Transcript emergency collectionx

Common medical emergencies
and drug toxicity
By
Dr. Mohamed Abdel Moneim Attia
PARASYMPATHOMIMETICS (Cholinomimetics)
This group of drugs produces pharmacological effects similar to that
produced by parasympathetic stimulation
Classification
1- DIRECTLY ACTING PARASYMPATHOMIMETICS
They directly stimulate the cholinergic receptors.
A. Choline esters:
•
•
•
•
Acetylcholine.
Carbachol.
Bethanechol
Methacholine
B. Alkaloids:
• Pilocarpine.
• Muscarine.
2- INDIRECTLY ACTING PARASYMPATHOMIMETICS
(CHOLINE ESTERASE INHIBITORS)
They inhibit cholineesterase enzymes leading to
accumulation of A.ch at the receptor sites which in turn
produces the cholinergic effects on (CNS, NMJ, Ganglia,
wall of blood vessels... etc.).
A. Reversible cholineesterase inhibitors.
• Physostigmine
• Neostigmine and its substitutes.
• Tacrine
• Donepezil
B. Irreversible cholineesterase inhibitors.
• Organophosphorous compounds.
ACETYLCHOLINE (A.Ch)
Pharmacokinetics
A.ch is inactive orally because it is poorly absorbed
being a quaternary ammonium compound. I.V. it has
very short duration of action because it is rapidly
metabolized by choline esterase enzymes.
True cholinesterase enzyme
Pseudocholinesterase
enzyme
Site
Cholinergic nerve - CNS –
RBCs
Plasma – liver – intestine
Synthesis
3 months
2-3 weeks
Specificity
specific
Not specific
►Pharmacodynamics
 Mechanism of Action: act via:
• Stimulation of the muscarinic receptors.
• Stimulation of the nicotinic receptors.
Cholinoceptors
• They are broadly subdivided into muscarinic and
nicotinic receptors.
A. Muscarinic receptors (peripheral, M receptors)
Types:
M1 receptors:
Are present in autonomic ganglia, CNS and parietal cells of the stomach
M2 receptors:
• Are present in heart.
• also present presynaptically on the cholinergic fibers to inhibit
acetylcholine release (feedback)
M3 receptors: are present in smooth muscle fibers and secretory glands.
M4 and M5 receptors: in the C.N.S.
B. Nicotinic receptors (central, N receptors)
►Types:
Nn (Neuronal nicotinic receptors): present in autonomic ganglia and
suprarenal medulla.
Nm (Muscle nicotinic receptors): present in the neuromuscular junction.
Pharmacological Effects
*C.V.S
• Heart:
Decreases all cardiac properties, except the conduction in the atria,
which is increased.
• Blood vessels: generalized vasodilatation.
• Blood pressure: blood pressure is decreased.
*G.I.T:
A.ch increases gastric and intestinal peristalsis and relax the
sphincters. It also stimulates salivary and gastric secretions.
*Lung:
bronchoconstriction and increased bronchial secretion.
*Urinary tract:
A.ch contracts the detrusor muscle and relaxes the sphincter of the
urinary bladder.
*Eye:
A.ch produces meiosis.
►Skeletal muscles: stimulate motor end plate.
►Therapeutic Uses
It has limited use because of its short duration and
non-selectivity.
►Untoward Effects
All effects produced by A.ch are untoward effect.
►INDIRECTLY ACTING PARASYMPATHOMIMETICS
(Cholinesterase Inhibitors)
►Mechanism of action
By inhibiting cholinesterase, the indirect – acting
agonists “amplify” the action of endogenous
acetylcholine. Therefore, the indirect agents have
muscarinic or nicotinic.
A- REVERSIBLE CHOLINESTERASE INHIBITORS
1- PHYSOSTIGMINE
►Chemistry
It is a tertiary amine
►Pharmacokinetics
Being a tertiary amine, it can diffuse readily through the mucous membranes.
It can cross blood brain barrier.
►Pharmacodynamics
 Mechanism of Action
Physostigmine binds to both esteratic and anionic sites of cholinesterase
enzymes.
The attraction between this drug and the enzyme is 10,000 times that of Ach,
but this binding is loose and the drug would dissociate gradually leaving the
enzyme free.
Binding of physostigmine to cholinesterase leads to accumulation of Ach in the
effector organs (CNS, NMJ, Ganglia, blood vessels and opposite the
parasympathetic nerve endings).
Pharmacological Effects
Muscarinic effects. (See above) , Nicotinic effects. (See above)
CNS effects: headache, restlessness, insomnia, nightmares, tremors and
convulsions.
►Therapeutic Uses
1-Treatment of glaucoma (locally in the eye)
2-To counteract the mydriatic effect and cycloplegia produced by atropine.
4-Treatment of atropine poisoning and tricyclic antidepressant toxicity.
5-Alzheimer disease.
Donepezil , Tacrine and Rivastigmine
Are new, centrally acting, reversible cholinesterase inhibitors that readily cross
the blood–brain barrier and act to increase the concentration of acetylcholine
at central cholinergic synapses. These drugs are used in the treatment of
Alzheimer’s disease .
►Untoward Effects
All the muscarinic effects. (See above)
All the nicotinic effects. (See above)
All the CNS effects. (See above)
2- NEOSTIGMINE (Prostigmine)
►Chemistry:
It is a synthetic quaternary ammonium compound.
►Pharmacokinetics
Being a quaternary ammonium compound, it is
irregularly absorbed from GIT and it cannot cross the
B.B.B.
►Pharmacodynamics
 Mechanism of Action
*Reversible inhibition of cholinesterase enzymes
(Muscarinic effects and Nicotinic effects ).
*Direct stimulant action on neuromuscular junctions.
*It has no CNS effects.
►Therapeutic Uses
1-Treatment and diagnosis of myasthenia gravis:
*S.C for diagnosis
*Oral for treatment.
2-Antidote to D-tubocurarine.
3-Treatment of postoperative retention of urine.
4-Treatment of paralytic ileus.
►Untoward Effects
All the muscarinic and nicotinic effects except that
intended for therapeutic purposes.
3- NEOSTIGMINE SUBSTITUTES
Neostigmine substitutes have been introduced with
the advantage of being more selective on the
neuromuscular junction or having a longer duration
of action to be more convenient for the treatment
of myasthenia gravis and other clinical purpose.
a- Pyridostigmine
b- Ambenonium : Similar to pyridostigmine.
c- Edrophonium
More selective on NMJ than neostigmine.
Very short acting (5 min.)
►Uses
• Diagnosis of myasthenia gravis.
• Treatment of myasthenic crisis.
• Differentiation between myasthenic crisis and
cholinergic crisis (Weakness due to over
treatment with anticholinesterase). It aggravates
cholinergic crisis, but improves myasthenic crisis.
• Antidote for D-tubocurarine.
Myasthenia Gravis
►Definition
Myasthenia gravis is a disease characterized by impaired
transmission at N.M.J.
Aetiology:
Autoimmune disease due to formation of antibodies that
attack the nicotinic receptors in N.M.J.
►Clinical picture
• Marked weakness of skeletal muscles.
►Diagnosis
• Edrophonium: it improves the contraction of skeletal
muscles in patient with myasthenia gravis.
• neostgmine but atropine is given before neostigmine
because atropine produced initial bradycardia followed by
tachycardia. This initial bradycardia potentiates bradycardia
caused by neostigmine → cardiac arrest.
►Treatment
• Choline estrase inhibitors:
• Ambenonium or pyridostigmine.
• Neostigmine + atropine ( If ambenonium or pyridostigmine
are unavailable).
• Ephedrine: Facilitates transmission at N.M.J.
• Immunosuppressives, corticosteroids, ACTH or
cyclosporine.
• Thymectomy.
• Kcl & Spironolactone
Myasthenic crisis
Cholinergic crisis
Cause
Deficient cholinergic
transmission
Excessive cholinergic
transmission e.g. ch. E
inhibitor overdosage.
Nicotinic manifestations
Flaccid paralysis.
Spastic paralysis. Weakness in
cholinergic crisis is due to
permanent depolarization of
nicotinic receptors at motor
end plate.
Muscarinic manifestations
No
↓ H.R. – ↓ B.P. – Miosis –
Colic – sweating.
Edrophonium test
Improves
Aggrevates.
Treatment
*Edrophonium or neostigmine 1-PAM (pralidoxime)+
+ atropine.
Atropine
*Artificial respiration
2. Artificial respiration
3. Stop causative drug
B- IRREVERSIBLE CHOLINESTERASE INHIBITORS
( ORGANOPHOSPHOROUS COMPOUNDS)
• Nerve gases: Sarin, Soman.
• Insect killers: Malathion, Parathion, TEPP
(tetraethylpyrophosphate)
• Drugs used clinically: DFP (Diisopropyl flurophosphate)
►Mechanism of Action
Organophosphorous compounds bind covalently (irreversibly) to
cholinesterase enzymes. In this situation the body has to replace
the inactivated enzymes. This replacement takes two weeks for
pseudocholine-esterase and three months for true
cholinesterase. A.ch. will accumulate at the effector sites in large
amounts producing parasympathomimetic effects.
Irreversible inhibition of the enzyme takes about 1-12 hrs after
exposure until the complex (enzyme and organophosphorous)
loses some alkyl and alkoxyl groups, a process known as aging of
the enzyme (i.e. the enzyme is no more suitable for functioning).
During the first 12 hrs after exposure the enzyme could be
reactivated.
►Pharmacological Effects (All are toxic effects)
►Toxicity
The signs and symptoms of over dosage are readily predicted
from the general pharmacology of acetylcholine.
Muscarinic Toxicity
• These include CNS stimulation , meiosis, spasm of
accommodation, bronchoconstriction, increased
gastrointestinal and genitourinary smooth muscle activity,
increased secretory activity (sweat glands, airway,
gastrointestinal tract), vasodilatation, and bradycardia.
Nicotinic Toxicity
These include CNS stimulation, ganglionic stimulation, and
neuromuscular endplate depolarization leading to fasciculation
and paralysis.
• Muscarinic effects. (See above)
• Nicotinic effects. (See above)
• CNS effects. (See above)
►Untoward Effects and Toxicity
• The indirect acting agents have toxicological
importance because of potential accidental
exposures to toxic amounts of pesticides. The most
toxic of these drugs, (e.g., parathion) is rapidly fatal
if exposure is not immediately recognized and
treated.
• Generally the clinical picture could be summarized
as follows:
Respiratory:
• Bronchospasm, respiratory distress, and paralysis of
respiratory muscles.
Cardiovascular:
• Bradycardia, hypotension and excessive cold sweating.
Gastrointestinal:
• Excessive secretions, abdominal colic, diarrhea, vomiting,
C.N.S:
• Severe meiosis, headache, irritability, skeletal muscle
fasciculation.
• Convulsions and coma are terminal manifestations.
• The usual cause of death is respiratory failure
(Bronchospasm, excessive secretions, inhibition of R.C. and
contraction of the intercostal muscles and diaphragm)
►Treatment of the Untoward Effects
Protection
• Farmers who spray the insecticides should wear gloves and masks.
• Thorough washing of vegetables.
• Glasses containing domestic insecticides should be kept away
from children.
Treatment
• Stomach wash.
• Wash the skin, if contaminated by sodium bicarbonate or ethyl
alcohol.
• Maintain the air passage open by sucking secretion and start
artificial respiration if needed.
• Atropine in high doses:
2 mg I.V. or I.M. every 5 -10 minutes until the patient is put on the
merge of atropine toxicity (dilated pupil, dry mouth, and
tachycardia).
The patient should be kept atropinized for 24 hours.
• The intoxicated patient may need up to 100 mg for
full atropinization.
• Atropine eye drops may relieve the headache
caused by miosis.
• Atropine will antagonize the peripheral and central
effects of organophosphorous compounds, but not
the action of N.M.J. and the ganglia.
• The patient should be maintained on atropine until
the enzymes are recovered.
*Convulsions may be controlled by anticonvulsants
(diazepam).
Cholinesterase re-activators (oximes):
• They should be given within 1/2 to 1 hr after exposure
maximum 12 hrs. i.e. before aging of the enzyme.
• During this period they are life saving because they react
directly with the alkylphosphorylated enzyme to free the
active unit (de-phosphorylation) of the enzyme.
• Moreover oximes compete with the enzyme for the
organophosphate i.e. (phosphorylated very easily so, they
divert the poison from cholinesterase to oximes.
Preparations
• Pralidoxime (PAM, Protopam): 2.5 gm in 100 ml I.V. infusion
(within 30 min.), 1 gm I.M. every 1 hr until recovery. 20 mg
/kg for infants and children.
• Diacetylmonoximes (DAM)
• Bisquaternary oxime.
PARASYMPATHOLYTICS (Muscarinic antagonists)
Definition
These are drugs, which block the muscarinic receptors.
Classification
A- Natural Alkaloids
Examples:
• Atropine : extracted from Atropa belladonna plant or
Datura stramonium plant.
• Scopolamine (L –Hyoscine).
B- SYNTHETIC ESTERS
These are either tertiary amines (lipid soluble and cross
the blood brain barrier or quaternary amines (lipid
insoluble) and cannot cross the blood brain barrier).
• They are classified according to their clinical uses into:
- Drugs mainly used to treat the manifestations of parkinson’s
disease:
Benzatropine ,Trihexyphenidyl ,Biperiden.
2- Drugs mainly used to produce mydriasis and cycloplegia:
Atropine, Homatropine, Eucatropine, Cyclopentolate
,Tropicamide .
3- Drugs mainly used to produce bronchodilation:
Ipratropium, tiotropium
4- Drugs mainly used as antisecretory and antispasmodic on
the GIT:
Hyoscine butylbromide ,Homatropine methyl bromide
,Propantheline
5- Drugs mainly used for its effect on the genitourinary
system:
Oxybutynin, Glycopyrrolate ,Emepronium.
►Pharmacokinetics of Atropine
Because it is a tertiary amine, atropine is relatively lipid soluble and
readily crosses membrane barriers. The drug is well distributed into
the CNS and other organs
The duration of action of normal doses is 4-8 hours except in the eye,
where effects last for 72 hours longer
Pharmacological Effects
The peripheral actions of muscarinic blockers are mostly predictable
effects derived from cholinoceptor blockade . These include the
ocular, GI, genitourinary, and secretory effects.
The CNS effects are less predictable. Those seen at therapeutic
concentrations include sedation, reduction of motion sickness, and,
reduction of some of the signs of parkinsonism.
Cardiovascular effects at therapeutic doses include an initial slowing
of heart rate caused by stimulation of the central vagal nucleus,
followed by the tachycardia and decreased atrioventricular
conduction time that would be predicted from peripheral vagal
blockade.
►Clinical Uses
The muscarinic blockers have several useful therapeutic applications in the
central nervous system, eye, bronchi, gut, and the urinary bladder.
Cardiovascular:
• Bradycardias and heart blook
• Treatment of bradycardia caused by excessive beta-blockers
• Treatment of reflex bradycardia caused by alpha stimulants e.g.
noradrenaline
Neurological:
• Motion Sickness:
• scopolamine is a standard therapy for motion sickness; this drug is one of
the most effective agents available for this condition.
• A transdermal patch formulation is available.
• Treatment of parkinsonism:
• benztropine, biperiden, and trihexyphenidyle are representative of
several antimuscarinic agents used in parkinsonism.
Eye (Local drops)
• Fundus examination: Antimuscarinic drugs (Substitutes are
better) are used to dilate the pupil and to paralyze
accommodation.
• To counteract the effect of miotics.
• Iritis and iridocyclitis:
• Alternatively with miotics to cut recent mild adhesions
between the iris and anterior surface of the lens.
Bronchi:
• Ipratropium is a quaternary antimuscarinic agent used by
inhalation to reduce bronchoconstriction in asthma and
chronic obstructive pulmonary disease (COPD). Although
not as effective as beta gonists, ipratropium is less likely to
cause cardiac arrhythmias. It has very few antimuscarinic
effects outside the lungs because it is poorly absorbed and
rapidly metabolized.
Gastrointestinal:
• To relieve spasm in the G.I.T (intestinal colic, spastic
colon and biliary colic)
• Muscarinic blockers can also be used to reduce
cramping and hypermotility in transient diarrheas.
Bladder:
• Cystitis: Glycopyrrolate, and similar agents may be
used to reduce urgency in mild cystitis and to reduce
bladder spasms following urologic surgery.
• Nocturnal enuresis: emepronium could be used for
treatment of nocturnal enuresis and urinary
incontinence
• To releive ureteric spasm in renal colics
In Pre-Anaesthetic Medication
Atropine is given half an hour before the administration
of the general anaesthetic to produce the following:
• Decrease salivary and bronchial secretion:
• This prevents or minimizes the possibility of inhalation
of the salivary secretions preventing the postoperative
lung infection.
• The inhibition of the mucus secretion in the bronchial
tree prevents the possibility of blockage of a main
bronchus, which could lead to lung collapse.
• Atropine protects the heart from excessive vagal tone,
which sometimes occur at the beginning of the first
plane of the surgical stage of anesthesia (Stage III).
• Counteracts the inhibitory effect of morphine and the
anaesthetic on the respiratory center.
►Side Effects
Mild side effects may develop after the use of therapeutic doses for
example:
• Dryness of the mouth.
• Skin flushing:
• Children are more susceptible to develop coetaneous V.D which
makes the child flushed and this is usually accompanied by slight
elevation of body temperature (Due to reduction of sweating)
especially in hot environments.
• Retention of urine especially in patients with enlarged prostate.
• Acute attack of glaucoma in patients who have or susceptible to
glaucoma.
►Toxicity
A traditional mnemonic for atropine toxicity is “Dry as a bone, red
as a beet, mad as a hatter “. This description reflects both
predictable antimuscarinic effects and some unpredictable actions.
In young children
• Blockade of thermoregulatory sweating may result in
hyperthermia or “ atropine fever”. This is the most dangerous
effect of the antimuscarinic drugs and is potentially lethal in
infants.
In adults
• Dryness of secretions:
• The condition is described by “dry as a bone “ because
sweating, salivation, and lacrimation are all significantly
reduced or stopped in the elderly.
• Acute angle – closure glaucoma may occur
• Urinary retention is possible.
• Constipation.
• Blurred vision is common adverse effects in all age groups.
• Full dilatation of the pupil and lost light reflex.
Other Toxicity
Toxicity not predictable from peripheral autonomic actions include the
following: , Dry as bone, Blind as bat, red as beet, mad as hatter.
CNS effects:
• CNS toxicity includes:
• sedation, amnesia, and delirium or hallucinations (“mad as a hatter”)
• convulsions and excitation may develop and later this excitation is followed
by depression in the form of coma and the cause of death is respiratory
failure.
Cardiovascular effects:
• At toxic doses, intraventricualr conduction may be blocked; this action is
probably not mediated by muscarinic blockade and is difficult to treat.
• Dilation of the cutaneous vessels of the arms, head, neck and trunk also
occurs at these doses; the resulting “atropine flush“ (“red as a beet”) may
be diagnostic of overdose with these drugs.
Treatment of Toxicity (symptomatic)
• Control of environmental temperature and
application of cold baths and sponges.
• Cathetrization if necessary.
• Protection of the respiratory system.
• Avoidance of over treatment of convulsions by
barbiturates.
• Physostigmine may be used to counteract the CNS
effects. Can we use nesostigmine?
The lethal dose in adults is more than 0.5 gm of
atropine and more than 0.2 -0.3 gm of scopolamine.
NEUROMUSCULAR BLOCKING AGENTS
The prototype non-depolarizing agent is d-tubocurarine; the
prototype-depolarizing drug is succinylcholine.
►Pharmacokinetics
• Succinylcholine is composed of two acetylcholine molecules
linked end to end.
• Succinylcholine is metabolized by plasma cholinesterase
(butyrylcholinesterase or pseudocholinesterase)
• It has a duration of action of only a few minutes if given as a
single dose. It is given by continuous infusion if prolonged
paralysis is required.
►Toxicity
1-Respiratory paralysis: succinyl choline apnea.
• Is due to abnormal deficiency of pseudocholinestrase enzyme activity.
• Treatment:
1-Artifecial respiration.
2-fesh plasma or blood tranfusion.
• Dibucaine number: It is a test of the ability of
pseudocholinestrase to metabolize succinylcholine.
Dibucaine is an enzyme inhibitor, which inhibit 80%
of normal enzyme and 25% of abnormal enzyme.
• Malignant Hyperthermia (Hereditary Condition)
– Multiple Triggering Mechanisms
• Anesthesia
• Drugs (general anesthesia, succinylcholine)
• Illness & Stress
– Triggering Mechanism Affects reuptake of calcium by
sarcoplasmic reticulum necessary for termination of muscle
contraction. It results in:
*Massive Muscle Contraction
*Excessive Lactate Production (acidosis, tachycardia, hypercarbia,
hypoxemia).
*Pronounced Increase In body Temperature due to unccoupling
oxidative phosphorylation.
Teatment:
1-I.V dantrolene.
• Interferes with excitation-contraction coupling
• Reduces release of Ca++ from the sarcoplasmic reticulum
• Blocks contraction
2-cooling.
3-corecxt acidosis.
• ANALGESICS
Opiate and Non-opiate analgesics.
Opiates (morphine)
Non-opiates (aspirin)
Type of pain relieved
Any type of pain except
itching
Low intensity pain
(headache, toothache,
muscle pain,..etc)
Site of action
Cortex and subcortex
Subcortex (thalamus)
Relief of pain is
accompanied by:
Euphoria, narcosis and
abnormal emotional reaction
for pain
No euphoria, narcosis or
modified emotional
reaction
Addiction
Almost occur
Never occurs
MORPHINE
Pharmacokinetics
90% a given dose is excreted in the urine; the remaining 10% is excreted in
the feces.
Pharmacologic effects
 CNS effects:
Dose-related analgesia.
patients taking morphine become euphoric (feel freedom for anxiety).
If morphine is given to a person who is pain-free, dysphoria, anxiety or
mental clouding may be produced.
Morphine can treat all types of pain except itching.
Morphine stimulates the chemoreceptor trigger zone, producing nausea and
vomiting.
Morphine produces miosis by stimulating the Edinger-Westphal nucleus and
pinpoint pupils are indicative of toxic dosage prior to asphyxia.
Morphine is a powerful respiratory depressant, which acts by reducing the
responsiveness of the respiratory centers in the brain stem to blood levels
of carbon dioxide. Due to the depressed respiration and increased arterial
carbon dioxide retention, cerebral vasodilatation can occur, causing an
increase in intracranial pressure
Morphine is a potent cough suppressant.
Autonomic effects:
Cardiovascular effects:
Histamine release:
Spasmogenic effects:
• Uses: 3As
Adverse effects
 CNS:
Dysphoria, restlessness, hyperactivity and mental
cloudiness can occur
Long-term chronic administration can result in
physical dependence.
Increased intracranial tension.
Tolerance and dependence:
Physical dependence occurs within 24 hours if given
/4 hours.
Respiratory:
Depression is the most important effect and is dose dependent.
Bronchoconstrictive action
 Gastrointestinal:
Nausea and constipation.
Increased biliary tract pressure can occur
 Genitourinary: Urine retention.
Prolongation of labor.
 Allergic reactions:
can occur and skin rashes are a common manifestation (due to histamine
release).
 Eye:
Pinpoint pupils are a consistent finding in addiction.
CVS:
Postural hypotension
A. Acute opioid (or morphine) toxicity:
Symptoms and signs:
The patient is comatosed with depressed respiration, pin point pupils, hypotension,
pulmonary oedema and shock may occur.
When death occurs, it is always due to respiratory failure.
Treatment:
If large amounts are taken orally, gastric lavage is done with potassium permnganate
solution.
Establish a patent airway and ventilate the patient by positive pressure ventilation if
pulmonary oedema is present.
Opioid antagonists as:
 Naloxone:
Naloxone is a pure antagonist to opiates.
Can produce dramatic reversal of the respiratory depression.
It is given in a dose of 0.4 - 0.8 mg and repeated every 2 - 3 minutes for 2 - 3 doses.
Care should be taken as the antagonist may precipitate a severe withdrawal syndrome.
 Nalorphine:
Agonist-antagonist like nalorphine can be used only when the diagnosis of morphine
poisoning is certain (its agonist effect aggravates respiratory depression).
Chronic opioid (or morphine) toxicity (addiction)
It results from addiction. The patient is emaciated,
constipated with frequent flushes and itching. The
intellectual functions are also depressed.
• Withdrawal:
It results in what is called the abstinence syndrome where
the patient becomes irritable, nervous, having tremors,
hypertension, sweating, vomiting and with abdominal
cramps.
These manifestations usually start 6-10 hours from last
dose and peak effect are seen at 36-48 hours, after
which manifestations gradually subside over 5-10 days.
• In severe cases cardiovascular collapse and death may
occur.
Treatment of morphine addiction:
• Hospitalization.
• Gradual withdrawal is essential otherwise acute
abstinence syndrome may occur. This is with
replacement by the synthetic morphine
substitute methadone.
• Once the patient is stabilized on methadone, its
dose should be gradually decreased to an end.
• Clonidine
• Sedative can be used
• Naltrexone (pure antagonist).
Classification of non opiate analgesics:
(Acetaminophen).
(Glafenine).
Nefopam .
Dipyron (Novalgin).
Non-steroidal anti-inflammatory drugs
(NSAIDs).
N.B
Prostaglandins are derived from arachidonic acid by the action of
cyclooxygenase (COX) enzyme which has 3 isoforms:
COX-1(physiological; constitutive):
Is normally present in the tissues i.e. constitutive and it is involved in synthesis
of protective PGs (e.g. PGE2, PGI2) responsible for protection of stomach
from HCl, regulation of RBF, regulation of platelet aggregation, etc.
COX-2 (pathological; inducible):
is involved in synthesis of undesirable PGs included in the inflammatory
reactions, bronchoconstriction, etc., therefore COX-2 activity is markedly
increased during these pathological conditions i.e. inducible
COX-3 (central):
Found only in the brain and may be included in synthesis of PGs responsible
for fever and pain sensation. Acetaminophen and dipyrone,
analgesic/antipyretic actions are assumed to be due to selective inhibition
of COX-3 enzyme..
ACETAMINOPHEN (PARACETAMOL)
Pharmacokinetics
Acetaminophen is completely and rapidly absorbed
from the gastrointestinal tract.
80%-90% is conjugated with glucuronic or sulfuric
acid in the liver and then excreted in the urine.
At high doses, one of these metabolites undergoes
spontaneous dehydration to form N-acetyl-Pbenzoquinone, the metabolite thought to be
responsible for hepatotoxicity.
Pharmacologic effects:
Acetaminophen is an effective analgesic and antipyretic
agent but it has no anti-inflammatory activity.
It appears to be an inhibitor of prostaglandin synthesis
in the brain, and thus explaining its analgesic and
antipyretic activity, but it is much less effective than
aspirin as an inhibitor of the peripherally located
prostaglandin biosynthetic enzyme system that plays
such an important role in inflammation.
It exerts little or no pharmacologic effect on the
cardiovascular, respiratory, or gastrointestinal
systems, on acid-base regulation, or on platelet
function as aspirin dose.
Therapeutic uses
Acetaminophen provides an effective alternative as analgesic and
antipyretic when aspirin is contraindicated (e.g. in-patients with
peptic ulcer or hemophilia) and when the anti-inflammatory
action of aspirin is not required.
Preparations and administration
Acetaminophen is available in tablet and liquid forms and is
administered orally in dose of 500 mg t.d.s.
Adverse effects:
A. At therapeutic doses, acetaminophen is well tolerated; however,
untoward effects include:
*Skin rash and drug fever (an allergic reaction to the drug).
*Rare instances of blood dyscrasias (haemolyticanaemia in with
G6PD deficiency, less than with phenacetin).
*Renal tubular necrosis and renal failure (more with phenacetin).
B.An overdose of acetaminophen(about 15 gm in an
adult; about 4 gm in a child)
can result in severe hepatotoxicity, resulting in
centrilobular hepatic necrosis. Doses greater than 20
gm are potentially fatal.
The toxic metabolite of acetaminophen appears to be
inactivated in the liver via glutathione.
It is thought that when glutathione stores are
consumed, the N-acetyl-p-benzoquinone metabolite
binds covalently to cellular constituents, producing
hepatocellular damage.
Although clinical symptoms, such as nausea and
vomiting, occur during the first 24 hours after toxic
ingestion, signs of hepatic damage (e.g. enzyme
abnormalities) may not occur for 2 - 6 days).
Treatment consists of:
Emptying the stomach & administering activated
charcoal
Hemodialysis, if begun within the first 12 hours after
ingestion.
Administration of sulfhydryl compounds (e.g.
acetylcysteine) which probably replenish hepatic
stores of glutathione.
NSAID:
Classification
A.Non-selective COX inhibitors (inhibit COX-1 and COX-2):
Salicylic acid derivatives: aspirin, aloxiprine, aminosalicylic acid,
diflunisal, methyl salicylate, etc.
Acetic acid derivatives: indomethacin, sulindac, diclofenac
Propionic acid derivatives:iboprufen, ketoprofen, fenoprufen,
naproxen.
Fenamic acid derivatives:mefenamic acid, fulfenamic acid.
Pyrazolonederivatives:phenylbutazone, azapropazone
Oxicams:piroxicam, tinoxicam.
B. Selective COX-2 inhibitors: Celecoxib, valdecoxib,
meloxicam.
Salicylate toxicity
1.Acute toxicity:
Cause: ingestion of large doses of salicylates.
Manifestations:
• Nausea, vomiting, hematemesis.
• Acidosis and dehydration.
• Pulmonary edema and cardiovascular collapse.
• Hyperpyrexia, hyperventilation, irritability, convulsions, coma.
• Treatment:
• Repeated gastric lavage with activated charcoal.
• Cold fomentations for hyperpyrexia.
• Vit K 10-30 mg i.m. to control hemorrhage.
• i.v. fluids to correct dehydration.
• i.v. sodium bicarbonate to correct acidosis.
• Alkalinization of urine: to enhance salicylate excretion.
• Hemodialysis in severe cases.
2.Chronic toxicity: (Salicylism):
Cause:
prolonged administration of salicylates.
Manifestations:
headache, tinnitus, tachypnea, respiratory alkalosis.
Treatment:
just stop salicylates. The condition is reversible.
ADRENOCORTICAL STEROIDS
The natural adrenocortical hormones are steroid
molecules produced and released by the adrenal
cortex. Secretion of adrenocortical steroids is
controlled by the pituitary release of ACTH.
• Metabolic Effects:
On carbohydrate metabolism: leading to increase
in serum glucose levels
On fat metabolism:
Catabolic and Antianabolic Effects:
• Anti-inflammatory and Immunosuppressive
Effects:
Glucocorticoids dramatically reduce the
manifestations of inflammation.
On the electrolytes and water balance:
On CVS:
Anti-shock effects:
Haematological effects:
On CNS:
On growth:
On bone:
Hormonal effects:
Glucocorticoids given chronically suppress the
pituitary release of ACTH, GH, TSH, and LH.
Development of the fetal lungs:
Enhance uric acid excretion:
Doses
Dosage requirements are variable and must be
individualized.:
Short-term therapy:
The patient needs duration less than 2 weeks.
Alternate day therapy:
The recommended dose is multiplied by 2 given every
other day (to give chance for the pituitary to release
ACTH and prevent sudden withdrawal symptoms).
Long term therapy:
The patient needs duration more than 3 weeks.
Small and large dose therapy:
Uses:
Replacement therapy:
A. Treatment of adrenocortical insufficiency:
In chronic adrenocortical insufficiency (Addison’s disease) e.g. TB of suprarenal
cortex.
B. In acute adrencortical insufficiency (Addisonian crisis), i.e.
Prolonged corticosteroid therapy produce feed back inhibition of
anterior pituitary which decrease ACTH secretion results in
decrease corticosteroid release from adrenal cortex. When the
exogenous corticosreoid therapy is stopped, its blood level
markedly decrease leading to severe hypoadrenal function, severe
hypotension and shock (adrenal crisis)
Treatment:
Therapy consists of correction of fluid and electrolyte abnormalities
Treatment of precipitating factors
Large amounts of parenteral hydrocortisone. Hydrocortisone sodium
succinate or phosphate in doses of 100 mg intravenously is given
every 8 hours until the patient is stable. The dose is then gradually
reduced, achieving maintenance dosage within 5 days.
Hypothalamo-pituitary-adrenal axis suppression
(addissonian crisis):
This can be avoided by:
*Gradual withdrawal of the corticosteroids to give chance for
the pituitary to release ACTH and stimulate adrenal cortex to
secrete endogenous corticosteroids.
*Alternate day therapy.
*Avoid prolonged use.
*Give long acting ACTH before stoping corticosteroids.
Side effects of glucocorticoids are related to large doses
and/or prolonged administrations. When the
glucocorticoids are used for short periods (less than 2
weeks), it is unusual to see serious adverse effects
even with moderately large doses.
Status epileticus:
Defined as recurrent or continuous seizure activity lasting longer than 30
minutes in which the patient baseline consciousness is not regained between
the seizures. OR occurrence of serial convulsions between which there is no
return of consciousness
Can lead to systemic hypoxia, acidosis, hyperpyrexia, cardiovascular collapse
and coma . Death occurs in 5-10%.
Treatment:
status epilepticus is life-threatening and must be treated immediately
with concomitant cardiovascular, respiratory and metabolic
management.
1-diazepem 10 mg I.V. repeat dose (5-10 mg) every 20-30 min.
2-clonazepam 1mg I.V. repeat dose (2-6 mg) every 20-30 min
3-phenytoin 10-20 mg I.V.
4-phenobarbitone 10-20 mg/kg slow I.V.
5-general anesthesia with propofol or thipentone should be
commenced immediately.
Causes of Status Epilepticus
• Prolonged febrile seizure (commonest) cause.
• Idiopathic status epilepticus
– Non-compliance to anti-epileptics
– Sudden withdrawal of anti-epileptics
– infection
• Symptomatic status epilepticus
– Encephalitis, meningitis
– Electrolyte disturbances, tumours
Paralytic ileus:
• Many causes but the postoperative (specially
intraperitoneal) type is the commonest.
• This type of ileus spontaneously resolves within 23 days after sigmoid motility returns to normal ,
however, the term postoperative adynamic ileus
or paralytic ileus is defined as ileus of the gut
persisting for more than 3 days following surgery.
• There is no mechanical obstruction and there is
accumulation of both gas and fluid within the
bowel.
• The longest duration of ileus is noted to occur
after colonic surgery.
Clinical picture:
• Patient may have distended tender and tympanic abdomen,
depending on degree of bowel distension.
• Absent bowel sounds (unlike high pitched sounds of intestinal
obstruction).
Treatment:
1-delay oral feeding until ileus resolves clinically
Most cases resolves with watchful waiting and supportive
treatment.
2-discontinue medications which can cause ileus as morphine.
3-NSAID may improve the condition by improving local
inflammation and by decreasing the amounts of narcotics
analgesics used.
4-prokinetics as neostigmine mosapride.
5-check and treat electrolyte imbalance as hypokalaemia.
Cardiac arrest:
Causes:
1-myocardial infarction.
2-anaphylactic shock.
3-…..anaesthetic agents….etc.
Clinical picture:
1-unconciousness.
2-pallor of the skin.
Absence of arterial pulse (radial and carotid). Try to
listen to heart sounds.
4-lack of bleeding from a surgical wound.
5-pupill will be dilated (late).
Treatment:
cardiopulmonary resuscitation should be performed
immediately as brain death will occur if oxygen is cut
off for 3 minutes:
• Positioning of the patient to help venous return.
• start external cardiac massage.
• Artificial respiration…..
• Adrenaline intracardiac (why?)
Toxicity of Iron
 Acute Iron Toxicity:
It is seen almost exclusively in young children who have accidentally ingested iron tablets.
Oral iron preparations should therefore always be stored in "childproof" containers and kept out of reach of
children.
Large amounts of oral iron cause:
Necrotizing gastroenteritis, with vomiting, abdominal pain and bloody diarrhea followed by shock, lethargy, and
dyspnea.
Subsequently, improvement is often noted, but this may be followed by severe metabolic acidosis, coma, and
death.
Treatment
Gastric aspiration should be performed, followed by lavage within 1 hour with phosphate or carbonate solutions to
form insoluble iron salts.
Desferoxamine (Desferal), a potent iron chelating compound:
5 gm in 100 ml water should then be instilled into the stomach to bind any remaining free iron in the gut. It is not
absorbed from GIT.
Deferoxamine 1-2 gm should also be given systemically by intermittent IMI or by continuous IV infusion of 15
mg/Kg/hour to bind iron that has already been absorbed and to promote its excretion in urine and feces.
Appropriate supportive or symptomatic therapy for gastrointestinal bleeding, metabolic acidosis, and shock must
also be provided.
Chronic Iron Toxicity:
Most commonly occurs in patients with haemochromatosis which is an inherited disorder characterized by:
excessive iron absorption
in patient who receive many red cell transfusions over a long period of time. It results in iron deposition in the
heart, liver, pancreas and other organs.
Keep calm and
study hard