaine, Bupivacaine
▪️Medium acting: Lidocaine
🔆 Lidocaine

Mechanism of Action:
Lidocaine can block Na+ and K+ ion channels and
regulate intracellular and extracellular calcium
concentrations through other ligand-gated ion
channels.
Its main mechanism of action is blocking voltage-
gated Na+ channels (VGSC/NaVs).

Pharmacokinetics:
The oral bioavailability is 35% and the topical
bioavailability is 3%. The elimination half-life of
lidocaine is biphasic and around 90 min to 120 min
in most patients.
 Therapeutic uses:
Lidocaine helps to reduce sharp/burning/aching
pain as well as discomfort caused by skin areas
that are overly sensitive to touch.

Adverse effect:
▫️Low blood pressure (hypotension)
▫️Swelling (edema)
▫️Redness at the injection site
▫️Small red or purple spots on the skin
▫️Skin irritation
▫️Constipation
▫️Nausea, Vomiting
▫️Confusion, Dizziness, Headache
▫️Numbness and tingling
▫️Drowsiness