Download Treatment - KSU Faculty Member websites

‫ماجد القنية‬
Majed Algonaiah
[email protected]
:‫الموقع‬
http://faculty.ksu.edu.sa/malgonaiah
0559875500 :‫جوال‬
‫ الفصل األول‬-1435\1434
Topic-1
Treatment of Amoebiasis
Amoebiasis,
Amoebiasis is an infection with Entamoeba histolytica, which is an anaerobic protozoan (a
protozoan = a unicellular eukaryotic organism). To complete its life cycle, it needs to enter
an animal body, and so, it is considered an obligate parasite. This parasite enters the human
body in the form of cysts by ingesting water or food contaminated with them. After leaving
the stomach, the cysts transform in the small intestine into trophozoites, which in turn travel
to the large intestine. In the large intestine, the trophozoites adhere to the surface of the
mucosal layer of the large intestinal wall, multiply, and then penetrate from the surface to
the inner part of the mucosal layer (the mucosal layer is the layer of the large intestinal wall
that faces the intestinal lumen). This causes chronic inflammation of the large intestine. The
disease sometimes becomes acute, manifested by ulceration of the large intestinal walls
with the production of bloody diarrhea, where the disease (amoebiasis) in this acute case is
called amoebic dysentery. In rare acute cases, the disease might become more severe,
where the trophozoites penetrate the large intestinal wall into the portal bloodstream,
where they migrate to the liver and cause liver abscesses, which can be fatal.
Notice that in amoebiasis the parasite can be present in four locations: the large intestinal
lumen, the surface of the large intestinal mucosa, the inner part of the large intestinal
mucosa, and (sometimes) the liver.
Treatment:
Metronidazole:
Fortunately, there is an effective and safe treatment of amoebiasis, thanks to the fact that
this parasite is an anaerobe. Metronidazole (or its chemically related drug: tinidazole) is
effective in the treatment of amoebiasis. Its mechanism of action is believed to be through
its conversion by the parasite anaerobic enzymes into an extremely chemically reactive and
toxic compound (a free radical (metronidazole radical)), which in turn attacks the parasite
DNA and damage it. The human cells are not damaged because they are aerobes, and their
aerobic enzymes do not convert metronidazole into the metronidazole radical.
The DNA is unlikely to be the only target of the attack by the metronidazole radical. Other
macromolecules in the parasite (e.g. important proteins and cell membrane lipids) are also
likely to be targets. This is because free radicals (compounds or atoms that contain an
unpaired electron in their outer shell) are generally extremely reactive and non-selective in
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their reactions, and once they are produced, they randomly attack many constituents of the
cell in a relatively non-selective manner.
Cell membrane of Entamoeba
histolytica
Metronidazole
Anaerobic
enzymes
donate one
electron to
metronidazole
Metronidazole radical
(extremely toxic and
chemically reactive)
Attacks and damages
DNA and probably
other important
macromolecules e.g.
cell membrane lipids
Nucleus
DNA
Figure: Mechanism of action of metronidazole
Metronidazole works systemically (not locally) in the treatment of amoebiasis i.e. it is
absorbed after oral administration into the blood stream and, from the systemic circulation,
it reaches its targeted parasites that have adhered to the surface of the mucosal layer of the
large intestinal wall, have penetrated from the surface to the inner part of the mucosal
layer, or have migrated to the liver.
Fortunately, until now, the parasite could not develop resistance against metronidazole.
Luminal agents (Paromomycin or diloxanide)
After oral administration, metronidazole (or tinidazole) is absorbed into the blood stream
almost completely before it can reach the large intestine, and so it cannot significantly kill
the parasites that did not adhere to the large intestinal mucosa and are present in the large
intestinal lumen. For killing these, the course of metronidazole treatment is usually
combined with a drug that works locally in the large intestinal lumen (a luminal agent).
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The luminal agent will also kill the parasites that adhered to the surface of the large
intestinal mucosa. Therefore, notice that the parasites that adhered to the surface of the
large intestinal mucosa will be attacked by both metronidazole and the luminal agent.
Paromomycin or diloxanide are luminal agents that can be used for this purpose.
Paromomycin, when taken orally, is not absorbed into the blood stream, and therefore, it
can reach the large intestine in full quantity and work locally there.
Paromomycin is a member of the aminoglycoside antibiotics, and it works by inhibiting
protein synthesis in the parasite. Although this mechanism of action of paromomycin, unlike
that of metronidazole, does not distinguish between anaerobic and aerobic cells,
paromomycin is not toxic to the human body for two reasons. Firstly, it works locally in the
large intestine, and secondly, it works selectively on the protein synthesis i.e. it has much
more affinity towards the protein synthesis machinery of the parasite than the protein
synthesis machinery of the human cells.
Diloxanide, after oral administration, can reach the large intestine in a significant quantity
and work locally there. Its mechanism of action is not clear.
As mentioned above, paromomycin or diloxanide are used in combination with (not as
alternatives to) metronidazole.
Notes:
1- Although metronidazole is safe and effective, there is a need for developing more drugs
to treat amoebiasis. This is because there are cases where the current therapy is
contraindicated e.g. metronidazole is contraindicated in the early months of pregnancy or in
patients who are allergic to it. Another reason for the need to develop new drugs is that the
parasite is expected to develop resistance to metronidazole in the future.
2- There are many potential targets for drug discovery in the treatment of amoebiasis. For
example, it is theoretically possible to block the following two steps: the adhesion of the
trophozoites to the surface of the large intestinal mucosal layer or the penetration of the
trophoziotes from the surface to the inner part of the mucosal layer.
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Topic-2
Treatment of Giardiasis
Giardiasis
Giardiasis is an infection with Giardia lamblia, which is, like Entamoeba histolytica, an
anaerobic protozoan and obligate parasite. This parasite enters the human body in the form
of cysts by ingesting water or food contaminated with them. After leaving the stomach, the
cysts transform in the small intestine into trophozoites, which adhere to the microvilli of the
small intestinal mucosa and multiply there (microvilli are the extensions found on the
surface of the small intestinal mucosa, whose function is the absorption of nutrients).
In the early stage, the infection might either be asymptomatic or cause diarrhea and
flatulence. After that, in the majority of cases the infection gets terminated from the body,
but in some cases the infection becomes chronic. If it becomes chronic, it can cause
malabsorption and growth retardation in children.
Treatment
Many drugs are effective. Metronidazole is effective, and unlike the case in amoebiasis, it is
effective alone in the treatment of giardiasis. This fact suggests that metronidazole, before it
is completely absorbed, can work locally to kill the parasites that are present in the small
intestinal lumen and did not adhere to the microvilli.
Also unlike the case in amoebiasis, the systemic action of metronidazole does not seem to
be necessary to treat giardiasis. The evidence for this is that paromomycin, which can work
only locally (because it is not absorbed), is alone effective in the treatment of giardiasis.
The reason that the local activity of metronidazole or paromomycin is sufficient alone to
treat the disease is that the parasite does not penetrate from the surface to the inner part of
the mucosal layer, and therefore it can be reached by a drug working locally in the small
intestine.
Another drug effective in treating giardiasis is nitazoxanide (do not confuse it with
diloxanide). Its mechanism of action seems to be through inhibiting energy production in the
parasite through blocking an enzyme involved in this process.
Paromomycin or nitazoxanide are used as alternatives to (not in combination with)
metronidazole in cases where the latter is contraindicated.
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Topic-3
Treatment of Toxoplasmosis
Toxoplasmosis:
Toxoplasmosis is an infection with Toxoplasma gondii, which is a protozoan and intracellular
obligate parasite. It enters the human body by ingesting vegetables contaminated with the
oocysts (oocyst is a form of the parasite). After ingestion by humans, the oocysts transform
into tachyziotes inside the human gastrointestinal cells, and then spread (after rupturing the
human cells) from the gastrointestinal tract into the blood circulation.
In men or non-pregnant women, circulating tachyziotes do not cause harm. On the other
hand, in pregnant women, although the circulating tachyziotes do not cause harm to the
mother (like in men or non-pregnant women), these tachyziotes can transmit from the
mother to the fetus and cause fatal diseases to the fetus e.g. encephalopathy.
The reason that circulating tachyziotes do not cause harm to the mother of a fetus, nonpregnant women, or men is that the immune system brings the infection under control.
However, the immune system does not completely eliminate the infection, where circulating
tachyzoites can enter the human cells in different tissues and transform into a less active
form, the bradyzoites, which can live for decades in human tissues without causing a
disease. Once the immune system is compromised e.g. in AIDS patients or patients taking
immunosuppressant medications, the parasite becomes active again and transform from
bradyzoites into tachyzoites, and because in this case the immune system is weak, the
tachyzoites can cause fatal diseases.
Treatment:
The treatment of choice is a triple combination of sulfadiazine, pyrimethamine, and folinic
acid (do not confuse it with folic acid).
Sulfadiazine and pyrimethamine block (inside the parasite) two subsequent important steps
in the synthesis of the parasite DNA. The first step is the conversion of pteridine into folic
acid, and this step can be blocked by sulfadiazine which inhibits dihydropteroate synthase,
which is the enzyme responsible for this step. The second step is the conversion of folic acid
into its reduced form: tetrahydrofolic acid, and this step can be blocked by pyrimethamine
which inhibits dihydrofolate reductase, which is the enzyme responsible for this step.
Human cells also use folic acid and tetrahydrofolic acid for the human DNA synthesis.
However, there are two important differences between the human cells and the parasite
that make sulfadiazine and pyrimethamine able to kill the parasite without killing the human
cells.
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The first difference is that human cells, unlike the parasite, do not enzymatically synthesize
folic acid at all, but rather they take all the needed amount of it ready from diet. This means
that the amount of folic acid needed by the human cells will not be decreased at all by
sulfadiazine.
The second difference is that although the human cells enzymatically convert folic acid into
tetrahydrofolic acid, pyrimethamine has a much more potent blocking activity against the
parasite enzyme than the human enzyme. This means that unlike the parasite, the human
cells will be able, in the presence of pyrimethamine, to enzymatically synthesize a significant
(although not full) amount of the needed tetrahydrofolic acid from folic acid.
Because pyrimethamine can cause a slight deficiency in tetrahydrofolic acid inside human
cells, the drug folinic acid is included in the treatment combination to correct this deficiency.
Folinic acid is a precursor drug which readily (non-enzymatically) converts into
tetrahydrofolic acid (not into folic acid) in the human body.
The parasite (although can be present inside the human cells) cannot use folic acid or
tetrahydrofolic acid that are available inside the human cells because the parasite cannot
transport them across its cell membrane. Also, the parasite cannot make benefit from
folinic acid because when this drug converts into tetrahydrofolic acid inside human body,
the parasite cannot transport the latter across its cell membrane.
Folinic acid
Folic acid
from diet
Pyrimethamine
_
Dihydrofol. reduct.
+
Tetrahydrofolic
acid
Cannot be transported
Cannot be transported
Pteridine
Sulfadiazine
Folic
Dihydropt. acid
-
Synth.
The human cell
membrane
Dihydrofol.
reduct.
Tetrahydrofolic
acid
-
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Human DNA
synthesis
The parasite membrane
Parasite DNA
synthesis
Pyrimethamine
Topic-4
Treatment of infection with intestinal worms
1-Strongyloidiasis:
Strongyloidiasis is an infection with Strongyloides stercoralis.
Treatment:
Ivermectin is very effective. It opens glutamate-gated chloride channels in the worm
muscles, which causes an increase in chloride conductance and subsequently
hyperpolarization, resulting in the paralysis of the muscles. These channels are not present
in humans, and thus, the drug is safe to humans.
2-Enterobiasis:
Enterobiasis is an infection with Enterobius vermicularis.
Treatment:
A drug used is pyrantel pamoate, which works through causing a phenomenon called
depolarizing neuromuscular blockade. In this phenomenon, the drug activates the nicotinic
receptors on the worm muscle, resulting in sodium influx through the channel of the
receptors, leading to a change in the muscle from resting potential state to partial
depolarization state. This makes the so called voltage-gated sodium channels (VGSCs) to
change from the ready-state to the open-state, allowing sodium influx through the channel,
leading to change in the muscle from a partial depolarization state to full depolarization
state, and this initiates an action potential. This initiates a muscle contraction, and in the
meanwhile the VGSCs change from the open-state to the inactive-state. In normal
physiological contraction, the full depolarization state decreases to resting potential state,
allowing the VGSCs to change from the inactive-state to the ready-state. However, in our
case the full depolarization state decreases only to partial depolarization state because the
drug does not stop activating the receptors, allowing sodium influx and partial
depolarization. This partial decrease in the depolarization is not enough for the VGSCs to
change from the inactive-state to the ready state, and therefore they remain inactive, which
means that there will not be a full depolarization state anymore and there will not be an
action potential and there will not be a muscle contraction i.e. the muscle will be paralyzed.
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Topic-5
Treatment of vomiting and nausea
Vomiting and nausea
Vomiting (emesis) is a physiological process that is beneficial and even lifesaving in some
cases e.g. food poisoning. However, in some cases, vomiting and nausea can be unbeneficial
and very unpleasant and cause harmful effects e.g. vomiting/nausea caused by cancer
chemotherapy, motion sickness, or pregnancy. In such cases, prevention of vomiting/nausea
is needed.
Vomiting is initially triggered by any of the following: (1) irritation in the gastrointestinal
tract (especially the stomach) followed by vagus nerve stimulation, (2) stimulation of the
vestibular system in the case of motion sickness, (3) stimulation of the chemoreceptor
trigger zone located near the CNS by circulating chemicals, or (4) by stimulating the cerebral
cortex by unpleasant smells or sights.
Any of the above initial triggers leads eventually to the stimulation of the so called the
vomiting center in the brain.
The activation of many receptors is involved in the above mentioned mechanisms, which
include: serotonin 5-HT3, dopamine D2, substance P NK1, histamine H1, and muscarinic
receptors, and therefore, blocking these receptors can prevent vomiting.
Drugs:
Histamine H1 receptor antagonists:
An example of this class is cyclizine, which blocks H1 receptors. H1 receptors are G-protein
coupled receptors, whose activation causes the activation of the intracellular enzyme:
phospholipase C, which catalyzes the formation of the messenger: inositol trisphosphate,
which in turn raises intracellular calcium. The rise in intracellular calcium in the neurons
containing H1 receptors activates these neurons, leading eventually to vomiting. Therefore,
blocking H1 receptors by cyclizine can prevent vomiting because this drug prevents the
initiation of the above mentioned sequence of events.
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Muscarinic receptor antagonists:
An example of this class is hyoscine (scopolamine), which competitively antagonizes the
action of acetylcholine on muscarinic receptors on the neurons containing these receptors.
Because the muscarinic receptors are widely distributed throughout the body and CNS,
hyoscine causes a wide range of side effects related to blocking these receptors e.g. vision
abnormalities.
Dopamine D2 receptor antagonists:
An example of this class is chlorpromazine, which works primarily by blocking dopamine D2
receptors. It can also block histamine H1 and muscarinic receptors.
D2 receptors are G-protein coupled receptors, whose activation activates an inhibitory Gprotein, which leads to the inhibition of the intracellular enzyme: adenylyl cyclase. Inhibiting
adenylyl cyclase prevents the formation of cyclic AMP (cAMP). The decrease (not the
increase) in intracellular concentration of cAMP in the neurons containing D2 receptors
stimulate these neurons, leading eventually to vomiting. Therefore, blocking D2 receptors by
chlorpromazine can prevent vomiting because this drug prevents the initiation of the above
mentioned sequence of events.
Other examples of this class include metoclopramide and domperidone, which also block D2
receptors. But unlike chlorpromazine, metoclopramide and domperidone do not significantly
block histamine H1 or muscarinic receptor. Domperidone has the advantage over
metoclopramide and chlorpromazine of being unable to cross blood brain barrier. Therefore,
domperidone will act on the D2 receptors in the periphery without causing the CNS side
effects that can be caused by metoclopramide and chlorpromazine.
The D2 receptor blockers that can cross the blood brain barrier (e.g. chlorpromazine and
metoclopramide) can cause CNS side effects related to their blockade of these receptors e.g.
Parkinson’s like effects. Chlorpromazine can also cause side effects (in the CNS and
elsewhere) related to its ability to block the histamine H1 and muscarinic receptors.
5-hydroxytryptamine (serotonin) 5-HT3 receptor antagonists:
An example of this class is ondansetron, which blocks 5-HT3 receptors. These receptors are
ligand-gated ion channels, whose activation causes cation influx followed by depolarization
and hence the activation of these neurons, leading eventually to vomiting. Therefore,
ondansetron can prevent vomiting because it prevents the initiation of the above mentioned
sequence of events.
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Substance P NK1 receptor antagonists:
An example of this class is aprepitant, which blocks NK1 receptors. These receptors are Gprotein coupled receptors, whose activation initiates the same intracellular pathway
initiated by activating the histamine H1 receptors i.e. the pathway of phospholipase C,
inositol trisphosphate, and intracellular calcium.
Other drugs:
Dronabinol is a cannabinoid that can prevent vomiting. It possibly works by activating (not
inhibiting) the cannabinoid receptors in the vomiting center, leading to the inhibition of the
vomiting center. This drug can cause side effects related to its action on the cannabinoid
receptors e.g. drug dependence.
Corticosteroids e.g. dexamethasone can prevent vomiting. The mechanism of action is not
clear.
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Topic-6
Treatment of constipation
Constipation
Constipation is characterized by a decrease in the number of times of going to the toilet less
than one’s habit. In constipation, the faeces becomes hard and causes difficulty in
defecation. This may cause harmful effects e.g. discomfort or intestinal obstruction. It may
also cause damage to the colon, rectum, or anus. Therefore, in some cases, constipation
should be treated.
Constipation occurs usually as a result of a combination of a decrease in the amount of fluids
in the large intestinal lumen and a decrease in the peristalsis of the large intestine.
Treatment
If an anti-constipation drug works through increasing the amount of fluids in the large
intestine, this will cause an increase in the peristalsis, where these two effects would reduce
constipation. Also, vice versa, if an anti-constipation drug works through increasing the
peristalsis, this will cause an increase in the amounts of fluids in the large intestine, where
these two effects would reduce constipation.
Before trying treatments, any possible cause of constipation should be eliminated. For
example, if constipation is caused by a prescribed drug, this drug should be replaced by one
that does not cause constipation if possible. After excluding possible causes of constipation,
the following treatments can be tried:
Dietary fibers
The dietary fibers are the indigestible parts of the consumed plants. After leaving the small
intestine undigested and unabsorbed, some of the fibers are fermented by bacteria in the
large intestine, while other fibers resist fermentation. The fermented fibers have the effect
of increasing the number of bacteria, where this increase in bacterial mass increases the
bulk of content of the large intestine, and this will stimulate peristalsis. Also, the
unfermented fibers can attract water (preventing its absorption by the intestinal mucosa),
increasing the amount of fluids.
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Osmotic laxatives:
Examples of this class include: magnesium sulfate, lactulose, and polyethylene glycol. These
drugs, being poorly absorbed, work by osmotically retaining water and preventing its
absorption by the intestinal mucosa. The retained water increases the fluid content of the
large intestine.
Surfactants:
Docusate sodium and docusate calcium are surfactants that promote mixing of aqueous and
fatty materials, thereby softening the faeces and easing defecation.
Irritant (inflammatory) drugs:
Examples include: sodium picosulfate, glycerol (do not confuse it with polyethylene glycol),
bisacodyl, and senna. These drugs work by inducing mild irritation (mild inflammation) to
the large intestinal mucosa, resulting in an increase in peristalsis.
Bisacodyl produces this effect likely through stimulating the production of the inflammatory
molecule: nitric oxide. The evidence is that it was found that experimentally inhibiting the
production of nitric oxide (through inhibiting nitric oxide synthase) prevents the
inflammatory (the anti-constipation) effect of bisacodyl.
On the other hand, senna produces its inflammatory effect through a mechanism different
from stimulating the production of the inflammatory molecule: nitric oxide. The evidence is
that it was found that experimentally inhibiting the production of nitric oxide (through
inhibiting nitric oxide synthase) does not prevent the inflammatory ( the anti-constipation)
effect of senna.
Prucalopride:
This drug increases peristalsis probably through activating the serotonin 5-HT4 receptors on
the terminals of neurons called intrinsic primary afferent (IPA) neurons in the submucosal
layer of the intestine. This leads to the release of acetylcholine from these terminals, which
in turn activates neurons called enteric nervous system (ENS) neurons whose cell bodies are
located in the submocosal layer. This leads to the release of also acetylcholine from the ENS
neurons from their terminals which are located in the muscle layer of the intestine, and then
acetylcholine activates the smooth muscles in the muscle layer, leading to an increase in the
peristalsis of the intestine.
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Prucalopride
IPA neuron
+
A smooth
muscle
+
+
The lumen
ACh
ACh
ENS neuron
Muscle layer
Submucosal layer
Mucosal layer
Figure: Mechanism of action of prucalopride.
Note:
Many of the drugs mentioned above can be taken orally, as suppositories, or by enemas.
Enema is the administration of large volumes of fluids to the rectum. Actually even without
adding any drug to enema, the enema fluid itself can treat constipation.
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