CPT CASE 3 TUBERCULOSIS

PAGE 31
1 WHAT GROUPS IN THE POPULATION IS THE HIGHEST RISK
FOR DEVELOPING PTB?
In general, adults > 65 years of age have the highest
incidence rate and <14 years of age.
2 HOW DOES VACCINATION WITH BCG AFFECT TST
(TUBERCULIN SKIN TEST) AND IGRA (INTERFERON GAMMA
RELEASE ASSAY) TEST RESULTS?
BCG: it provides false positive reactions, because BCG is
derived from an attenuated strain of M. bovis. Thus, TST
measrues the response to antigenic stimulation by T cells
that resides in the skin rather than response of
recirculating memory T cell.
IGRA (for latent TB): measures T cell release of IFN-y in
response to stimulation with the highly TB specific
antigens EAST-6 and CFP-10.It also measures the
response of recirculating memory T cellsnormally part
of a reservoir in the spleen, bone marrow and lymph
nodesto persisting bacilli producing antigenic signals. It
is said to be more specific than the TST as a result of less
cross-reactivity due to BCG vaccination and sensitization
by nontuberculous mycobacteria.
3 IN PATIENTS WITH LABORATORY-CONFRIMED DRUG
SUSCEPTIBLE, ACTIVE PULMONARY MYCOBACTERIUM
TUBERULOSIS (MTB), WHAT ARE THE STANDARD
MEDICATIONS AND DURRATION OF TREATMENT? HOW
WOULD THS DIFFER IF THE PATIENT WERE HIV POSTIVE?
Patients with lab confirmation:
2 months initial or intensive phase of:
Rifampin:
o MOA: inhibits DNA-dependent RNA
polymerase, thereby blocking production
of RNA.
o Bactericidal activity against susceptible
bacteria and mycobacteria. Resistance is
increased if it used as monotherapy.
o Toxicity: orange color of urine, sweat and
tears. Rash, thrombocytopenia and
nephritis.
Page 1 of 38

Isoniazid
o MOA: inhibits synthesis of mycolic acids,
an essential component of mycobacterial
cell walls.
o It penetrates into macrophages and is
active against both extracellular and
intracellular organism.
o Bacteriostatic against slowly dividing
organisms.
o It is generally well tolerated and has
established efficacy and inexpensive
o Toxicity: drug induced hepatitis (major),
peripheral neuropathy---administer
pyridoxine (10-25 mg/d)
Pyrazinamide
o MOA: converted to the active pyrazinoic
acid under acdic conditions in
macrophage lysosomes.; bacteriostatic
o Adverse effects: hepatotoxicity, nausea,
vomiting, drug fever, and hyperuricemia.
Ethambutol
o MOA: inhibits mycobacterial arabinosyl
transferases which are involved in the
polymerization reaction of arabinoglycan,
an essential component of the
mycobacterial cell wall.
o Bacteriostatic
o Adverse effects: retrobulbar neuritis
resulting in loss of visual acuity and redgreen color blindness
Followed by 4 months continuation phase
Rifampin and Isoniazid
For HIV positive patients:
o Main aim in the management of HIV associated TB is
to initiate ant TB treatment and to immediately
consider initiating or continuing ART in which all
HIV-infected YB patients regardless of CD4+ T cell
count, are candidates for ART.
o ART should be started within the first 2 weeks of TB
treatment for patients with CD4+ T cell counts of
<50 /uL.
o 6 month daily regimen is efficacious it is just that
Rifampin is a potent inducer of enzymes of CYP450
system, lowers serum levels of many HIV protease
inhibitors and some NRTIs. In such case, Rifabutin
Page 2 of 38

has less enzyme inducing activity, has been used in

place of Rifampiin.
4 THE PATIENTS LIVER FUNCTION TESTS ARE SLIGHTLY. WHY
IS THIS IMPORTANT AND DOES IT CHANGE THE
MANAGEMENT OF HER TB INFECTION?
- The most common adverse reaction of significance is
hepatitis.
-patients should be carefully educated about the signs
and symptoms of drug-induced hepatitisdark urine, loss
of appetiteand should be instructed to discontinue the
treatment promptly and seek medical help.
5 HOW IS THERAPEUTIC EFFICACY ASSESSED IN THE
TREATMENT OF TB?
Bacteriologic evaluation: causing culture of smear
microscopy is essential in monitoring the response to
treatment for TB.
Patients weight should be monitored regularly and
drug dosage adjusted with any significant weight
change.
With the recommended regimen, >80% of patient will
have negative sputum cultures ate the end of the 2 nd
month of treatment; by the end of 3rd month: virtually
all patients should be culture negative.
When patients sputum culture remain positive >3
months, treatment failure and drug resistance or poor
adherence to the regimen are likely and testing of drug
resistance should guide the choice of the best
treatment option.
A sputum specimen should be collected by the end of
treatment to document cure.
A CXR obtained at the end of the treatment may be
useful for comparative purposes.
6 IF SPUTUM RESULT WOULD SHOW RESISTANCE TO INH,
WOULD THIS AFFECT DRUG COMBINATION AND DURATION
OF DRUG THERAPY?
Resistance to INH due to:
Is associated with mutations resulting in overexpression
of inhA, which encodes an NAOH-dependent acyl carrier
protein reductase.
Mutation or deletion of the KatG gene

Page 3 of 38

Promoter mutations resulting in overexpression of ohpC

a putative virulence gene involved in protection of cell
from oxidative stress
Yes, instead use RZE (Rifampin, Pyrazinamide,
Ethambutol) throughout (6-9) months.

7 HOW WOULD THE CLOSE CONTACTS OF THIS PATIENT BE

TREATED?
Subject the person to TST to confirm exposure: Tuberculin
Reaction size: >5 mm
Contact investigation is an important component of
efficient TB control
Measures to limit such transmission includes respiratory
isolation of person with suspected TB
Proper ventilation in rooms of patient with infectious TB.
PAGE 35
CASE 3 TUBERCULOSIS
I

PULMONARY TUBERCULOSIS
Tuberculosis (TB), a multi systemic disease with
myriad presentation and manifestations, is most
common cause of infectious disease- related mortality
worldwide. It is caused by Mycobacterium tuberculosis,
a rod shape, non spore forming, thin aerobic
bacterium, measuring 0.5m by 0.3m. The bacteria
usually attack the lungs, but TB bacteria can attack
any part of the body such as the kidney, spine, and
brain. TB is spread through the air from one person to
another.
TB is classified as pulmonary, extrapulmonary, or
both.
Pulmonary tuberculosis (TB) is a contagious
bacterial infection that involves the lungs. It may
spread to other organs.

Pulmonary tuberculosis (TB) is caused by the bacterium Mycoba

tuberculosis (M. tuberculosis). TB is contagious. This means the ba
easily spread from an infected person to someone else. You can ge
breathing in air droplets from a cough or sneeze of an infected per
resulting lung infection is called primary TB.

Page 4 of 38

1 Basis of the problem

CC:
Cough for the past 3 weeks and 3 nights ago
+ hemoptysis
Sharp pain on the chest
HPI:
+ productive cough, yellowish phlegm, within
the last 4 weeks pain
Occasional SOB on exertion, body malaise, mild
non-pleuritic substernal chest
Had periodic night sweats
PPD test (+)
Social Hx:
Resides in the slums in Tondo
ROS:
Weight loss of 5kgs over the past 2 months
PE:

T: 38oC, RR: 20 cpm

HEENT: slightly congested tonsil
Chest: occasional rales ate the
posteriorly

left

apex

Labs:
Inc. WBC count
+ AFB smear
2 Therapeutic Objectives
The two aims of TB treatment are (first 2 from
Harrison):
to prevent morbidity and death by curing TB
while preventing the emergence of drug
resistance
to interrupt transmission by rendering patients
non-infectious
to prevent development of drug resistance
to prevent relapse
to prevent complications
3 Non-pharmacologic management
Page 5 of 38

Teach the patient about the infectious nature

of tuberculosis and the need to prevent its
spread.
Place the patient in a negative pressure room
and in a private room.
All nurses and visitors entering the patient's
room should wear an N-95 mask.
Put
a
mask
on
the
patient
during
transportation to other departments.
Keep the door to the patient's room shut and
place an isolation sign at a visible location near
the door.
Use standard precautions when providing
direct care to the patient. This includes
wearing gloves, gowns and effective hand
washing.
Teach patient how to avoid spreading the
disease by sneezing or coughing into doubly
ply tissue instead of their bare hands, washing
their hands after this and disposing of the
tissue into a closed plastic bag.
Teach the tuberculosis patient to stay in well
ventilated areas and limit contact to other
people while he or she is still able to spread
the infection.

PREVENTION AND CONTROL

Children
BCG vaccine should only be considered when a
child has a negative tuberculin test (PPD
test) and is continually exposed and cannot be
separated with adults who:

Have untreated or ineffectively treated

tuberculosis; and,
Have TB caused by strains of the bacterium
which
are
resistant
to isoniazid and rifampin.

Health care workers

Page 6 of 38

BCG vaccine is considered for health care

workers on an individual basis in settings
where:

The percentage of patients who have TB

that is resistant to isoniazid and rifamipin is
high;
An ongoing transmission of the drugresistant TB is happening and the possibility
of infection is likely; and,
A
wide-ranging
TB
infection-control
precaution has been implemented but has
not been successful.

Counselling should be done first to the health

care workers before the immunization of BCG
regarding its risks and benefits, together with
the information on the treatment of latent
tuberculosis.
Administration Summary
Type of Vaccine: Live bacterial
Number of Doses: One
Schedule: At or soon as possible after birth
Booster: None
Contraindications: Symptomatic HIV infection
Adverse reactions: Local Abscess, regional
lymphadenitis;
rarely
distant
spread
to
osteomyelitis, disseminated disease
Special
precautions: Correct
intradermal
administration is essential.
A special syringe and needle is used for the
administration of the BCG vaccine
Dosage: 0.5 mL
Injection site: Outer Upper left arm or shoulder
Injection type: Intradermal
Storage: Store between 2 to 8 degrees Celsius
(but not the diluent)
Long-Term Monitoring
After completion of treatment for pulmonary
TB,
patients
remain
at
risk
for
late
complications,
which
include
Page 7 of 38

relapse, aspergilloma, bronchiectasis,

broncholithiasis, fibrothorax, and possibly
carcinoma. A copy of the chest radiograph at
the time of completion of therapy should be
provided to the patient to facilitate the
diagnosis of late complications.
The
relapse
rate
following
appropriate
completed therapy is only 0-4% and occurs
within the first 2 years after completion.
Aspergilloma is a fungus ball that develops in a
residual lung abnormality (eg, pneumatocele,
bulla, bleb, cyst). It may appear as a crescent
sign on chest radiographs.
4 Pharmacologic management
RECOMMEND DOSAGE FOR INITIAL TREATMENT OF TUBERCULOSIS IN
ADULTS
Drug
Daily dose
Thrice-weekly dosing
RIFAMPIN (R)
10mg/kg, max 600mg 10mg/kg, max 600mg
ISONIAZID (H)
5mg/kg, max 300mg
10mg/kg, max 900mg
PYRAZINAMIDE (Z)
25mg/kg, max 2g
35mg/kg, max 3g
ETHAMBUTOL (E)
15mg/kg
30mg/kg

Page 8 of 38

Efficacy

Suitabili
ty

RIFAMPICIN

ISONIAZID

(+++)
An
antibiotic
which
in
vivo
has
bactericidal
effect
on
strains of M.
tuberculosis
located not
only
extracellula
r but also
intracellular
ly. In the
treatment
of TB it has
a
rapid
onset
of
action which
results in a
sterilizing
affect.
It
has a high
sterilizing
activity.
(+++)
Inhibits
DNAdependent
RNA
polymerase
of sensitive
bacterial
strains, but
without
affecting
the
correspondi
ng
mammalian
enzyme.

(+++)
Specific anti
tuberculosis
agent
exerting
a
strong
bactericidal
effect mainly
on
rapidly
growing
populations
of
M.
tuberculosis

(+++)
MOA
is
probably
based
on
chiefly
on
inhibition of
mycolic acid
synthesis
which
is
important
constituent
of
the
mycobacteria
l cell wall.

PYRAZINAMI
DE
(+++)
Highly
specific and
bactericidal
for
M.
tuberculosis
hominis
at
an acidic pH
and
has
potent
sterilizing
activity. The
minimal
inhibitory
concentratio
n at pH 5.5
in vitro is 2050mcg/ml.

(+++)
Clinically,
has
been
shown to be
especially
effective
against
mycobacteri
a
growing
slowly in an
acidic
environment,
eg. caseous
foci,
pulmonary
cavities.
Primary

ETHAMBUTOL
(+++)
A
bacteriostatic
antimycrobial
drug
prescribed to
treat
tuberculosis.
- It works by
obstructing
the formation
of cell wall.
Mycolic acid
attach to the
5'-hydroxyl
groups of Darabinose
residues
of
arabinogalact
an and form
mycolylarabinogalact
anpeptidoglyca
n complex in
the cell wall.
(+++)
It
disrupts
arabinogalact
an synthesis
by inhibiting
the
enzyme
arabinosyl
transferase.
Disruption of
the
arabinogalact
an synthesis
inhibits
the
formation of
this complex
and leads to
increased
Page 9 of 38

Safety

Cost

resistance of
M.
tuberculosis
is very rare.
(+)
(+)
GI
effects, Hepatotoxici
hypersensitiv ty,
nausea,
ity.
vomiting,
Peripheral
anorexia.
neuropathy,
Hematologic
convulsions,
al
and
liver damage, lymphatic
hyperglycemi changes.
a, acidosis.
Mild myalgia,
hypersensiti
vity reaction.

(+++)
well
tolerated.
AE
is
common on
intermittent
therapy
or
after
restarting
interrupted
treatment.
GI adverse
effects:
nausea,
vomiting,
diarrhea,
epigastric
distress.
Administrati
on on an
empty
stomach is
recommend
ed
for
maximal
absorption
but has to
be balanced
against
administrati
on after a
meal
to
minimize GI
intolerance.
(+++)
(+++)
P8.90

(+++)

permeability
of the cell
wall.
(+)
Optic
neuritis, Redgreen
color
blindness,
Peripheral
neuropathy,
Hepatotoxicit
y,
Hyperuricaem
ia,
Vertical
nystagmus

(+++)

Page 10 of 38

5 Identify the DOC (basis)

Isonaizid
Rifampicin
Pyrazinamide
Ethambol
2 months for HRZE: INITIAL/BACTERICIDAL PHASE
4 month HR: CONTINUATION/STERILIZING phase
6 Discuss
the
pharmacokinetics
pharmacodynamics of the chosen drug.

and

ISONIAZID
Pharmacodynamics
Isoniazid = bactericidal to rapidly-dividing mycobacteria, but is
bacteriostatic if the mycobacterium is slow-growing.

Isoniazid is a prodrug and must be activated by bacterial catalase

Specficially, activation is associated with reduction of the
mycobacterial ferric KatG catalase-peroxidase by hydrazine and
reaction with oxygen to form an oxyferrous enzyme complex. Once
activated, isoniazid inhibits the synthesis of mycoloic acids, an
essential component of the bacterial cell wall. At therapeutic
levels isoniazid is bacteriocidal against actively growing
intracellular
and
extracellular Mycobacterium
tuberculosis organisms. Specifically isoniazid inhibits InhA, the
enoyl reductase from Mycobacterium tuberculosis, by forming a
covalent adduct with the NAD cofactor. It is the INH-NAD adduc
that acts as a slow, tight-binding competitive inhibitor of InhA.

Pharmacokinetics
Isoniazid = rapidly and almost completely absorbed with peak
Page 11 of 38

blood levels reaching about 1 to 2 hours.

Bioavailability is reduced when it is administered with food. I
diffuses readily in all body fluids (including cerebrospinal, pleural
and ascitic), tissues, organs, and excreta (saliva, sputum and
feces). The drug also passes through the placental barrier and into
milk in concentrations comparable to those in the plasma
Isoniazid
is
<
10%
bound
to
plasma
proteins.

Isoniazid is metabolized by the liver mainly by acetylation and

dehydrazination. The N-acetylhydrazine metabolite is believed to
be responsible for the hepatotoxic effects seen in patients treated
with isoniazid.
The half-life is 2 to 5 hours.
Elimination is largely independent of renal function, however the
half-life may be prolonged in liver disease. Isoniazid and its
metabolites are excreted in the urine with 75 to 95% of the dose
excreted in 24 hours. Small amounts are also excreted in saliva
sputum and feces. Isoniazid is removed in hemodialysis and
peritoneal dialysis.

Indications
Isoniazid is recommended for all forms of tuberculosis in which
organisms are susceptible. However, active tuberculosis must be
treated with multiple concomitant anti-tuberculosis medications to
prevent the emergence of drug resistance. Single-drug treatmen
of active tuberculosis with isoniazid, or any other medication, is
inadequate therapy.
Other Indications

<Newly infected patients

<Household members and close associates of people recently
diagnosed wtih TB
<To those with the following:
Positive TB skin test with positive non-progressive chest x
ray
Positive
TB
skin
test
with
underlying
disease
o
immunosuppression
Positive TB skin test, <35 years old; >35 years old weigh use
against risk of hepatitis

Contraindications
Isoniazid is contraindicated in patients who develop severe
hypersensitivity reactions, including drug- induced hepatitis
Page 12 of 38

previous isoniazid-associated hepatic injury; severe adverse

reactions to isoniazid such as drug fever, chills, arthritis
and acute liver disease of any etiology, and to pregnancy.

Drug Interactions
>Aluminum Hydroxide Gel: Decreases gastrointestinal absorption
of isoniazid; isoniazid should be administered at least 1 hou
before
the
antacid.

>Anticonvulsants: Isoniazid inhibits hepatic metabolism o

carbamazepine
and
phenytoin,
resulting
in
increased
anticonvulsant concentrations and toxicity in some patients. I
isoniazid and carbamazepine or phenytoin are administered
concurrently, serum concentrations of the anticonvulsant should
be monitored, the patient observed for evidence of toxicity and
the dosage of the anticonvulsant should be reduced accordingly.

>Cycloserine: In combination with isoniazid may result in

increased cycloserine CNS side effects such as dizziness o
drowsiness.

>Disulfiram: Coordination difficulties and psychotic episodes have

occurred in patients receiving isoniazid and disulfiram; concurren
administration
of
the
drugs
should
be
avoided.

>Ketoconazole: Concentrations may be decreased by isoniazid

possibly
decreasing
the
antifungal
effect.

>Rifampin: Hepatotoxicity has been reported to occur more

frequently when rifampin and isoniazid are given concurrently. The
incidence may be higher in slow isoniazid acetylators, those
receiving high doses of isoniazid or those with pre-existing live
disease.

Toxic Effects
>In CNS: Peripheral neuropathy (occurs most often in the
malnourished and is usually preceded by paresthesias of the fee
and
hands)
is
the
most
common.
Convulsions,
toxic
encephalopathy, optic neuritis and atrophy, and toxic psychosis
may
occur
rarely.
>Gastrointestinal:

nausea,

vomiting,

epigastric

distress.

>Hepatic: elevated serum aminotransferases (ALT, AST) and

bilirubin concentrations (10 to 20%), hepatitis with or withou
jaundice. Isoniazid-associated, occasionally severe and sometimes
Page 13 of 38

fatal hepatitis
hypersensitivity

is

generally

considered

>Hematologic:
agranulocytosis,
hemolytic,
aplastic
anemia;
thrombocytopenia;

an

unpredictable
reaction

sideroblastic
o
eosinophilia.

>Hypersensitivity:
fever,
skin
eruptions
(morbilliform
maculopapular, purpuric, or exfoliative), lymphadenopathy
vasculitis. Hypersensitivity reactions usually occur in the first 3 to
7
weeks
of
therapy
>Metabolic and
hyperglycemia,

Endocrine: pyridoxine deficiency, pellagra

metabolic
acidosis,
gynecomastia.

>Miscellaneous: rheumatic syndrome

erythematosus like syndrome.

and

systemic

lupus

RIFAMPICIN
Pharmacodynamics
The bactericidal actions are secondary to interfering with the
synthesis of nucleic acids by inhibiting bacterial DNA-dependen
RNA polymers at the B-subunit thus preventing initiation of RNA
transcription, but not chain elongation.

Rifampicin has high activity against mycobacterial organisms

including Mycobacterium tuberculosis and M.leprae. It is also
active
against
Staphylococcus
aureus,
coagulase-negative
staphylocci, Listeria monocytogenes, Neisseria meningitidis
Haemophilus influenzae, Legionella spp., Brucella, some strains o
E. coli, Proteus mirabilis, anaerobic cocci, Clostridium spp., and
Bacteroides.

Rifampicin is also reported to exhibit an immunosuppressive effec

which has been seen in some
animal experiments, but this may not be clinically significant in
humans.
Rifampicin may be bacteriostatic or bactericidal depending on the
concentration of drug attained at site of infection.
Pharmacokinetic

Rifampicin is readily absorbed from the gastrointestinal tract

Peak serum concentrations in a single 600 mg oral dose o
rifampin is about 7 mcg/mL but may vary from 4 to 32 mcg/mL.

Absorption of rifampicin is reduced by about 30% when the drug

Page 14 of 38

is ingested with food.

It is present in effective concentrations in many organs and body
fluids, including cerebrospinal fluid. Rifampicin is about 80%
protein bound. Most of the unbound fraction is not ionized and
diffuses freely into tissues.

Mean biological half-life of rifampicin in serum averages for 3

hours after a 600 mg oral dose, with increases up to 5.08 2.45
hours after a 900 mg dose. With repeated administration, the half
life decreases and reaches average values of approximately 2 to 3
hours. The half-life does not differ in patients with renal failure a
doses not exceeding 600 mg daily, and consequently, no dosage
adjustment is required.

After absorption, rifampicin is rapidly eliminated in the bile, and

an
enterohepatic circulation ensues.
During
this
process
rifampicin undergoes progressive deacetylation so that nearly al
the drug in the bile is in this form in about 6 hours. This
metabolite has antibacterial activity. Intestinal reabsorption is
reduced by deacetylation, and elimination is facilitated.

Up to 30% of a dose is excreted in the urine, with about half o

this being unchanged drug.

Toxic effects
Blurred vision
convulsions (seizures)
dizziness, faintness, or lightheadedness when getting up
suddenly from a lying or sitting position
fast, pounding, or irregular heartbeat or pulse
full feeling in the upper abdomen or stomach
itching
low blood pressure or slow pulse
nausea or vomiting
pain in the upper abdomen or stomach
reddish-orange to reddish-brown color of the urine, stool
saliva, sputum, sweat, and tears
swelling around the eyes or face
unconsciousness
unusual tiredness or weakness
yellow eyes or skin

Page 15 of 38

Contraindications
Rifampicin is contraindicated in known cases o
hypersensitivity to the drug.

It may be contraindicated in pregnancy (because o

teratogenicity noted in animal studies and since the
effects of drugs on fetus has not been established) except
in the presence of a disease such as severe
tuberculosis.

It is contraindicated in alcoholics with severely impaired

liver function and with jaundice.
Drug Interaction
Alfentanil

Rifampicin may decrease the serum concentration of A

Amiodaron Rifampin may decrease serum concentrations of the a

e
of Amiodarone. Specifically, desethylamiodarone
decrease.
Rifampin may decrease theserum concentration of Am

Amlodipine Rifampicin may decrease the serum concentration of

Calcium channel blockers.
This primarily affects oral forms of calcium channel bl
Amrinone

Rifampicin may decrease the serum concentration

Blockers.
This primarily affects oral forms of calcium channel bl

Apixaban

CYP3A4 Inducers (Strong) may decrease the seru

Apixaban.

Apremilast CYP3A4 Inducers (Strong) may decrease the seru

Apremilast.

Aprepitant Rifampin may decrease the serum concentration of Ap

Aripiprazol CYP3A4 Inducers may decrease the serum concentrat

e
Artemethe
r

CYP3A4 Inducers (Strong) may decrease serum conce

active metabolite(s) of Artemether. Specifically,
concentrations
may be reduced. CYP3A4 Inducers (Strong) may decre
concentration of Artemether.

PYRAZINAMIDE
Indication: For the initial treatment of active tuberculosis in adults
Page 16 of 38

and children when combined with other antituberculous agents.

Pharmacodynamics:
Pyrazinamide kills or stops the growth of certain bacteria tha
cause tuberculosis (TB). It is used with other drugs to trea
tuberculosis. It is a highly specific agent and is active only agains
Mycobacterium tuberculosis. In vitro and in vivo, the drug is active
only at a slightly acid pH. Pyrazinamie gets activated to Pyrazinoic
acid in the bacilli where it interferes with fatty acid synthase FAS
I. This interferes with the bacteriums ability to synthesize new
fatty acids, required for growth and replication.
MOA:
Pyrazinamide diffuses into M. tuberculosis, where the
enzyme pyrazinamidase converts pyrazinamide to the active form
pyrazinoic acid. Under acidic conditions, the pyrazinoic acid tha
slowly leaks out converts to the protonated conjugate acid, which
is thought to diffuse easily back into the bacilli and accumulate
The net effect is that more pyrazinoic acid accumulates inside the
bacillus at acid pH than at neutral pH. Pyrazinoic acid was though
to inhibit the enzyme fatty acid synthase (FAS) I, which is required
by the bacterium to synthesise fatty acids. However, this theory
was thought to have been discounted (PMID: 11914348). However
further studies reproduced the results of FAS I inhibition as the
putative mechanism first in whole cell assay of replicating M
tuberculosis bacilli which have shown that pyrazinoic acid and its
ester inhibit the synthesis of fatty acids (PMID: 17101678). This
study was followed by in vitro assay of tuberculous FAS I enzyme
that tested the activity with pyrazinamide, pyrazinoic acid and
several classes of pyrazinamide analogs. Pyrazinamide and its
analogs inhibited the activity of purified FAS I (PMID: 17485499). I
has also been suggested that the accumulation of pyrazinoic acid
disrupts membrane potential and interferes with energy
production, necessary for survival of M. tuberculosis at an acidic
site of infection. Pyrazinoic acid has also been shown to bind to
the ribosomal protein S1 (RpsA) and inhibit trans-translation. This
may explain the ability of the drug to kill dormant mycobacteria
(PMID: 21835980).

Pharmacokinetics:
Absorption: is well absorbed from the gastrointestinal tract
Distribution: Pyrazinamide is widely distributed to most fluids and
tissues, including liver, lungs, kidneys, and bile. It has excellen
penetration into CSF, ranging from 87 to 105% of the
corresponding serum concentration.
Protein binding: PyrazinamideLow (10 to 20%)
Biotransformation: is hydrolyzed by a microsomal deamidase to
pyrazinoic acid, an active metabolite, and then hydroxylated by
Page 17 of 38

xanthine oxidase to 5-hydroxypyrazinoic acid

Time to peak serum concentration: Pyrazinamide- 1 to 2 hours

Pyrazinoic acid-4 to 5 hours
Peak serum concentration:
Pyrazinamide:
Approximately 19 mcg/mL after a single dose of 14 mg/kg
Approximately 39 mcg/mL after a single dose of 27 mg/kg
Pyrazinoic acid:
Approximately 3 mcg/mL after a single dose of 14 mg/kg
Approximately 4.5 mcg/mL after a single dose of 27 mg/kg
Half life
9-10 hours (normal conditions)
Elimination:
Renal; approximately 3% of unchanged pyrazinamide, 33% o
pyrazinoic acid, and 36% of remaining identifiable metabolites
excreted in urine within 72 hours%
In dialysis- A single 3- to 4-hour hemodialysis session reduces
serum pyrazinamide concentrations by approximately 55% and
pyrazinoic acid concentrations by 50 to 60%

Toxic effect/Side effects: include liver injury, arthralgias, anorexia

nausea and vomiting, dysuria,malaise and fever, sideroblastic
anemia, adverse effects on the blood clotting mechanism o
vascular integrity, and hypersensitivity reactions such as urticaria
pruritis and skin rashes.
Special Precaution:
Cross-sensitivity and/or related problems
Pregnancy/Reproduction- Adequate and well-controlled studies in
humans have not been done; the risk of teratogenicity has no
been determined. FDA Pregnancy Category C

Drug Interaction:
Allopurinol or
Colchicine or
Probenecid or
Sulfinpyrazone
(pyrazinamide may increase serum uric acid
concentrations and decrease the efficacy of gout therapy; dosage
adjustments of these medications may be necessary to contro
hyperuricemia and gout when antigout medications are used
concurrently with pyrazinamide;

Rifampicin- May enhance the hepatotoxic effect of Rifampin

Severe (even fatal) liver injury has been reported in patients
receiving these 2 drugs as a 2-month treatment regimen for laten
TB infection.
Page 18 of 38

ETHAMBUTOL
Indication: as
tuberculosis.

an

adjunct,

in

the

treatment

of

pulmonary

Pharmocodynamics:
Ethambutol diffuses into actively growing M. tuberculosis such as
tubercle bacilli. Ethambutol appears to inhibit the synthesis of one
or more metabolites, thus causing impairment of cell metabolism
arrest of multiplication, and cell death. No cross resistance with
other available antimicrobial agents has been demonstrated.
MOA: Ethambutol inhibits arabinosyl transferases which is
involved in cell wall biosynthesis. By inhibiting this enzyme, the
bacterial cell wall complex production is inhibited. This leads to an
increase in cell wall permeability.

Pharmacokinetics:
Absorption:
Ethambutol
is
rapidly
absorbed
from
the
gastrointestinal tract following oral administration.
Distribution: Ethambutol is distributed to most tissues and body
fluids, except CSF. Ethambutol does not penetrate intac
meninges, but 10 to 50% may penetrate the meninges of patients
with tuberculous meningitis.
Protein binding: EthambutolLow (20 to 30%)
Biotransformation: Up to 15% of ethambutol is metabolized to
inactive metabolites.
Time to peak serum concentration: Ethambutol2 to 4 hours
Half life
In patients with normal renal function, 3 to 4
hours. In patients with impaired renal function, up to 8
hours.
Peak serum concentration: 2 to 5 mcg/mL after a single dose of 25
mg/kg
Elimination: Renal; by glomerular filtration and tubular secretion
up to 80% excreted within 24 hours (at least 50% excreted
unchanged and up to 15% as inactive metabolites).
Fecal; 20% excreted unchanged
In dialysis
ethambutol is removed from the blood by hemodialysis and
peritoneal dialysis.
Side Effect:
loss of appetite
upset stomach
vomiting
numbness and tingling in the hands or feet

Toxic effect: The most commonly recognized toxic effect o

Page 19 of 38

ethambutol is optic neuropathy,

blurred vision
inability to see the colors red and green
sudden changes in vision
skin rash
itching

Special precaution
History of allergy to ethambutol or to any drugs
tell your doctor if you have or have ever had kidney disease, gout
or eye disorders such as cataracts.
tell your doctor if you are pregnant, plan to become pregnant, o
are breast-feeding. If you become pregnant while taking
ethambutol
Pediatrics
Ethambutol may cause reversible optic neuritis; therefore
patients should be monitored regularly for visual acuity, visua
fields, and red-green color discrimination. Because cooperation is
essential for performance of these tests, use of ethambutol in
young children whose visual acuity cannot be monitored requires
careful consideration of risks and benefits

Drug interaction:
Antacids interfere with ethambutol, making it less effective. Take
ethambutol 1 hour before or 2 hours after antacids.
Food interaction: Take with food to reduce irritation.

PAGE 37
HYPERTENSION
A BASIS OF THE PROBLEM

BP: 150/95 mmHg

Past Medical History: Diagnosed with Hypertension
3 months ago
Family History: 2 siblings (+) for hypertension

B THERAPEUTIC OBJECTIVES

Control patients blood pressure

Prevent further complications of hypetension
Page 20 of 38

C NON-PHARMACOLOGIC MANAGEMENT
1 Dietary salt reduction - <6g NaCl
2 DASH dietary plan Diet rich in fruits, vegestables and
low fat dairy products with reduced content of
saturated and total fat
3 Weight reduction Attain and maintain BMI <25kg/m2
4 Physical Exercise Regular aerobic activity e.g. brisk
walking for 30 min/day
5 Moderation of alcohol consumption For those who
drink alcohol, consume <2 drinks/day in men and <1
drink/day in women.
D PHARMACOLOGIC
GIVEN FOR HTN)

MANAGEMENT

(ENUMERATE

DRUGS

E IDENTIFY THE DRUG OF CHOICE (BASIS)

Emergency Drug for Hypertension
Drug class of choice:
Drug of choice: Sodium Nitroprusside
- 25 mg/ml injectable solution
Maintenance Drug for Hypertension
Drug class of choice: Angiotensin Receptor Blockers
Drug of choice: Losartan
- ?
*Other maintenance drugs:
Beta Blockers (B1 selective) cause heart to beat
more slowly and with less force. The heart pumps
less blood through the blood vessels, and the blood
pressure goes down.
i.e Atenolol, Betaxolol, Esmolol
Calcium Channel Blockers (CCBs) keep calcium from
entering the muscle cells of your heart and blood
vessels. This causes blood vessels to relax, and the
blood pressure goes down.
i.e Amlodipine, Verapamil
Vasodilators open blood vessels by directly relaxing
the muscle in the vessel walls, causing blood
pressure to go down and given if there is severe
hypertension.
Page 21 of 38

 i.e Nitroglycerin (Sublingual)

F DISCUSS
THE
PHARMACOKINETICS
PHARMACODYNAMICS OF THE CHOSESN DRUG

AND

Emergency drug: SODIUM NITROPRUSSIDE

Sodium Nitroprusside is indicated for the immediate

reduction of blood pressure of patients in
hypertensive
crisis.
Concomitant
longer-acting
antihypertensive medication should be administered
so that the duration of treatment with sodium
nitroprusside can be minimized.
It is also indicated for producing controlled
hypotension in order to reduce bleeding during
surgery.
Also indicated for the treatment of acute congestive
heart failure.

Pharmacodynamics
o MOA:
- Relaxes vascular smooth muscle to reduce
afterload and preload by producing NO
- Also dilates coronary arteries
- A vasodilator that works by relaxing the
muscles in your blood vessels to help them
dilate (widen)
- Lowers blood pressure and allows blood to
flow more easily through your veins and
arteries
o Usage:
- Used to treat congestive heart failure and
life threatening high blood pressure

Pharmacokinetics
o Half-life: parent drug: 2 minutes, metabolite
(thiocyanate): 3 days, longer in patients with
impaired renal function or hyponatremia
o Onset of action: <2 minutes
o Duration: 1-10 minutes
o Metabolism: in blood (100%); ferrous ion in
nitroprusside molecule reacts rapidly in liver
and kidney by rhodanese to thiocyanate
o Metabolites: Thyocyanate (inactive)
Page 22 of 38

o Excretion: Mainly in urine, excreted entirely as

metabolites, principally thiocyanate

Adverse effects:
o More common: Hypotension. Bradyarrhythmia,
Palpitations, Dizziness, Headache, Confusion,
Methemoglobinemia
o Less common: Mild skin rash, irritation on the
injection site
Contraindications:
o It is contraindicated in patients who are
hypersensitive to any component of this
product.
o It should not be used to produce hypotension
during surgery in patients with known
inadequate cerebral circulation, or in moribund
patients coming to emergency surgery.
o It should not be used for the treatment of
acute congestive heart failure associated with
reduced peripheral vascular resistance such as
high-output heart failure that may be seen in
endotoxic sepsis.
o It should not be used in the treatment of
compensatory
hypertension,
where
the
primary
hemodynamic
lesion
is
aortic
coarctation or arteriovenous shunting.

Maintenance Drug: LOSARTAN

Angiotensin II Receptor blockers help relax your

blood vessels, which lowers your blood pressure and
makes it easier for your heart to pump blood.
Angiotensin II is a natural substance in your body
that affects your cardiovascular system in many
ways, such as narrowing your blood vessels.
This narrowing can increase your blood pressure
and force your heart to work harder. Angiotensin II
also starts the release of a hormone that increases
the amount of sodium and water in your body, which
can lead to increased blood pressure.
Angotensin II can also thicken and stiffen the walls
of your blood vessels and heart.
Pharmacodynamics
o MOA:
Page 23 of 38

Blocks binding of angiotensin II to type 1

angiotensin
II
receptors;
blocks
the
vasoconstrictor and aldosterone secreting
effects of angiotensin II
- Belongs to a group of drugs called
angiotensin II receptor antagonists
- It keeps blood vessels from narrowing,
which lowers blood pressure and improves
blood flow
o Usage:
- Used
to
treat
high
blood
pressure
(hypertension)
- Also used to lower the risk of stroke in
certain people with heart disease
- Used to slow long-term kidney damage in
people with type 2 diabetes who also have
high blood pressure
-

Pharmacokinetics
o Half life: 1-2 hours
o Bioavalability: 36%
o Suggested Initial dose: 50 mg/d
o Usual maintenance dose range: 25-100 mg/d
o The active metabolite of losartan has a half life
of 3-4 hours
o Absorption: Losartan is well absorbed and
undergoes substantial first-pass metabolism;
Mean peak concentrations of losartan and its
active metabolite are reached in 1 hour and in
3-4 hours, respectively. When given with a
meal, absorption slows down and Cmax
decreases.
o Protein binding: 99.7%, primarily to albumin
o Metabolism: Hepatic. Losartan is metabolized
to a 5-carboxylic acid derivative (E-3174) via
an aldehyde intermediate (E-3179) primarily by
cytochrome P450 (CYP) 2C9 and CYP3A4. E3174 is an active metabolite with 10-40-fold
higher potency that its parent compound,
losartan.
o Route
of
elimination:
Following
oral
administration, 35% of the dose is recovered in
the urine and about 60% in the feces.
Following an IV dose, 45% is recovered in urine
and 50% in the feces.
Page 24 of 38

Adverse effects:
o Common: Angioedema, Back ache, Head pain,
muscle weakness
o Infrequent: Chest pain, Dizziness, Acute
infection of the nose, Diarrhea, Throat
irritation
o Rare: Abnormal liver function test, decreased
blood platelets

Contraindication:
o It is contraindicated in patients who are
hypersensitive to any component of the
product
o Do not co-administer aliskiren with losartan in
patients with diabetes
o It also contraindicated in pregnant patients

PAGE 39
Type II Diabetes Mellitus
A. Basis of the Problem
HPI: Age 55 yrs old,
Evaluated with Type II DM
PMH: Diagnosed of HPN and DM 3 months ago
FH: 2 siblings diagnosed of HPN
Social History: Metformin 500 mg PO BID currently taken
ROS; weight loss , decrease urinary frequency when in
MetforminG
Physical Examination:
General: slightly Overweight
Vital signs: BP 150/95 mmHg, BMI: 29.30 (Overweight)
LABORATORY TEST
GLUCOSE: 153 mg/dl or 8.5 mmol/L
HBA1c : 7.2 %, 55 mmol/mol Hgb
B. Therapeutic Objectives
a. Glycosylated A1c <6% is the primary goal
b. Lowering Blood Pressure to <140/80 mmHg
c. Lowering Blood Sugar to Normal Values ( 70- 130 mg/dl)
d. Improve symptoms of Diabetes mellitus and prevent further
complications

Page 25 of 38

C. Non-pharmacologic Management (ADA recommendations)

a. Diabetic diet
(Low fat and low salt intake)
b. Weight reduction
(Exercise atleast 30-45 mins everyday)
c. Blood sugar and BP monitoring
D. Pharmacologic treatment
A. Sulfonylureas
a. Glipizide, Glimeperide,Glyburide
B. Biguanides
a. Metformin
C. Glitinides
a. nateglinides, repaglinides
D. Alpha-glucosidase inhibitor
a. Acarbose, Miglitol
E. Thiazolidinediones
a. Rosiglitazone, pioglitazone
F. Incretins
a. Sitagliptin, Exenatide
G. Amylin analog
a. Pramlintide
E. Identify the Drug of choice and Basis
Name of Patient: CD
Age: 55 yrs old
Rx
Metformin 500 mg
(Glucophage)

#60 tabs

Sig. Take 1 tab twice a day.

(0-1-1)
________________________________________________
Glimepiride 2mg
(Norizec)

#30 tabs

Sig. Take 1 tab in the morning after meal.

Jimong Boy S. Quiroz, M.D, Dermatologist ()
License No: XUV-819 (plate number)
Page 26 of 38

Basis: The patient is currently taking Metformin 500 mg PO BID

and diagnosed of Type II DM 3 months ago. But still the
Glucose level and the HBA1c didnt reach the normal values
and patients condition may progress the symptoms due to its
comorbidities condition such as HPN, systemic bacterial
Infection, depression and Overweight. So we should add
another OHAs that will help maintain the blood sugar into
Normal level, like your Sulfonylureas. Still give the Metformin
on its original schedule.
F. Pharmacokinetic and Pharmacodynamics

[
[

Metformin
Mechanism of Action
Decreases hepatic glucose production; decreases GI glucose
absorption; increases target cell insulin sensitivity
Absorption
Bioavailability: 50-60%
Peak plasma time
Regular-release: 2-3 hr
Extended-release: 4-8 hr
Distribution
Protein bound: Minimal
Vd: 650 L (regular-release)
Metabolism
Metabolism: Not by liver
Elimination
Half-Life: 4-9 hr
Dialyzable: Yes (hemodialysis)
Renal clearance: 450-540 mL/min (regular-release)
Excretion: Urine (90%, by tubular secretion)
Glimepiride
Mechanism of Action
Initial effect to increase insulin secretion from beta cells; may
also decrease rate of hepatic glucose production and increase
insulin receptor sensitivity
Absorption
Bioavailability: 100%
Initial effect: 1 hr
Peak plasma time: 2-3 hr
Max effect: 2-4 hr
Duration: 24 hr
Distribution
Vd: 8.8 L
Protein bound: 99.5%
Page 27 of 38

Metabolism
Metabolized extensively by hepatic P450 enzyme CYP2C9 to
less-active metabolites
Metabolites: Cyclohexyl hydroxy methyl derivative (M1; mildly
active) and the carboxyl derivative (M2; inactive)
Elimination
Half-life: 5-9 hr
Total body clearance: 47.8 mL/min
Excretion: Urine (60%); feces (40%)
PAGE 41
IV. DEPRESSION
A. WHAT IS THE BASIS OF THE PROBLEM?
a History of depression. Patient was diagnosed with
depression 9 months ago.
b Loss of a family member (Deceased father and husband, 5
and 3 years ago, respectively.)
c Separation from relatives: two daughters live in Samar.
B THERAPEUTIC OBJECTIVE
1. to avoid further complications
2. to assess the appropriate regimen for the patient
3. to achieve normal lifestyle as posible
4.to improve sign and symptoms and lessen the probability of
suicide.
C. NON PHARMACOLOGIC MANAGEMENT
1. Psychotherapy to correct interpersonal conflicts and to help women
develop interpersonal skills
2. Cognitive-behavioral therapy to correct negative thinking and
associated behavior;
3.Expose yourself to a little sunlight every day.Sunlight can help
boost your mood. Take a short walk outdoors, have your coffee outside,
enjoy an al fresco meal, people-watch on a park bench, or sit out in the
garden. Aim for at least 15 minutes of sunlight a day. If you live
somewhere with little winter sunshine, try using a light therapy box.
Talk about your feelings to someone you trust, face-toface. Share what youre going through with the people you love
and trust. Ask for the help and support you need. You may have
Page 28 of 38

retreated from your most treasured relationships, but they can

get you through this tough time. If you dont feel that you have
anyone to confide in, look to build new friendships. Start by
joining a support group for depression.
Try to keep up with social activities even if you dont feel
like it. When youre depressed, it feels more comfortable to
retreat into your shell. But being around other people will make
you feel less depressed.
Get up and moving. Studies show that regular exercise can be
as effective as antidepressant medication at increasing energy
levels and decreasing feelings of fatigue. You dont have to hit
the gym. A 30-minute walk each day will give you a muchneeded boost.
Aim for 8 hours of sleep. Depression typically involves sleep
problems. Whether youre sleeping too little or too much, your
mood suffers. Get on a better sleep schedule by learning healthy
sleep habits.
Practice relaxation techniques. A daily relaxation practice
can help relieve symptoms of depression, reduce stress, and
boost feelings of joy and well-being. Try yoga, deep breathing,
progressive muscle relaxation, or meditation.

4 Fast mood boosters that can lift you out of a funk

Getting the blues can happen to anyone, but it doesn't mean you have
a chronic medical condition like depression. A little diversion might
help you feel like yourself again. "If you're down about something, step
away from it for a period and do something else," suggests Dr. Michael
Craig Miller, assistant professor of psychiatry at Harvard Medical
School. Consider these boosters, and take the steps to fit them into
your life.
Mood booster 1: Exercise
Exercise is healthful right down to the cellular level. It improves
circulation and nerve function, it helps to regulate mood, and it makes
you feel better about yourself
Action steps: For a quick pick-me-up, try a medium- to high-intensity
workout such as a brisk 30-minute walk, an aerobics class, or a game
of tennis. For a remedy that will stay with you, go for a daily activity
you can sustain, such as a daily lower-intensity walk.
Mood booster 2: Meditate
Meditating produces brain changes that promote positive emotions and
reduce negative emotions such as fear and anger. It can lower your
heart rate, blood pressure, breathing rate, oxygen consumption,

Page 29 of 38

adrenaline levels, and levels of cortisol, a hormone released in

response to stress.
Action steps: Many health centers offer meditation classes. Sign up
for one, or consider taking yoga, which combines physical and mental
practices. If it's hard for you to get to a class, buy a guided meditation
book or CD, which can introduce you to meditation practice.
Mood booster 3: Socialize
Being isolated can lead to loneliness, which can make you sad.
Spending time with others helps improve mood. We're wired to be
social. Focusing on others can move you off a preoccupation with selfdefeating thoughts.
Action steps: Avoid isolation. Get together with a friend, family
member, or group at least once a month. Visit with friends at home.
Get out of your house, go to a movie, or check out an art exhibit. If you
don't have someone to spend time with, go to church or take a class.
Mood booster 4: Find purpose
Dedicating time to a meaningful activity improves mood, reduces
stress, and keeps you mentally sharp. The activity can be as simple as
taking up a new hobby or volunteering your time. You worry less about
every little ache and pain in your own life when you move the focus to
a new interest.
Action steps: Volunteer for a library, hospital, school, day care center,
or charitable group. Tutor neighborhood kids. Babysit. Contact the
chamber of commerce to mentor young business people. Take up
gardening, painting, dancing, or gourmet cooking.
1. Get in a routine. If youre depressed, you need a routine, says Ian
Cook, MD. He's a psychiatrist and director of the Depression Research
and Clinic Program at UCLA.
Depression can strip away the structure from your life. One day melts
into the next. Setting a gentle daily schedule can help you get back on
track.
2.Set goals. When you're depressed, you may feel like you can't
accomplish anything. That makes you feel worse about yourself. To
push back, set daily goals for yourself.
3. Exercise. It temporarily boosts feel-good chemicals called
endorphins. It may also have long-term benefits for people
withdepression. Regular exercise seems to encourage the brain to
rewire itself in positive ways, Cook says.
Page 30 of 38

How much exercise do you need? You dont need to run marathons to
get a benefit. Just walking a few times a week can help.
4. Eat healthy. There is no magic diet that fixes depression. It's a
good idea to watch what you eat, though. If depression tends to make
you overeat, getting in control of your eating will help you feel better.
Although nothing is definitive, Cook says there's evidence that foods
with omega-3 fatty acids (such as salmon and tuna) and folic
acid (such as spinach and avocado) could help ease depression.
5. Get enough sleep. Depression can make it hard to get enough
shut-eye, and too little sleep can make depression worse.
What can you do? Start by making some changes to your lifestyle. Go
to bed and get up at the same time every day. Try not to nap. Take all
the distractions out of your bedroom -- no computer and no TV. In time,
you may find your sleep improves.
6. Take on responsibilities. When youre depressed, you may want
to pull back from life and give up your responsibilities at home and at
work. Don't. Staying involved and having daily responsibilities can help
you maintain a lifestyle that can help counter depression. They ground
you and give you a sense of accomplishment.
If you're not up to full-time school or work, thats fine. Think about
part-time. If that seems like too much, consider volunteer work.
7. Challenge negative thoughts. In your fight against depression, a
lot of the work is mental -- changing how you think. When you're
depressed, you leap to the worst possible conclusions.
The next time you're feeling terrible about yourself, use logic as a
natural depression treatment. You might feel like no one likes you, but
is there real evidence for that? You might feel like the most worthless
person on the planet, but is that really likely? It takes practice, but in
time you can beat back those negative thoughts before they get out of
control.
8. Check with your doctor before using supplements. "There's
promising evidence for certain supplements for depression," Cook
says. Those include fish oil, folic acid, and SAMe. But more research
needs to be done before we'll know for sure. Always check with your
doctor before starting any supplement, especially if youre already
taking medications.
Page 31 of 38

9. Do something new. When youre depressed, youre in a rut. Push

yourself to do something different. Go to a museum. Pick up a used
book and read it on a park bench. Volunteer at a soup kitchen. Take a
language class.
"When we challenge ourselves to do something different, there are
chemical changes in the brain," Cook says. "Trying something new
alters the levels of [the brain chemical] dopamine, which is associated
with pleasure, enjoyment, and learning."
10. Try to have fun. If youre depressed, make time for things you
enjoy. What if nothing seems fun anymore? "That's just a symptom of
depression," Cook says. You have to keep trying anyway.

D. DRUGS GIVEN FOR DEPRESSION (ENUMERATE DRUGS GIVEN

FOR DEPRESSION)
Major types of antidepressants include:
Tricyclic antidepressants (TCAs) are some of the first
antidepressants used to treat depression. They primarily affect the
levels of two chemical messengers (neurotransmitters), norepinephrine
and serotonin, in the brain. Although these drugs are effective
in treating depression, they have more side effects, so they usually
aren't the first drugs used. Example of TCAs drug are Imipramine,
Clomipramine and Amytriptyline.
Monoamine oxidase inhibitors (MAOIs) are another early
form of antidepressant. These drugs are most effective in people
with depression who do not respond to other treatments. Substances in
certain foods, like cheese, beverages like tap beer or certain wines,
and some cough syrups and other medications can interact with an
MAOI, so people taking an MAOI must adhere to strict dietary
restrictions (see below). For this reason these antidepressants also
aren't usually the first drugs used. Example of MAOI's drug are
Isocarboxacid, Phenelzine, Selegiline and Tranylcypromine.
Selective serotonin reuptake inhibitors (SSRIs) are a newer
form of antidepressant. These drugs work by altering the amount of a
chemical in the brain called serotonin. Examples of SSRI's are
Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetin and
Sertraline.
Page 32 of 38

Serotonin and norepinephrine reuptake inhibitors

(SNRIs) are another newer form of antidepressant medicine such as
Duloxetine, Milnacipran, Venlafaxine. They treat depression by
increasing availability of the brain chemicals serotonin and
norepinephrine.

5-HT2 antagonist
inhibition of 5HT2a receptors in both animal and human studies have
substantial anti-anxiety, anti-psychotic and anti-depressant effect such
as Trazodone and Nefazodone. Adverse reactiin such as sedation
(trazodone) probably because of their potent H1-blocking activity. Both
Trazodone and Nefazodone are a-blocking agents,have dose related
orthostatic hypotension in some patients. Nefazodone has been
associated with hepatoxicity.

Tetracyclic and Unicyclic anti-depressants

-Bupropion - action poorly understood, it acts as a weak dopamine and
norepinephrine reuptake inhibitor to alleviate the symptoms if
depression. It has virtually no direct effect on serotonin system but
cause presynaptic release of cathecolamines.
-Mirtazapine - blocks the presynaptic a2-adrenoceptors causing release
of NE & 5HT. It is an antagonist of 5HT2 and 5HT1 receptors. It is
adventagious in patients with depressio having sleep difficulty.
Atypical antidepressants

Augmentation is a common strategy for treatment-resistant

depression. It consists of adding a medication with a different
mechanism of action to the therapeutic regimen.

Lithium carbonate (Eskalith, Lithane, Lithobid)

Lithium carbonate can be used as an effective augmenting agent

in combination with an antidepressant in cases of treatmentresistant depression. It can also be used to treat or prevent
episodes of depression. Lithium is contraindicated in patients
with significant renal impairment.

It is important to note that lithium interacts with many drugs.

Use of lithium often requires monitoring of lithium levels and
renal and thyroid function tests.
Page 33 of 38

Buspirone (BuSpar)
Buspirone is marketed as an antianxiety medication; however, it
may have antidepressant effects at doses above 45 mg/day. The
antidepressant effects may increase when buspirone is used in
combination with SSRIs and TCAs in patients with treatmentresistant depression. Buspirone is a partial 5-HT1A agonist with
serotonergic and some dopaminergic effects in the CNS. It has
anxiolytic effects but may take up to 2-3 weeks for full efficacy.

NICE

TO KNOW:
ST. Johns wort (Hypericum perforatum)

Page 34 of 38

All available antidepressants appear to work via one or more of the

following mechanisms[128] :

Presynaptic inhibition of uptake of 5-HT or NE

Page 35 of 38

Antagonist activity at presynaptic inhibitory 5-HT or NE receptor

sites, thereby enhancing neurotransmitter release
Antagonism of NE beta or serotonin 5-HT2 receptors
N-Methyl-D-aspartate (NMDA) receptor antagonism
Induction of brain-derived neurotrophic factor (BDNF)
Inhibition of monoamine oxidase, thereby reducing
neurotransmitter breakdown

E. IDENTIFY THE DRUG OF CHOICE

Fluoxetine 20 mg bid - reason SSRI produces less toxic effects
among other antidepressant considering that treatment for depression
is long term so I suggest this drug to avoid untowards effects during
the course of the treatment as well as patient is with other co morbid
disease under treatment though this condition should not be overlook
as it may lead to suicidal ideation if left untreated.
Efficacy
Suitability
Safety
Cost

SSRI
+++
+++
+++
++

SNRI
+++
++
++
++

TCA
+++
++
++
+++

MAOI
++
++
+
++

F. DISCUSS THE PHARMACOKINETICS AND

PHARMACODYNAMICS OF THE CHOSEN DRUG
FLUOXETINE brand names ( ADEPSSIR, DEPRIZAC, DRAFZIN,
MAGRILAM, MOTIVEST, PRODIN)
Mechanism of action: potent and highly selective serotonin (5-HT)
reuptake inhibitor with no afffinity for adrenoceptors or histamine,
GABA-B or muscarinic receptors.
Pharmacokinetics: Absorption -oral administration, readily absorbed
from the GI tract; peak plasma concentrations after 6-8 hours.
Distribution -widely distributed, enters breast milk. Protein binding 95%
Metabolism -extensively hepatic bt demethylation to norfluoxetine
Excretion -via urine, elimination half-life 1-3 days (fluoxetine) 4-16 days
(nofluoxetine)
Page 36 of 38

Pharmacodynamics
The serotonin transporter (SERT) is a glycoprotein with 12
transmembrane regions embedded in the axon
Terminal and cell body membranes of serotonergic neurons. When
extracellular serotonin binds to receptors on the
transporter, conformational changes occur in the transporter and
serotonin, Na + , and Cl are moved into the cell.
Binding of intracellular K + then results in return of the transporter to
its original conformation and the release of
serotonin inside the cell.
SSRIs allosterically inhibit the transporter by binding the receptor
at a site other than active binding site for
serotonin. At therapeutic doses, about 80% of the activity of the
transporter is inhibited.
SSRIs have modest effects on other neurotransmitters. Unlike
TCAs and SNRIs, there is little evidence that
SSRIs have prominent effects on adrenoceptors or the
norepinephrine transporter, NET. Binding to the serotonin
transporter is associated with tonic inhibition of the dopamine system,
although there is substantial interindividual
variability in this effect.
The SSRIs do not bind aggressively to histamine, muscarinic, or
other receptors.
Pregnancy Category C
Uses:
Fluoxetine is a selective serotonin reuptake inhibitors (SSRI)
antidepressant. Fluoxetine affects chemicals in the brain that may
become unbalanced and cause depression, panic, anxiety, or
obsessive-compulsive symptoms.
Fluoxetine is used to treat major depressive disorder, bulimia nervosa
(an eating disorder) obsessive-compulsive disorder, panic disorder, and
premenstrual dysphoric disorder (PMDD).
Contraindication:

Fluoxetine is contraindicated in patients known to be

hypersensitive to it.

Fluoxetine is contraindicated in patients on monoamine oxidase

inhibitor therapy.

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Adverse effects: dry mou, GI disturbances (nausea, vomiting,

dyspepsia, constipation, diarrhea, anorexia and weight loss), excessive
sweating, pruritus, skin rashes, urticaria. Angioedema, anapylactic
shock, hyponatremia, hyperprolactinemia, galactorrhea, arthralgia,
myalgia, chest pain and chills
Drug interactions: synergistic effect with MAOIs, increase
Benzodiazepine plasma concentration. Elevates plasma levels of
thiordazine and anticonvulsants. Elevates blood levels of haloperidol &
clozapine.
Price: capsue 20 mg x 30's (P1,282), P 42.73 per capsule

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