Anesthetics: General and Local

Introduction
During surgery several drugs are used for many reasons. These include analgesics, muscle
relaxants, antiseptics and anesthetics-both general and local. They are used in combination
with the ultimate goal of producing unconsciousness or insensitivity to pain and stimulation
in the anesthetist, who specialized in this category of drugs. Since the nurse works with the
doctor’s pre and post-surgery, she should be familiar with these drugs and the stages of
anesthesia. Anesthetics may produce same or similar effects, but the dosage and route of
administration may make all the differences. Nevertheless, anesthetics are classified into
two main groups – general and local anesthetics.

General Anesthetics
Before discussing the specific drugs, it is necessary to outline stages of anesthesia. Stages of
anesthesia are divided into four, with the third stage broken down into further subdivisions.
Generally, stages in anesthesia have to do with the degree and effect of the drugs on various
body organs, starting with CNS depression, analgesia, respiration, muscle tone and reflexes,
and changes in the eyeball and pupil size. The first stage is marked with induction of the
drug when analgesia occurs; there is awareness of loss of pain. There may be different types
of feelings, from lacrimation to warmth. The patient may be quite awake with no changes in
respiration, pulse or pupil size.
The second stage is characterized by loss of consciousness, excitement or delirium and
varied symptoms coming from the low centers of the brain e.g. the patient may struggle, the
pulse and respiration may not be normal and the eyeballs may show movement.
The third stage, known as surgical stage, is subdivided into four planes. During this
stage, there are different degrees of unconsciousness, muscle relaxation and respiration. The
heart rate may be normal or increased but the eyeball reflexes may be lost. This is the stage
when respiration will progress to shallow and irregular; the pulse will be very slow;
hypotension occurs, the pupil reflexes are lost with eyeballs dilated..
The fourth stage of anesthesia is the period of toxic symptoms, in which respiratory centre
is highly depressed and the muscles paralyzed, followed by circulatory failure. The
anesthetist constantly monitors the patient’s vital signs. The nurse may participate in this
aspect of drug monitoring during surgery.
General anesthetics may be grouped into those that are administered by inhalation (e.g.
halothane, enflurane, isoflurane, methoxyflurane and nitrous oxide) and those administered
by intravenous injection e.g. thiopental sodium.
Simplified stages of anesthesia
Stage Effects on organs CNS Respiration Eyeball
1 Analgesia Normal Normal
2 Delirium/Unconsciousness Abnormal Abnormal
3 (Panel 1) Unconsciousness Abnormal Abnormal
(Panel 2) Unconsciousness Low Fixed
(Panel3) Unconsciousness Low & Shallow Fixed
(Panel 4) Unconsciousness Very shallow Fixed
4 Toxic Phase Very deeply unconscious Respiratory paralysis

Halothane (Fluothane)
Halothane is an effective volatile anesthetic which can produce stage IV anesthesia,
especially when administered in combination with nitrous oxide and oxygen. It has
numerous actions and effects on various organs of the body. Because of its lack of
flammability, it has made such drugs like ether and cyclopropane to become obsolete.
Halothane has tremendous effect on the blood circulation. It depresses the cardiovascular
system resulting in hypotension, decreased cardiac output and peripheral resistance. The
cardia rhythm may be altered to cause some types of cardiac arrhythmias, such as
bradycardia. On the respiratory system, it is non-irritating. Depression of respiration occurs,
with increase dosage. However, it has bronchodilatory effect on smooth muscles, and as a
result it is preferable in patients suffering from bronchial asthma. Halothane is not an
effective relaxant of skeletal muscle. It has to be administered with other drugs to achieve
the level of muscle relaxation needed for surgery.
Although halothane is partially metabolized in the liver like other anesthetics, unlike
most of them it is not as hepatotoxic.

Absorption, metabolism and elimination

Most of the administered drugs (about 60 to 80%) absorbed in the pulmonary epithelium is
eliminated by exhalation. About 12 to 20% undergoes metabolism in the liver and the
metabolites are excreted in the urine.

Therapeutic uses
Halothane is commonly used because it has fewer side effects. It is non-irritating and non-
flammable. In combination of other drugs, halothane has been found useful in all surgical
operations.

Adverse reaction
Depending on the frequency and dosage administered, halothane may cause liver damage,
arrhythmias, hypotension and circulatory failure.

Enflurane
Enflurane has pharmacological actions and effects similar to halothane. Anesthesia can be
rapidly and smoothly induced by use of enflurane within a very short period of time (about
10 minutes). Unless, in deep anesthesia, respiration is not seriously depressed. It has a better
muscular relaxing effect than halothane, especially with increased dosage. Circulatory
failure, seizure activities, arrhythmias may be precipitated by enflurane.
It has similar metabolism, elimination, side effects and therapeutic uses as halothane.

Isoflurane
Isoflurane is essentially similar to enflurane and halothane. However, it has the advantage
of being very useful in emergency cases, where induction of anesthesia is promptly needed.
It is rapid and effective at lower concentration than enflurane and therefore less toxic. Like
halothane and enflurane, isoflurance affects the circulation by decreasing the arterial blood
pressure in relation to depth of anesthesia. It causes vasodilation of the skin and muscle. It
does not seem to affect the cardiac output and other myocardial activities as halothane or
enflurane. It may increase heart rate but does not precipitate arrhythmias. On respiration, it
has progressive depression with increased concentration. At low concentration, it may
irritate respiratory reflexes. This may lead to increased secretion, spasms and cough. It acts
on the nervous system, resulting in increased blood flow with decreased metabolism.
Convulsions associated with enflurane. Regarding muscle relaxation, it is more potent than
halothane. Its effect on renal blood flow is negligible, and so it is quite safe in patients with
renal disease.
Most of the drugs are eliminated by exhalation. Only very small percentage, about
0.2% is metabolized. This may be responsible for its lack of liver and kidney damage.
Because of the advantages it has over halothane (rapid onset of action, less side effects,
especially on the heart, liver and kidney), isoflurance has been used in all types of surgical
procedures.

Methoxyflurane
Methoxyflurane is the most potent of all anesthetics presently available. It has strong
analgesic property at low concentration. With deep anesthesia achieved with increased
concentration, respiration is depressed, blood pressure is reduced, and cardiac output is
decreased.
Unlike isoflurane, methoxyflurane causes liver and kidney damage.

Absorption, metabolism and elimination

Methoxyflurane is extensively absorbed and metabolized in the liver. About 50 to 70% is
metabolized in the liver to various metabolites, and these substances are responsible for
liver damage. The rate of metabolism may affect the duration of action in the body.
Consequently the toxic effects and prolonged effect after surgery limit the use of
methoxyflurane in general anesthesia.

Nitrous oxide
Nitrous oxide is a gaseous general anesthetic that is widely used in all types of surgery. Its
popularity is partly due to its ability to induce analgesia. As a result, combination with other
drugs and oxygen makes nitrous oxide a safe drug used in anesthesia. Nitrous oxide acts on
the CNS to produce analgesia. It does not adversely affect cerebral blood flow. Its effects
on the cardiovascular system as compared to the volatile anesthetics are insignificant. It is
usually combined with oxygen, enflurane, and halothane and in each case the dose of each
drug is reduced, and adverse effects are therefore minimized.
Nitrous oxide is essentially non-toxic to the CNS at the anesthetic dose. It does not
depress respiration, and skeletal relaxation is not prominent. On various organs of the body
e.g. kidney, liver, heart and gastrointestinal tract, the side effects are minimal.
As a gas, it is rapidly exhaled and there is no evidence of significant metabolism in the
body.
Although nitrous oxide has analgesic property, it is considered to be a weak
anesthetic, with no skeletal muscle relaxant property. However, it is not flammable or
irritating. It is usually used in combination with other drugs in major surgery, and patients
do recover quickly from its administration. As a sole anesthetic it may be used during
labour and dental surgery to provide analgesia.

Other anesthetics
Cyclopropane, ethylene, diethylether and ethylchloride for once were popular anesthetics.
But the arrival of better agents discussed above has made them inferior and obsolete. For
one thing, they are all flammable and explosive at the anesthetic concentration. Chloroform
is not used again because of its damaging effects on the liver and kidney.

Nitrous oxide
Nitrous oxide is a gaseous general anesthetic that is widely used in all types of surgery. Its
popularity is partly due to its ability to induce analgesia. As a result, combination with other
drugs used in anesthesia. Nitrous oxide a safe drug used in anesthesia. Nitrous oxide acts on
the CNS to produce analgesia. It does not adversely affect cerebral blood flow. Its effects
on the cardiovascular system as compared to the volatile anesthetics are insignificant. It is
usually combined with oxygen, enflurane, and halothane in each case the dose of each drug
is reduced, and adverse effects are therefore minimized.
 Nitrous oxide is essentially non-toxic to the CNS at the anesthetic dose. It does not
depress respiration, and skeletal relaxation is not prominent. On various organs of the body
e.g. kidney, liver, heart and gastrointestinal tract, the side effects are minimal.
As a gas, it is rapidly exhaled and there is no evidence of significant metabolism in the
body.
Although nitrous oxide has analgesic property, it is considered to be a weak
anesthetic, with no skeletal muscle relaxant property. However, it is not flammable or
irritating. It is usually used in combination with other drugs in major surgery, and patients
do recover quickly from its administration. As a sole anesthetic it may be used during
labour and dental surgery to provide analgesia.

Other anesthetics
Cyclopropane, ethylene, diethyl ether and ethyl chloride for once were popular anesthetics.
But the arrival of better agents discussed above has made them inferior and obsolete. For
one thing, they are all flammable and explosive at the anesthetic concentration. Chloroform
is not used again because of its damaging effects on the liver and kidney.

Intravenous anesthetics
Thiopental sodium, thiamylal sodium and methohexital sodium are derivatives of barbituric
acid that are administered intravenously to induce anesthesia for the purpose of surgery.
When adequate dosage is administered, the progression to stages of anesthesia and effects
on various organs of the body are quite similar to that of inhalation anesthetics. The CNS,
muscular tone, cardiac functions and respiratory centres are all depressed to variable
degrees.
These ultra-short acting barbiturates induce rapid and smooth anesthesia, with
relatively fast recovery post surgery. They are often used in out patient services to provide
anesthesia for short procedures, like dental and minor obstetrical surgery. The major
disadvantages should have been respiratory depression, except that they are very short
acting barbiturates, and cannot stay in the body used to exert prolonged effect. Thiopental
should be used with caution in asthmatics, as it may cause bronchospasm.

Adjuncts to anesthetics in surgery

Benzodiazepines (discussed under antianxiety drugs) and opioid analgesics (discussed undr
narcotics) are among other drugs used in combination with anesthetics prior to and, during
surgery. Benzodiazepine may be used as muscle relaxant, while opioid analgesics are used
for sedative and analgesic purposes.
Ketamine is another anesthetic that has been found useful in very short surgical procedures
involving the head, face and abdominal cavity. It offers analgesia very rapidly, without
significant depression of the respiratory centre and is therefore indicated in cases of
emergency.
Pre-anesthetic medications include anticholinergics, narcotics, sedatives, antianxiety
drugs and phenothiazine’s. Skeletal muscle relaxants commonly used during surgery are
succinylcholine and tubocurarine.

Local anesthetics
Local anesthetics are so called because their effects are localized to the area of the body
applied. Their actions are reversible on the blockade of nerve conduction. This action takes
place on any tissue or organ of the body. The first local anesthetic developed is procaine,
and others have been synthesized based on the chemistry and structure of procaine. Most of
the local anesthetics commonly used are procaine, lidocaine, mepivacaine, ethidocaine,
tetracine and dibucaine. For purposes of brevity, their actions and uses will be presented
together.

Mechanism of action
Local anesthetics act mainly on the cell membrane. They delay electrical stimulation in the
nerve, and slow down impulse propagation. This delay further the generation of action
potential with the consequent blockade of nerve impulse conduction. The overall effect is
attributed to the ability of local anesthetics to disrupt ionic equilibrium across the cell
membrane. This affects the transport of sodium ion and other complicated processes
involving potassium, calcium and hydrogen ions which we cannot go into details in this
text. The local anesthetics therefore act by blocking transmission in the neurons, resulting in
loss of pain, touch and pressure sensation in the area infiltrated with them. This effect is for
a short period of time, and it is also reversible. Although the anesthetics effects may be
local, if a large dosage is administered to sustain a longer period of anesthesia, and a large
quantity is therefore absorbed in the systematic circulation, several organs of the body may
be affected. It is important to discuss the effects of local anesthetic on three organs of the
body the heart, the lungs and brain.

Cardiovascular effects (Heart)

If a large amount of drug is absorbed into the systemic circulation, it may cause
vasodilation, hypotension and circulatory failure may result. The myocardium may be
depressed leading to bradycardia and low cardiac output. The ability of lidocaine to depress
the myocardium has been therapeutically applied in the treatment of some arrhythmias.

CNS (Brain) effects

At high concentration, local anesthetics cause CNS stimulation, resulting in excitement,
fear, tremors and disorientation. Clonic convulsion has been reported in some cases.
Prolonged effect may lead to depression and respiratory failure. The degree of CNS effects
is also influenced by the ability of the specific drug employed to cross the bood-brain
barrier e.g. cocaine produces more CNS effects than procaine.

Uses of local anesthetics

In the use of local anesthetics, there is loss of pain or touch sensation to the specific area
without loss of consciousness. Essentially all physiological functions are normal, unless
systemic absorption is quite appreciable.
a. Surface anesthesia: This occurs when the local anesthesia is topically applied to the
mucous membrane of the nose, mouth or throat and in the skin. Those that penetrate
poorly are not useful. Lidocaine (2 to 5%), cocaine (4%) and tetracaine (2%) are very
useful as surface anesthetics.
b. Infiltration anesthesia: This is done by parenteral administration mainly intradermally
or subcutaneously around the area of operation. Lidocaine, procaine and bupicacaine are
commonly used. Addition of epinephrine. (1:200,000) which causes vasoconstriction
will delay the rate of absorption and increases the local anesthetic duration and effect.
c. Nerveblock anesthesia: This is a special technique in which the local anesthetic is
injected to block cervical plexus or segment of the spinal cord.
d. Spinal anesthesia: Spinal anesthesia, sometimes called intrathecal or subarachnoid
block involves blockade of the spinal cord. This type of technique is used when surgical
procedures at lower part of the body is necessary, and it has the advantage of the patient
 being awake. As a result, there is no change in physiologic function to be concerned
about. Lidocaine, procaine, tetracaine and dibucaine are used in spinal anesthesia.
e. Epidural anesthesia: when the local anesthetic is injected into the spaces surrounding
the dura matter of the spiral canal, it is known as epidural anesthesia. This technique is
again reserved for the experts who know what advantages that could be gained over the
other methods of administration.

Absorption, metabolism and elimination

Most of the local anesthetics are rapidly absorbed following parenteral administration.
Depending on the structure, they are easily metablilzed by the liver oxidases, esterases and
hydroxylases. The action of those that are fast metabolized by the esterases in the plasma
may be delayed by the addition of epinephrine as stated earlier. Various metabolized in the
liver by liver oxidases, while cocaine for instance is metabolized by the plasma esterases.
The site of metabolism may affect the duration of action.

Toxic reactions
At the usual concentrations, local anesthetics are generally safe drugs. However, high
systemic absorption will lead to CNS stimulation, followed by depression. Respiratory
depression, cardiac disorders, hepatic and renal damage are among serious side effects.
Hypersensitivity is not common and where it occurs, there is cross sensitivity among the
group. This may be shown by episodes of asthmatic attacks and dermatitis. If lidocaine is
administered very rapidly in large dosage, the toxic effect may be characterized by
drowsiness, dizziness, diplopia, hausea, vomiting, convulsion, and respiratory depression.
Generally, these are amides and have the ability to cross the placenta. In toxic dosage, both
the mother and fetus may show sighs of toxicity.
Procaine has the advantage of not being very toxic. It is rapidly inactivated by plasma
cholinesterase. Consequently, even at very large dosage, the toxic effects on the CNS,
cardiac and respiratory systems are low as compared to other drugs. However, some
patients are more allergic to procaine than other anesthetic amides.
Preparations of anesthetics in common use
Generic names Brand names
A. General anesthetics
Sodium thiopental Pentothal
Sodium methohexital Brevital
Sodium thiamylal Surital
Ketamine hydrochloride Ketalar
B. Local anesthetics
Ethyl aminobenzoate Benzocaine
Dibucaine Nupercaine
Lidocaine Xylocaine
Procaine Novocaine
Tetracaine Pentocaine
Ethylchloride
Etiodocaine Duranest
Cyclomethycaine Surfacaine
Mepicacaine carbocaine
 Antiepileptic Drugs

Introduction
Epilepsy or convulsion may be defined as a clinical syndrome in which there are episodes
of brain dysfunction, due to abnormal electrical discharge from the cerebral neurons.
Convulsions could be violent, or several contractions of voluntary muscles in sequence or
involuntary contractions. It is estimated that about 0.5 – 1.5% of a given population suffer
from some form of epilepsy or convulsions. From the onset, it should be made clear that
one has to have several seizure or convulsive attacks to be called an epileptic. This is
necessary as the words convulsion and epilepsy are used interchangeable, and there is great
social stigma attached to epilepsy.
The causes of convulsions have been attributed to brain tumor, scar tissue, metabolic
toxins and infections. In some cases the cause cannot be identified. There are some
instances where several members of a particular family have the disease.
Convulsion or epileptic attack is a medical emergency, where drugs must be administered
immediately to suppress the activity. For this reason, it becomes important to know types of
epileptic seizures and drugs that are used for their management. Seizure activities have been
broadly classified into partial and general seizures with smaller groupings.

Classification of convulsion
Simple partial seizures
Complex partial seizures
Partial seizures secondarily generalised

A. Generalized seizure
Absence seizure (petit mal)
Tonic-clonic seizure (grandmal)
Myoclonic
Tonic
Clonic
Atonic
Infantile spasms

Each specific seizure has its characteristics which will not be detailed here. Textbooks in
physiology and pathology will give a good review. However, the classification is essentially
for proper drug therapy. The ability of each drug to inhibit cerebral impulses determines the
degree of effectiveness.

Anticonvulsant or antiepileptic drugs

Several drugs have been developed in the treatment of convulsive disorders. The
mechanism of action of some of these are not yet known.
Generally, an ideal anticonvulsant drug should be free from toxic effects;
-have good patient acceptance, with long duration of action.
-It should not cause sedation or have potential for tolerance, and above all it should be
available at cheap prizes. None of the present drugs so far qualify as an ideal anticonvulsant
drug.
Several years ago, bromides were commonly used but have become obsolete,
because of the arrival of new drugs that are less toxic. Barbituric acid derivatives
-phenobarbtone are still in common use. They have the disadvantage of sedation.
Principal anticonvulsants
Hydantoins
Phenytoin (diphenylhydantoin) and mephenytoin are two related hydantoins that act on
the CNS to suppress seizure activity. Phenytoin has the advantage of causing no sedation at
therapeutic dosage, and this property distinguishes it from all other anticonvulsants.
The mechanism by which phenytoin abolishes convulsion of sodium in the neuronal fibers.
This retards excitation and delays spread of impulse from one part of the brain to the other.

Absorption, metabolism and elimination

Phenytoin has good oral absorption and, with high tissue distribution to the brain and liver.
Because of its high protein-duration of action that it can be administered and maintained
with once a day therapy. Phenytoin is metabolized in the liver, with some of the metabolites
being active. The metabolites and a small fraction of unchanged drug are excreted in the
urine. Phenytoin has two main therapeutic uses; in the treatment of grandmal seizures, and
in the management of cardiac arrhythmias especially if induced by digitalis preparations.
Phenytoin has been extensively studied to the point that therapeutic response can be easily
correlated with plasma concentration.

Adverse reactions
Toxic effects usually manifest at high plasma concentration, which may sometimes be
influenced by frequency and route of administration. At such high concentration, toxic signs
include cardiac disorders, hypotension and CNS depression, nystagmus, diplopia, ataxia
and tremors, among other major complaints.
Gastrointestinal side effects include nausea and vomiting. Allergic reactions are not
common, and are usually not severe enough to withdraw the drug. Prolonged administration
causes gingival hyperplasia, folic acid deficiency (megalobastic anemia), and hirsutism.
There are several drug-drug interactions involving phynytoin and drugs such as
phenobarbitone, discoumarol, phenylbutazone carbamazepine and isoniazid
Mephenytoin
The pharmacology of mephenytoin is similar to that of phenytoin. However, mepheytoin
differs from phenytoin because it causes more sedation, is more potent and therefore shows
more toxic reactions. Mephenytoin has the additional disadvantage of causing bone marrow
depression and hyperpigmentation.

Barbiturates
Barbiturates are generally effective in the suppression of most tonic-clonic seizures
including status epilepticus and tetanus-induced seizure. Phenobarbitone, mephobarbitone
and methbarbitone are the most commonly used barbiturates.
Phenobarbitone is a non-selective anticonvulsant drug that is effective below
sedative doses. It increases the seizure threshold and thus limits its spread from the point of
detonation. Other properties including adverse reactions have been discussed under
sedatives and hypnotics. However, prolonged use for years may cause exfoliative
dermatitis, and sudden withdrawal lowers seizure threshold and the patient may have
episodes of seizure. Slow withdrawal is recommended, and if it becomes necessary,
followed with replacement by another anti-convulsant.
Mephobarbitone
Mephobarbitone is essentially similar to phenobartitone in all respects, except that
mephobarbitone is less potent. Its gastrointestinal absorption is incomplete, and majority of
the drug is metabolized in the liver to phenobarbitone.

Primidone
The parent drug primidone is not a barbiturate, because it does not have the same chemistry
as barbiturates. But it is grouped under barbiturates because it is oxidized in the liver to
phenobarbitone. Another metabolite of primidone is active, and has anticonvulsant effects.
it is not popularly used because it does not have much advantage over phenobarbitone. It
has the drawback of sedation, drowsiness and megaloblastic anaemia.

Drugs useful in petitmal seizures

Siccinimides
Ethosuximide, phensuximide, methsuximide are the three main drugs used in the treatment
of absence seizures. Ethosuximide is often used, and the next two do not have significant
advantage over it. It causes least sedation among the three derivatives. It has a long duration
of action. Thus once a day administration will enhance compliance.
Ethosuximide is well absorbed orally an is extensively metabolized in the liver.

Adverse reactions
Gastrointestinal disturbances (anorexia, nausea and vomiting) and neurologic symptoms
(euphoria, dizziness, drowsiness and headache) are common. Other rare side effects include
blood dyscrasias, hepatic and renal dysfunction. Ethosuximide and derivatives are
selectively effective only in absence seizure.

Oxazolidines
Trimethadione and paramethadione belong to this group, and they are only useful in
absence seizures. Trimethadione has analgesic, anticonvulsant and sedative properties. It is
mainly used in treating petimal especially in children where it appears to be more effective
than in adults.

Absorption, metabolism and elimination

Trimethadione has complete gastrointestinal absorption following oral administration. It is
extensively metabolized in the liver and the by-products are excreted in the urine.

Adverse reactions
At therapeutic dose, it may cause nausea, vomiting, skin eruptions, photosensitivity and
blurred vision. Patients with hepatic or renal disease as well as disease of the optic nerve
should be given trimethadione with caution. Large doses may be toxic as it may cause
sedation, ataxia, coma and possible respiratory dysfunction. Bone marrow depression which
is reversible on withdrawal of the drugs has been reported. Rare toxic effects include
agranulocytosis, and a condition similar to nephritic syndrome.

Valoproic acid (sodium valproate)

Valoproic acid is effective as anticonvulsant in both partial and generalized seizures. It has
relatively low CNS side effects and sedation. It appears to be more effective in absence than
in tonic-clonic seizures.

Absorption, metabolism and elimination

Valproic acid has good gastrointestinal absorption after oral administration. It is widely
distributied into body fluids and tissues and is highly protein bound. Valproate is
metabolized in the liver to active metabolites. Both the unchanged drug and the metabolites
are excreted by the kidney.

Adverse reaction
Valproate causes gastrointestinal disturbances- anorexia, nausea and vomiting. Sedation
occurs in about half of the patients on the drug. Ataxia, tremor, alopecia and rash have been
observed. CNS side effects include insomnia, irritability and hallucinations. Other serious
but rare effects include hepatitis and pancreatitis. Valproate interacts with phenobarbitone
by about 40%. This may be due to inhibition of metabolizing enzymes of phenobarbitone.

Uses
It is a drug of choice for absence seizures, myoclonic and tonic-clonic seizures.

Carbamazepine (Tegretol)
Carbamazepine, formally used for trigeminal neuralgia, is currently approved for the
treatment of all types of seizures. The action of carbamazepine is similar to that of
phenytoin in many respects. It has several other actions whose mechanisms have not been
well understood.

Uses
It is indicated in patients who cannot benefit from the administration of other antiepileptic
drugs. It is also useful in some cases of tonic-clonic, psychomotor and mixed seizures.

Toxic effects
Carbamazepine has several toxic effects which include hepatitis, cholestatic jaundice,
hypertension, urinary dysfunction, hormone imbalance, vision disturbance, dizziness,
drowsiness and poor coordination. Other rare side effects include congestive heart failure,
allergic reactions (skin rash), and thrombophlebitis.
With so many side effects on various organs of the body, patients who are finally
placed on carbamazepine should be closely monitored. The renal, liver and blood studies
should be closely monitored.
Phenacemide and acetazolamide are antiepileptic drugs that have been found useful
in the treatment of grandmal, petitmal, psychomotor seizures or combination of these.
However, these drugs are very toxic and thus have limited uses. They are reserved for those
situations where other routine drugs are not effective. Where indicated, they are used in
combination with other antiepileptic drugs, and the medical team is usually alert to watch
for the toxic effects.

Benzodiazepines
Benzodiazepines have been extensively discussed under antianxiety drugs. Few of them
found useful in seizure control will be mentioned here. Diazepam by injection is useful for
the control of status epilepticus (continuous seizure activity without resting period).
Administered orally, it has not been found to be as effective as intravenous injection.
However, it may be administered orally in combination with other anticonvulsant drugs (see
chapter on antianxiety agents for metabolism and side effects of diazepam).
Clonazepam and clorazepate are other benzodiazepines that have recently been
approved for treatment of absence seizures, status epilepticus, myoclonic and akinetic
seizures. They are not effective in generalized toni-clonic seizures. The exact mechanism of
their seizure suppression is not yet clear.
Commonly used antiepileptic drug
Generic Names Brand Names Daily Adult dose (g)
Phenytoin Dilantin, Epanutin 0.2-.06
Mephenytoin Mesantoin 0.2-0.6
Ethotoin Peganone 2-3
Ethosuximide Zarontin 0.75-1.5
Methsuximide Celontin 0.6-1.2
Phensuximide Milontin 1.5
Primidone Mysoline 0.25-2
Trimethadione Tridione 1-2
Valproic acid Valproate 0.75-2
Mephobarbitone Mebaral 0.2-0.8
Metharibitone Germonil 0.2-0.8
Acetazolamide Diamox 0.5-1
The drugs are effective when administered orally. They have good oral absorption and
metabolized in the liver to various inactive metabolites.

Adverse effects
These are quite similar to other benzodiazepine derivatives which have been listed under
antianxiety drugs. However, it is important to mention that cases of worsening of seizures
activities have been reported in many patients (2-10%). On prolonged administration, some
patients experience ataxia, drowsiness, excessive salivation and abnormal increase of liver
enzymes.

Analgesics
Introduction
Analgesia means loss of reactivity to painful stimulations without loss of consciousness.
Those drugs that cause relief of pain are called analgesics. There are two main
classifications of analgesics. Narcotic analgesics are those which in addition to relief of pain
depress the CNS to a point of causing stupor or sleep. The opiates and their derivatives
constitute this class, since they affect the CNS. Non-opiates that relieve pain without
depressing the CNS are called non-narcotic analgesic. Details of these two main classes of
analgesics will be presented in this unit. An ideal analgesic is one that provides maximum
pain relief irrespective of etiology; has minimum side effects and is non-addicting. An ideal
analgesic should act promptly when given for pain relief; and for a long duration of time.
None of the groups-narcotic and non-narcotic analgesics can be said to be ideal analgesics.

Narcotic analgesics
Morphine and codeine are two main narcotic analgesics which are alkaloids from opium.
Several other morphine derivates including some semi-synthetic and synthetic compounds
with similar pharmacologic effects are called opiates. As a natural alkaloid, morphine has
all the characteristics and pharmacological actions which other derivatives share with it. It
is the oldest and best studied of all narcotics, and therefore is used often to compare the
analgesic properties of the semi-synthetic and synthetic products that were developed later.
There may be quantitative and qualitative differences, but essentially the pharmacology of
narcotic analgesics is quite similar and morphine will be used as a standard for comparison.

Actions
The exact mechanism of action of morphine and related derivatives is not well established,
but it is known that morphine acts on certain areas of the brain to relieve pain, induce sleep,
and relieve fear and apprehension. It depresses the respiratory centre and causes orthostatic
hypertension in some patients when administered orally, this is due to its direct contractions
and spasms of the smooth muscles. Morphine has various effects on the skin and
genitourinary system i.e. it causes diaphoresis, and histamine release, and decreased urinary
output.

Absorption, metabolism and elimination

Morphine has poor oral absorption and it is better administered parenterally. It has fairly
wide tissue distribution. Very small amount is needed in the brain for the observed
pharmacologic action. Most of the drugs are degraded in the liver by biotransformation,
forming some active (codeine) and inactive metabolites that are excreted by the kidney.

Therapeutic uses
Morphine and related derivatives are used only when it is necessary − i.e. when other
analgesics fail to relieve pain. Morphine is used in cases of myocardial infarction, because it
will relieve pain, allay fear and may even improve cardiac function. It is used effectively as
a premedication drug in patients who are apprehensive of surgery. It is useful in pulmonary
edema, and the opium tincture known as paregoric is used in the treatment of diarrhea due
to direct contraction of the smooth muscles. It may be used to relieve severe pain in cancer
patients. Morphine and the synthetic and semi-synthetic derivatives develop tolerance if
administered for a long time.

Adverse effects
Respiratory depression is a major side effect, depending on duration and dosage used.
Morphine poisoning is marked by pinpointed pupils, shallow respiration and deep sleep.
Other side effects include nausea, vomiting, mental clouding, restlessness, constipation,
urticaria and insomnia.
Morphine may be administered by SC, IM and IV. Morphine and derivatives should be
given with caution in patients with gallbladder disease, and pancreatitis.

Comments on some morphine derivatives

Since the pharmacology of morphine is representative of the group, comments will be
useful on drugs where it is of pharmacologic importance.
1. Heroin is very addicting; it is more potent but has no therapeutic advantage over
morphine.
2. Codeine is a natural alkaloid. It is less potent than morphine. It may produce excitement,
has respiratory effect and is effective antitussive agent for control of cough. It is well
tolerated orally unlike morphine that must be given parentally.
3. Nalorphine has the advantage of having less respiratory depression, less vomiting effects
and less addicting potential. Thus it may have therapeutic advantage over morphine.
4. Hydromorphone has the advantage of being more potent, oral absorption and onset of
action are better than that of morphine, but it has shorter duration of action.
5. Mepridine has no significant advantage over morphine.
6. Methadone is effective orally with long duration of action quite unlike morphine. It is
used to gradually withdraw addicts for morphine or as a substitute for heroin to prevent
withdrawal symptoms.
7. Levorphan is more potent than morphine but has the only advantage of oral absorption;
other wise it is equally as addicting as morphine.

Analgesics
Narcotic analgesics
A. Opium alkaloids: Morphine
B. Semisynthetic: Heroin, Nalbuphine, Hydromorphone, Oxymorphone, Codeine.
C. Synthetic: Meperidine, Diphenoxylate, Loperamide, Fentayl, Methadone Propoxyphene,
Methorphan, Levorphan, Pentazocine
D. Opiate (Narcotic antagonists): Nalorphine, Naloxone, Levallorphan
Non-narcotic analgesics
Non-steroidal anti-inflammatory agents (NSAID)
Aspirin and other salicylates
Ibuprofen
Naproxen
Indomethacin
Phenylbutazone
Tolmetin
Sulindac
Other analgesics and antipyretics
Acetaminophen, paracctamoll

Narcotic antagonists
Narcotic antagonists abolish the narcotic actions and effects when administered with
narcotic analgesics. Because they have analgesic effects and properties similar to morphine,
they are said to be weak narcotics that displace the strong ones at their receptors.
ANALGESICS

Narcotic Non-narcotic (Synthetic)

A B C D NSAID E
Natural Semisynthetic Synthetic Anti-inflammatory Antipyretic
antipyretic only

NARCOTIC
ACTIONS

Abolish Narcotic Antagonist

Schematic classification of Analgesics

1. Nalorphine hydrochloride is poorly absorbed orally. It is only available for parental
administration.
2. Levallorphan tartrate is more potent than malorphine but has the agonist’s effects and
therapeutic uses
3. Naloxone hydrochloride is the drug of first choice in treating narcotic-induced
respiratory depression. It has only morhine-antagonistic effects. It is more potent than
nalorphine and has no narcotic effects common to nalorphine and levallorphan. It is
useful both in the diagnosis of physical dependence on narcotics and in abolishing acute
respiratory depression caused by narcotic overdosage. It is available for parenteral
administration.

Non-narcotic Analgesics
Several analgesics, unrelated to the opiates have in addition to analgesic effects anti-
inflammatory properties and antipyretic. Majority of them have analgesic as well as anti-
inflammatory properties are called nonsteroidal anti-inflammatory drugs. Aspirin and
salicylates belong to this group of nonsteroidal anti-inflammatory drugs (NSAID). Aspirin
and derivatives have analgesic, anti-inflammatory and antipyretic properties which many
drugs under this group do not have. These properties have made aspirin very popular
analgesic in common use. Aspirin will be used to discuss the pharmacology of other
NSAID that have similar actions.
Some Common Narcotic Preparations
Generic Name Brand Name Dose Range (in mg)
Narocties
Morphine Sulphate Morphine 10
Nalbuphine HCL Nubain 1.5
Codeine phosphate Codeine 30-60
Meperidine HCL Demerol, Pethidine 50-100
Hydromorphone HCL Dilaudid 1.5
Oxymorphone HCL Numorphan 1.5
Hydrocodone bitartrate - 5
Diphenoxylate HCL Lomotil 2.5
Methadone HCL Dolophine, Methalone 10
Pentazocine Talwin 3.-50
Narcotic Opioid
Antagonists
Nalorphine Nalline 2
Levallorphan tartrate Lorfan 0.5
Naloxone Narcan 0.4

Aspirin and salicylates

Aspirin is generally called acetylsalicylic acid. This is important because it is not very
stable and undergoes hydrolysis very easily to -salicylic acid and acetic acid.

Action
The mechanism of action by which aspirin and other NSAID cause their antipyretic, anti-
inflammatory and analgesic effects is due to their ability to inhibit prostaglandin synthesis.
This involves a series of sequential synthesis and enzyme inhibition that are not within the
scope of this text. In summary, the so-called prostaglandins elicit various actions in the
body which these drugs abolish. Prostaglandins, for instance, mediate inflammatory
reactions in arthritis; administration of salicylates or any of the NSAIDS will abolish or
reduce these inflammatory reactions. By the same or similar reactions, they abolish pyrexia
by reducing body temperature and exert analgesic property. This is why they are commonly
used in rheumatic fever and arthritis. Salicylates depress the CNS and its analgesic effect is
not accompanied by sedation or euphoria quite unlike the opiates. At normal dosage,
salicylates are well tolerated and various organs of the body are not affected. But a large
and chronic dosage, salicylates may stimulate respiration which may lead to acid-base
imbalance. The gastrointestinal system is adversely affected by NSAIDS, and this may
include nausea, vomiting, minor ulceration to frank hemorrhage. Salicylates and other
NSAIDS have various effects on uric acid excretion, skin reactions and kidney functions.

Absorption, metabolism and elimination

Aspirin is well absorbed orally, metabolized in the liver and quickly eliminated by the
kidney. This makes frequent administration necessary. Administration with food may delay
absorption and at the same time reduce some of the gastrointestinal side effects.

Therapeutic uses
The major use is as analgesic in the treatment of minor aches and pains e.g. headache,
neuritis, rheumatoid arthritis and rheumatic fever, neuralgia, dysmenorrheal and to reduce
or prevent fever. Aspirin is very useful in relieving pain associated with inflammation.
Major salicylates include aspirin which is available in tablet form, (plain, enteric, coated
and buffered tablets). Sodium salicylate is also mainly available in tablet form while choline
salicylate is available in liquid form. Aspirin is so popular that it is part of several drug
combinations all over the world.

Side-effects
With so many effects on various organs of the body, salicylates and all the NSAIDs have
numerous side effects enumerated, include gastric irritation and aggravation of ulcers and
therefore bleeding in severe cases. Aspirin poisoning (salicylism) is characterized by
nausea, vomiting, auditory and visual disturbances, dizziness and hypoventilation. Skin
eruptions, depression, coma, hypotension, irregular pulse and respiratory failure are other
toxic effects. Hypersensitivity reactions may occur in patients after ingesting very small
amount of aspirin. This may be characterized by bronchoconstriction, urticaria, and
anaphylactic shock. Those allergic to aspirins may stay away from NSAIDs as cross
sensitivity may occur. Aspirin and other NSAIDs may interact with some drugs like
anticoagulants and oral hypoglycemic agent increasing their activities.
Nursing teaching before administration of NSAIDs and ASA should include all these
aspects.

Comments on other NSAIDs

Essentially, as stated before, all NSAIDs have the same mechanism of action as aspirin.
They inhibit prostaglandin synthetase. They are all useful in the treatment of chronic
inflammatory diseases like rheumatoid arthritis, gouty arthritis, osteoarthritis and
ankylosing spondylitis. Some have been indicated in the relief of menstrual pain.
1. Pyrazolone derivatives include dipyrone (Novalgin for its antipyretic action),
sulfinpyrazon (used for uricosuric action), phenylbutazone and oxyphebutazone. These
are mainly used in the treatment of gout and rheumatoid arthritis. However,
administration should not exceed one week. Common side effects include
hepatotoxicity, renal damage, aplastic anaemia, agranulocytosis and thrombocytopenia.
Minor side effects are edema, nausea, vomiting and gastrointestinal ulceration.
2. Propionic acid derivatives include ibuprofen, naproxen and fenaprofen. Except for
differences in the rate of absorption, metabolism and elimination, these drugs have
similar pharmacological effects. However, some may be less potent than aspirin.
3. Acetic acid derivatives include indomethacin, tolmetin sodium and sulindac. These
share same pharmacological actions and effects as other NSAIDs with some individual
exceptions. Both the indications and side effects are essentially the same.

Other analgesics
Acetaminophen (paracetamol) and phenacetin stand on their own as alternative to aspirin.
Phenacetin and acetaminophen have the disadvantage of not being anti-inflammatory. They
are used as analgesics and antipyretics in the relief of pain, aches and fever. They may
relieve pain by producing vaso-dilation and increasing heat elimination, thus effecting anti-
pyretic action. Or they may act similar to aspirin by the mechanism of inhibition of
prostaglandins.
Both drugs are used in combination with aspirin and caffeine in the formulation of
commonly used analgesics like APC. These drugs relatively safe, but chronic and large
dosage administration may damage the liver and kidney. They do not cause gastrointestinal
disturbances as aspirin, and therefore form good substitute for those allergic to or who
cannot tolerate aspirin.

Non-narcotic preparation
Generic Name Brand Name
Acetaminophen Paracetamol, Tylenol
Ibuprofen Motrin, Brufen
Aspirin Bayer
Fenoprofen Nalfon
Dypyrone Novalgin
Naproxen Naprosyn
Idomethacin Indocin, indocid
Tolmatin Tolectin, Buta
Phenylbutazone Clinoril
Sulindac Talwin, Fortwin
Pentazocine -
Oxyphenylbutazone
Sodium Salicylate
Analgesic Combinations
Aspirin, Phenacetin, Caffeine APC
Aspirin, Cafferine Anacin, Cafenol, Phensic
Aspirin, Paracetamol Assia
Propozyphen, Acetaminophen Avalpro
Aspirin, Codeine Codis
Aspirin, Calcium Carbonate Dispirin
Aspirin, Meprobamate
ethoheptazin Equagisic