****** CARBON MONOXIDE ******
Characteristics
1. Tasteless,
odorless and colorless gas that is produced by incomplete combustion of organic
matter.
e.g.
automobile exhaust, improperly vented gas heating system, fire
2. Has 210 times greater
affinity to hemoglobin molecule than oxygen. Upon exposure to CO, oxyhemoglobin
is converted to carboxyhemoglobin, reducing the delivery of oxygen to the
tissues and resulting in tissue hypoxia and anoxia.
Carbon monoxide toxicity: %
(v/v) in air
0.01% – allowable for an exposure of several hours
0.04 – 0.05% –
can be inhaled for 1 hour without appreciable effect
0.06 – 0.07% –
causing a just noticeable effect after 1 hour exposure
0.1 – 0.12% – causing
unpleasant but not dangerous symptoms after 1 hour
exposure.
0.4 and above
– fatal in exposure of less than 1 hour
Effects of carboxyhemoglobin
%
Carboxyhemoglobin Effect
10 shortness
of breath on vigorous exertion
20 shortness
of breath on moderate exertion,
slight
headache
30 decided
headache, irritation, fatigue
40
– 50 headache,
confusion, collapse & fainting on exertion
60
– 70 unconsciousness,
respiratory failure and
death
if exposure is continued for a long time
80
rapidly
fatal
Over
80 immediately
fatal
Qualitative determination of
carbon monoxide
1.
Alkaline hematin
Dilute the
blood 20–40 times with distilled water
Add 0.5 ml of
NaOH solution and mix
Result:
Normal blood =
(+) greenish brown color formed at once
Blood with CO
= retains a pink hue for some time
2.
Katayama’s test
To 2 ml of
diluted blood, add 2 ml of yellow ammonium sulfide
Add 2 ml of
30% acetic acid
Result:
Normal blood =
(+) green
Blood with CO
= remains red
3.
Hoppe–Seyler’s Test
Caustic soda
of specific gravity 1.3 produces a greenish color if added to normal blood but
retains the bright red color if carbon monoxide is present in the blood.
4.
Kunkel test
The blood,
diluted with 4 volumes of water, is mixed with 3 times its volume of 1% tannic
acid solution and shaken well. Carbon monoxide blood forms a crimson–red
coagulum, which retains its color for several months. Normal blood forms a
coagulum which is at first red, becomes brown in the course of one or two hours
and then becomes grey in 24 to 48 hours. The blood saturated even with 10%
carbon monoxide responds to this test.
5.
Potassium ferrocyanide test
If 15cc of
blood is mixed with an equal amount of 20% potassium ferrocyanide solution and
2cc of dilute acetic acid and shaken gently, a bright red coagulum will form,
if the blood contains carbon monoxide, while dark brown coagulum will form if
the blood is normal.
6.
Palladium test
Carbon
monoxide will reduce palladium in solution. In one method based on that
reaction, CO gas diffuses into a solution of PdCl2, reducing it to
metallic palladium. An excess of KI is then used to convert the unreacted PdCl2
to a solution of colored PdI2, which is measured colorimetrically at
490 mu. The procedure takes several hours, but it is possible to determine
amounts of CO as small as 0.1 ul.
A second
method, originated by Polis, et.al., involves reacting CO with PdCl2
phosphomolybdic acid in acetone and measuring the molybdenum blue produced.
7.
Winkler solution
The classical
method for the analysis of CO and other fluids using the Van Slyke apparatus
and Roughton–Scholander syringes should not be overlooked.
Winkler’s
solution, containing cuprous chloride, ammonium chloride and copper is used to
absorb CO from a gas phase and the change in volume is measured in a
microcapillary glass syringe. It is possible to measure as little as 0.02 ml of
CO / 100 ml in a 0.5 ml sample, corresponding to the measurement of 0.2 ul of
CO. It is also possible to absorb the CO from a gas sample into a solution
containing Hb and then to measure the COHb.
Quantitative determination of
carbon monoxide
1.
Base on release of gas from hemoglobin
complex with subsequent direct or indirect measurement of gas
a. Gasometric
technique
b. Gas
chromatography
c. Infrared
spectrophotometry
d. Microdiffusion
Carbon
monoxide gas is released from hemoglobin by the action of dilute sulfuric acid
or lactic–ferricyanide solution. Carbon monoxide then reduces palladium
chloride to metallic palladium presenting silver black film on the surface of
the reagent.
PdCl2
+ CO + H2O ------------> Pd + CO2 + 2HCl
The amount of
carbon dioxide is then estimated indirectly by determining the amount of
palladium reduced (colorimetric method) or by amount of hydrochloric acid
produced by the reaction (titrimetric).
Sulfuric acid
was originally used but there are some substances like formic acid that may be
converted to carbon monoxide by this method, giving rise to false positive
results.
To avoid this
reaction, lactic acid, ferricyanide solution has been recommended as the
liberating agent.
2.
Estimation of carboxyhemoglobin by
it’s typical color absorption bands
a. Spectrophotometric
analysis
(1) Tietz and
Fiereck
A dilute
hemolysate of blood is treated with sodium dithionite which
reduces methemoglobin and oxyhemoglobin but does not affect carboxyhemoglobin.
The absorbance of this solution is measured at 541 nm and 555 nm, the
absorbance ratio of A541 nm / A555 nm is calculated and the percent
carboxyhemoglobin is determined from the calibration chart.
(2) IL482 co–oximeter
****** ETHANOL (ETHYL ALCOHOL) ******
Characteristics
1. In gastric and
intestinal mucosa, it is readily absorbed 1 hour after ingestion.
2. In lungs and
kidneys, it is excreted unchanged.
3. In the liver,
it is primarily metabolized
4. In the nervous
system, ethanol’s toxic form, acetaldehyde is known to give its toxic effect.
Toxicity ratings in ethanol
poisoning
1.
35 mg/dl – will
interfere with judgement of distance, speed and causes euphoria.
2.
50 – 100 mg/dl – intoxicated
to operate a motor, characterized by euphoria and loss of normal social
inhibitions.
3.
200 – 300 mg/dl – correlated
with mood exaggeration, slurred speech, apathy, disorientation and loss of
coordination
4.
400 – 500 mg/dl – coma and
death
Symptoms and actions in acute
alcohol poisoning
1.
0.2% or less
a. Release of
inhibition leading to talkativeness, boisterous behavior, delayed reflexes,
minor muscular incoordination and sometimes nystagmus
b. Marked
cutaneous dilatation
c. As the blood
concentration is increased, muscular control and mental activity becomes
increasing difficult
2.
0.25 – 0.3%
a. Blurring of
vision
b. Lack of acuity
of the conjunctiva
c. Reddening of
the conjunctiva
d. Dilatation of
the pupils
e. Diplopia
(double vision)
f.
Difficulty
of focusing
g. Nystagmus
(involuntary surging movement)
3.
0.4 – 0.5%
a. Complete loss
of motor activity
b. Stupor or coma
may intervene
c. Shallow and
slow respiration
d. Death may
occur from respiratory failure
e. Circulation
remains relatively intact except for the effect of cyanosis
Adverse reaction of ethanol
ingestion
Respiratory disease like pneumonia is
common among alcoholic due to increase heat loss and respiratory depression.
Habitually heavy drinker shows
considerable tolerance so that higher concentrations are required for
impairment of function.
On recovery from alcohol intoxication,
acidosis, edema of the brain and swelling of the liver and kidneys have been
observed. Headache noted after is due to edema of the brain. Liver function is
diminished during alcohol intoxication and the liver becomes susceptible to
injury by chemical agents like carbon tetrachloride or chloroform.
Death due to alcohol depression is due
to respiratory failure and occurs 1–10 hours after taking about 24 hours or
more for one to recover from alcohol depression.
Fate and excretion
Ethyl alcohol is rapidly distributed
to all the tissues in nearly equal concentrations. At equilibrium, the brain
contains slightly more than the blood, while the urine contains 1.2 to 1.3
times as much as the blood.
Less than 10% of ingested alcohol finds
its way into urine and expired air. The remainder is burned in the body to
carbon dioxide and water at a rate of about 8 grams per hour. Blood alcohol and
probably tissue alcohol decreases at the rate of from 170 – 270 mg/kg/hr. The
intermediate product in the oxidation of alcohol is acetaldehyde.
Method of determination
1. Gas–liquid
chromatography
2. Enzymatic
analysis using alcohol dehydrogenase
Ethanol is
oxidized in the presence of ADH to acetaldehyde. In the course of the reaction,
NAD, a coenzyme is reduced.
C2H5OH
+ NAD ----------> CH3CHO + NADH + H+
The increase NADH
can be measured by the increase in absorbance at its absorption maximum at 340
nm.
Equilibrium
for this reaction lies strongly to the left. At neutral pH and at normal NAD
concentration less than 1% of ethanol present is oxidized to acetaldehyde.
The reaction
however can be driven almost completely to the right by maintaining a high pH
and removing the acetaldehyde as it formed by reacting it with semicarbazide.
Precaution in specimen
collection
1. Serum, urine
or saliva can be used as a specimen
2. Sodium
fluoride is the anticoagulant of choice if plasma will be used.
3. If blood will
be used, the venipuncture site should be cleaned with a disinfectant that does
not contain alcohol
4. Specimen
should be analyzed immediately or kept stoppered and refrigerated until tested.
5. Serum, plasma
and saliva concentrations of ethanol are 20% higher than those of whole blood.
****** METHANOL (METHYL ALCOHOL) *****
Characteristics
1. It is used as
solvents in paints, varnishes and paint removers.
2. It is also
used as an anti–freeze fluid.
3. Poisoning is
usually due to accidental ingestion by children or by alcoholism.
Symptoms of toxicity
1. Nausea and
headache or progressing to convulsion and coma and blurring of vision, which
may progress to temporary or permanent blindness.
2. Death may occur
from ingestion of as little as 10 to 30 ml.
3. Methanol is
converted to formaldehyde and formic acid in man, resulting in an accumulation
of formic acids and other acids. This reduces the alkali reserve resulting in a
metabolic acidosis.
4. Elevation of
amylase due to necrosis in the pancreas may also be noted.
Methods of determination
1. Gas–liquid
chromatography
2. Colorimetric
method using CTA
Methanol is
oxidized to formaldehyde with permanganate. Chromotropic acid, CTA (4,5–dihydroxynapthalene–2,7–disulfonic
acid), which is specific for formaldehyde, is then added for development of
purple color.
Disadvantages
of drawbacks to the method
a. Methanol is
not quantitatively oxidized to formaldehyde. Further reaction may also take
place in which formaldehyde can be oxidized to formic acid and further to
carbon dioxide.
b. The presence
of reducing substance other than methanol will affect the system so that the
procedure can no longer be applied quantitatively. Alcohol is the most common
substance that interfere in cases of methanol poisoning
The above
drawback can be obviated by
(1) The procedure
must be carried out in the same manner for both standards and unknown.
(2) An excess of
ethanol is added to both standard and unknown resulting in a constant
interference.
c. A minor
drawback is the use of concentrated sulfuric acid for the development of the
final color.
A false high
result may be obtained due to the dehydrating effect of concentrated sulfuric
acid on appropriate organic compounds. This is encountered occasionally in
patients with severe acidosis. Some substances may appear in TCA filtrate such
as glycolic acid which reacts as follows:
H2C(OH)COOH
------------------> HCHO + CO + H2O
The above
interference can be detected by running a blank for comparison. This is done by
running the same procedure to a portion of the filtrate but the oxidation
procedure is omitted. Any color that develops in the unoxidized specimen is due
to formaldehyde or glycolic acid.
Methanol can
be separated by subjecting the specimen to steam distillation or microdiffusion
in a Conway unit
3. Other methods
a. Hindbery and
Wierth method
b. William et.al
method
***** BARBITURATES
*****
Malonyl carbamide (barbituric acid)
was first synthesized by Adolf von Baeyer in 1863.
In 1903, Emil Fisher and Joseph von
Mering synthesized diethyl barbituric acid (barbitone) from urea and malonic
acid. This was the first barbituric acid compound with hypnotic qualities and
marketed under the trade name Veronal. While over 1,500 different barbiturates
have been prepared, only a few are used in medicine today.
Medicinal value:
1. Prescribed for
insomnia and epilepsy
2. Prescribed for
treatment of high blood pressure
3. For diagnosis
and treatment of mental illness
4. Used for
releasing patient before and during surgery
5. To relieve
pain
Classification of barbiturates
1.
Long acting barbiturates – are
distributed more evenly and have long elimination half–lives, making them
useful for treatment of epilepsy.
e.g.
Phenobarbital, diallybarbituric acid
2.
Intermediate acting barbiturates
3.
Short acting barbital
4.
Ultra–short acting barbiturates – are highly
lipid–soluble and rapidly penetrate the brain to induce anesthesia, then are
quickly redistributed to other tissues. For this reason, the duration of
effects is much shorter than the elimination half–life for these compounds.
e.g. hexobarbital, thiamytal,
thiopental
Mechanism of toxicity
All barbiturates cause generalized
depression of neuronal activity in the brain. These effects are primarily
mediated through enhanced GABA–mediated synaptic inhibition. Hypotension that
occurs with large doses is caused by depression of central sympathetic tone as
well as by direct depression of cardiac contractility.
Symptoms of toxicity
1.
Obstruction
of the airway by vomitus, secretions, laryngeal spasms and the relaxed tongue.
2.
Head
injuries, internal injuries, burns, scalds, and fractures may result from
falling.
3.
Bronchopneumonia,
pneumonitis, pulmonary edema and atelectasis may develop.
4.
Acute
heart failure and failure of peripheral circulation (circulatory collapse) may
occur.
5.
Vomiting
and lack of fluid intake can cause serious disturbance of electrolyte and water
balance.
Toxic dose
Small amounts of barbiturates taken in
produces relaxed sociable feeling and decrease alertness and slower reactions.
Larger amounts of barbiturates
consumed will produce sluggishness in person. He becomes gloomy and often
quarrelsome. Muscular steadiness, tremor, hypotenia, difficulty of speech and
sometimes excitement are noted. There may be flushing of the skin and he will
gradually slump into a deep sleep.
Much larger doses may result in coma
and may exhibit hyperthermia or pinpoint pupils. At first, the unconsciousness
is associated with slow and shallow breathing, cyanosis, normal or dilapidated
pupil which react to light if depression is not too deep; nystagmus, a
diminishing blood pressure and loss temperature. The EEG waves are slow in deep
sleep due to barbiturates but in coma, the voltage is low with rapid rhythm
superimposed on slow waves.
The vasomotor and respiratory centers
are depressed to a greater degree than with alcohol. Pre–medication doses of
amobarbital or pentobarbital in aged person with hypotension maybe associated
with a fall of 20 – 100 mm/Hg.
Smooth muscles are inhibited and
visceral ganglia are depressed.
Urinary excretion of reducing
corticoid is doubled but there is no change in 17–KS excretion in barbiturate
poisoning.
Barbiturates and analgesics are said
to be dangerous in the presence of porphyria and should not be used to relieve
pain associated with the disease.
The danger is said to be dangerous in
the presence of porphyria and should not be used to relieve pain associated
with the disease.
The danger is said to be associated
with the increased secretion of anti–diuretic hormones produced by such
mixtures. Barbiturates are especially dangerous when taken along with
alcohol because the depressant action of one multiples, the depressant action of
the other leading to death.
Intravenous administration of the more
concentrated solution occasionally causes venous thrombosis if inadvertently
the needle punctures through the skin or fails to enter the vein.
A phenomenon occasionally associated
with coma due to barbiturates and other depressants is dermatitis characterized
by patches of erythema surmounted by bulbous vesicles.
Fate and excretion
Barbital is excreted into the urine
mostly unchanged, 75% being excreted in 48 hours. It can be identified in the
urine as early as 1 hour after ingestion.
Only 25% of a large of phenobarbital
case be recovered from the urine; the remainder is destroyed in the body.
The liver seems to be the chief organ
of detoxification. Hyperthyroidism hastens the process.
Cause of death
From oral dose = acute early
death is due to respiratory illnesses
Delayed death = usually due
to pneumonia
Intravenous administration may cause
death from circulatory collapse.
The severity of depressant action of
barbiturates will depend upon the following factors:
1. Dose of
barbiturates
2. Mode of
administration
3. Degree of
tolerance
4. Presence or
absence of other drugs in the body
5. State of
excitability
****** OPIUM, OPIUM DERIVATIVES AND NEWER SYNTHETIC
ALKALOIDS *****
Opium is the dried juice obtained from
the unripe seed capsule of the opium poppy, Papaver somniferum as
well as the stem.
Morphine makes up 10% of the weight of
the official opium (from Asia minor) while about 1–2% is made up of codeine,
noscapeine, papavereine, thebaine and a number of minor alkaloids.
Drugs artificially prepared
from morphine
1. Diacetylmorphine
2. Dihydromorphine
Synthetic substrate for
morphine and codeine
1. Meperidine
(Demerol)
2. Methadone
3. Dihydrocodeinone
4. Dihydrohydrocodeinone
5. Levorphan
6. Anileridine
7. Pentazocaine
8. Propoxyphene
Absorption
Opium
alkaloids are moderately absorbed from the alimentary tract
Morphine
is 2–4 times as toxic when given hypodermically.
Concentration
of 1 mg / ml of blood represents a large dose.
Toxic dose
1. Fatal dose –
2–5 grams or morphine and 0.07–0.5 grams of its salt represent dose in robust
adults. One milligram of morphine has been fatal to an infant. Ten milligram of
morpine given hypodermically to and aged has caused respiratory failure.
2. Codeine – 0.5
mg is often fatal
3. Diacetylmorphine
(heroin) – 2–3 times as toxic as morphine
4. Dihydromorphine
(Dilaudid) – 5–10 times as toxic as morphine.
Symptoms of toxicity from morphine
1. Slow
respiration, shallow or sighing or Cheyne–Strokes type
2. Unconsciousness
3. Cyanosis
4. Construction
of pupil
5. Hyperglycemia
and glycosuria may be present
6. Perspiration
is often present
7. When
depression become deeper and the respiration slower and inadequate, prostration
with loss of reflexes and relaxation of the muscles takes place, skin becomes
pale, cold and moist; pupils dilate; heart beat becomes slower and latter
irregular, rapid and weak; convulsion may be observed due to asphyxia and morphine
stimulation of the cord.
8. Death is due
to central respiratory paralysis
9. If the patient
recovers, he experiences physical and mental fatigues for several days. He also
suffers from obstinate constipation.
10. Occasionally,
a person may respond atypically to a therapeutic dose. Instead of gradual
development of cerebral depression, there is cerebral excitement, nausea,
vomiting, headache and even delirium.
A.
Codeine
1. Minimal lethal
dose of codeine is reported to be 80 mg.
2. In general,
codeine and morphine behaves similarly in the body.
3. Cerebral and
cord hyperirritability are more marked with codeine compared to morphine so
that delirium and convulsion may occur during coma.
4. Pupils are not
contracted as with morphine and are dilated during delirium.
5. Constipation
is less compared to morphine.
6. Nausea is more
frequent compared to morphine
7. Respiratory
and circulatory effects are practically identical.
B.
Diacetylmorphine
1. Large
proportion of acute poisoning occurs among addicts who have taken a dose beyond
their tolerance.
2. Fatal dose: 10 – 600 mg%
C.
Synthetic substitutes
1. Dihydroxyhydroxycodeinone
– hallucination effects
2. Dihydroxycodeinone
– often causes dizziness
3. Meperidine –
causes mydriasis and release histamine from mast cells.
4. Pentazocine –
dose of 30 – 60 mg by injection causes drowsiness, dizziness, euphoria,
rhinorrhea, incoordination, weakness, tremors, convulsion, allergic edema,
insomnia and hallucination.
Etiology
a. Addiction
developed through the medicinal use of drug
b. Influence of
the drug through vice.
Symptoms and
actions
a. Stimulation and
depression of the CNS simultaneously.
b. Tolerance
development occurs more readily toward the depressant effect than toward the
excitant effect.
c. Repeated
administration of morphine leads to less euphoria and depression of the dose
remains constant.
d. Excessive
dosing is usual; there is mental dullness, contraction of pupils and certain
hypersensitiveness to sudden stimuli.
e. Skin is
usually dry.
f.
Diminish
salivary excretion.
g. In women,
menses are diminished or suspended.
h. Conception is
rare.
i.
Decreased
libido.
Sudden
withdrawal of the drug:
a. Feeling of
anxiety, restlessness, furtiveness, dilation of the pupils.
b. Followed by
vague or sometimes acute pain the abdomen, skeletal muscles and joints.
Chronic poisoning by opium
derivatives
Chronic use leads to a physical
dependence, a condition usually called addiction. Instead of using addiction and
habitation, the WHO used the word drug abuse and drug dependence.
Drug abuse – persistent
or sporadic use of excessive drug which is inconsistent with unrelated to
acceptable medical practice.
Drug dependence – a state,
psychic or sometimes physical, resulting from the interaction between a living
organism and a drug, characterized by behavioral and other responses that
always include a compulsion to take the drug on a continuous or periodic basis
in order to experience the psychic effects and sometimes to avoid the
discomfort of its absence.
Difference between CODEINE and
MORPHINE
CODEINE MORPHINE
Excess alkali hydroxide precipitated soluble
Excess alkali ammonia soluble precipitated
Iodic acid does not reduce acid reduces acid
Neutral FeCl3 no color
produced blue color
Ferric chloride Prussian blue Prussian
blue
Potassium ferricyanide negative positive
Test for Morphine
1.
Preliminary Test
a. Acidic portion
of the aqueous alkaline solution with sulfuric acid.
b. Add a few drop
of iodic solution
c. Extract with
chloroform
d. Result:
A violet color
at the choloroform layer is positive for morphine
2.
Nitric Acid Test
a. Dissolve
morphine in nitric acid solution
b. Orange color –
positive for morphine
3.
Froehde Test
a. Dissolve
morphine in Froehde’s reagent
b. Result:
Fine violet
color changing to blue to green and finally red.
4.
Ferric chloride test
a. Add a few
drops of FeCl3 to a neutral solution of morphine.
b. Result: Blue
color is positive for morphine
5.
Marquis Test
a. Dissolve
morphine in Marquis reagent
b. Result: Purple
red color changing to violet to pure blue
6.
Selenious sulfuric acid test
a. To a portion
of the dried extract, add a few drop of freshly prepared 0.5% solution of
selenious.
b. Result:
Formation of a green color is positive for morphine. The test is said to be
positive to a 0.01 mg of morphine.
7.
Microscopic test
a. Dissolve a
portion of the extract in 1–2 gtts of 1/10N HCl.
b. Place a drop
of the solution on a glass slide and a drop of Wagner’s reagent.
c. The slow
formation of red brown plate or large needles one or both sides of which are
deeply serrated shows the presence of morphine.
d. Marme’s
solution precipitates clusters of slender needles from solution of morphine as
dilute as 1:1000.
e. The detection
of alkaloid of opium can be performed on the residue of the extract with
alkaline chloroform and amyl alcohol followed by performance of the color
reaction of alkaloids.
f.
For
each of these tests, a small portion of the residue remaining after evaporation
of the alkaline chloroform extract should be dissolved in a few drops of dilute
HCl.
g. A reaction
specific for apomorphine is purple red with Fluekiger’s reagent
(1) Codeine –
green brown color with Mandelin’s reagent
(2) Morphine –
purplish red with Mandelin’s reagent and Mecke’s reagent
(3) Alkaloids can also be separated from each other by
paper chromatography
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