FEBRUARY 2020

B.Sc. (Nursing) DEGREE EXAMINATION

SECOND YEAR
PAPER III – PHARMACOLOGY, PATHOLOGY AND GENETICS
Time: Three Hours Maximum: 75 Marks
SECTION - A (PHARMACOLOGY)
I. ELABORATE ON: (1 X15 = 15)
1. A) CLASSIFY SEDATIVES AND HYPNOTICS. B) MECHANISM OF ACTION AND USES OF
DIAZEPAM. C) MANAGEMENT OF DIAZEPAM POISONING.
Sedative:

 A drug that subdues excitement and calms the subject without inducing sleep,
though drowsiness may be produced.
 Sedation refers to decreased responsiveness to any level of stimulation; is
associated with some decrease in motor activity and ideation.
Hypnotic

 A drug that induces and/or maintains sleep, similar to normal arousable sleep.
This is not to be confused with ‘hypnosis’ meaning a trans-like state in which the
subject becomes passive and highly suggestible.

The sedatives and hypnotics are more or less global CNS depressants with
somewhat differing time-action and dose-action relationships. Those with
quicker onset, shorter duration and steeper dose-response curves are preferred
as hypnotics while more slowly acting drugs with flatter dose-response curves
are employed as sedatives. However, there is considerable overlap; a hypnotic at
lower dose may act as sedative. Thus, sedation—hypnosis—general anaesthesia
may be regarded as increasing grades of CNS depression.
CLASSIFICATION
1. Barbiturates Long acting Short acting Ultra-short acting Phenobarbitone
Butobarbitone Thiopentone Pentobarbitone Methohexitone
2. Benzodiazepines Hypnotic Antianxiety Anticonvulsant Diazepam DiazepamDiazepam
Flurazepam Chlordiazepoxide Lorazepam Nitrazepam Oxazepam Clonazepam
Alprazolam Lorazepam Clobazam Temazepam Alprazolam Triazolam
3. Newer nonbenzodiazepine hypnotics Zopiclone Zolpidem Zaleplon Chloral hydrate,
Triclophos, Paraldehyde, Glutethimide, Methyprylon, Methaqualone and Meprobamate
are historical sedative-hypnotics no longer used
MECHANISMOF ACTION :
•Gamma - aminobutric acid(GABA) is the principle inhibitory neurotransmitter of the
CNS and it acts through GABA receptors.
 BZD bind to the GABA-A receptor and increase the frequency of chloride channel
opening.
 This in turn leads to increased flow of chloride into the neurons, resulting in
hyperpolarisation.
 This result in inhibition of propagation of action potential further result in
inhibitory effect on different sites of the brain especially motor cortex, and
limbic system
 BZDs bind to the receptor and increase the frequency of chloride channel
opening.this in turn lrad to increased flow of chloride ions into the
neurons,resulting in hyperpolarization
Benzodiazepines

Bind to GABAA receptor

Frequency of CI channel opening

Flow of chloride ions into neurons

Hyperpolarization

Depresses synaptic transmission

CNS
depression

Benzodiazepines

 These agents are used in pre-anestheticmedication,induction,maintaining and

supplementing anesthesia as well as for ‘conscious sedation’.
 They slighty decrease respiration,blood pressure and cardic contractility when
given in combination with opioids.
  They produce amnesia,sedation and unconsciounsness within 5-10
minutes,when given in slighty higher doses.
 The side effects such as nausea or vomiting are uncommon with BZDs.
 The common indications of BZDs are endoscopies,anglography,cardiac
catheterization, setting of fractures,local/regional anesthesia.
 Flumazenil in a dose of 0.5-2 mg IV is used for the reversal of anesthetic
effects of BZDs.

USES OF BZDs
 Insomnia: when drugs are to be use to treat insomnia,BZDs are the agents of
choice.lorazepam,oxazepam,temazepam,nitrazepam or triazolam may be
used.
 In anxiety states: BZDs are the most commonly used anxiolytics for the
treatment of anxiexty states and anxiety neurosesany of the BZDs except the
ultra short acting ones may be used.
 As anticonvulsants: IV diazepam is the drug of choice in the treatment of
status epilepticus.clonazepam or clobazam are used as adjuncts with other
antiepeileptic drugs
 Muscle relaxant: BZDs are centrally acting muscle relaxants used in chronic
muscle spasm and spasticity.
 As preanesthetic medication: for there sedation and anaxiolytic effects BZDs
are useful.
 During alcohol withdrawal: BZDs are useful in patients during withdrawal of
alcohol or other sedative-hypnotics.
 General anesthesia: IV midazolam or diazepam is used as an intravenous
anesthetic.BZDs are also use to supplement anesthesia.
 Minor procedures like endoscopies,fracture reduction,cardiac catheterization,
prior to ECT intravenous diazepam is used.
 In paychiatry: For the initial conrol of mania,diazepam is used as an adjuvant.
 Nurses Responsibility
• Nursing considerations for benzodiazepines also involve careful monitoring of
the patient’s condition and education of medication regimen.
• Benzodiazepines are a Schedule IV drug, so the patient should be assessed
for drug-abuse potential and dependence.
• Since benzodiazepines change intraocular pressure, patients with narrow-
angle glaucoma should not receive these drugs. Liver and kidney function
should also be monitored, and respiratory depression may result if the
patient is taking other CNS depressants
• Common side effects include drowsiness and dizziness. If a patient receives an
overdose of benzodiazepines, flumazenil (Romazicon) should be administered to
reverse the CNS depression.
 • Oxygen and resuscitation equipment should be nearby to treat respiratory
depression, since flumazenil (Romazicon) should not be given because of the
need to stop the seizures
• Do not mix these drugs with others because they tend to precipitate and are
irritating to the veins.
• Patient teaching should include avoiding alcohol, OTC drugs, and herbal
medications without notifying the prescriber, due to CNS depression.

II. Write Short Notes on: (3 x 5 = 15)

1. ROLE OF CAPTOPRIL IN HYPERTENSION.

Captopril is an ACE inhibitor and works by relaxing blood vessels so that blood can flow
more easily.Captopril is a potent, competitive inhibitor of angiotensin-converting
enzyme (ACE), the enzyme responsible for the conversion of angiotensin I (ATI) to
angiotensin II (ATII). ATII regulates blood pressure and is a key component of the
renin-angiotensin-aldosterone system (RAAS).captopril is an oral drug and a member
of a class of drugs called angiotensin converting enzyme (ACE) inhibitors.

 ACE inhibitors are used for treating high blood pressure, heart failure, and for
preventing kidney failure due to high blood pressure and diabetes.
 Other ACE inhibitors
include enalapril (Vasotec), quinapril (Accupril), ramipril (Altace), fosinopril
(Monopril), benazepril (Lotensin), lisinopril
 Angiotensin II is a very potent chemical that causes the muscles surrounding
blood vessels to contract, thereby narrowing the vessels.
 The narrowing of the vessels increases the pressure within the vessels
causing high blood pressure (hypertension).
 Angiotensin II is formed from angiotensin I in the blood by the enzyme
angiotensin converting enzyme or ACE.
 ACE inhibitors are medications that slow (inhibit) the activity of the enzyme
ACE and decrease the production of angiotensin II.
 As a result, blood vessels enlarge or dilate, and blood pressure is reduced.
The lower blood pressure makes it easier for the heart to pump blood and
can improve the function of a failing heart.

USES:

 It is used to treat high blood pressure (hypertension).

 Lowering high blood pressure
 helps prevent strokes,
 heart attacks,
 and kidney problems.
 It is also used to treat heart failure, protect the kidneys from harm due
to diabetes, and to improve survival after a heart attack.
 SIDE EFFECTS: Captopril generally is well tolerated, and side effects are usually mild
and transient.

 Dizziness,
 light headedness,
 loss of taste.
 Dry and persistent cough
 abdominal pain,
 constipation
 diarrhea,
 rash,
 dizziness,
 fatigue,
 headache,
 loss of taste,
 loss of appetite,
 nausea,
 vomiting,
 fainting and
 numbness or tingling in the hands or feet.
 kidney failure and
 increased levels of potassium in the blood.
 liver failure and
 angioedema (swelling of lips and throat that can obstruct breathing).

2. MECHANISM OF ACTION AND USES OF OFLOXACIN.

OFLOXACIN:

Ofloxacin is a quinolone antimicrobial agent.

 ofloxacin and other fluoroquinolone antimicrobials involves inhibition of

bacterial topoisomerase IV and DNA gyrase (both of which are type II
topoisomerases), enzymes required for DNA replication, transcription,
repair and recombination.
Place the dropper directly over your ear and administer the prescribed number of
drops. If you are using the single-use containers, empty the contents of the
prescribed number of containers into your ear. For outer ear infections, to help the
drops roll into the ear, adults should hold the earlobe up and back.

 FLUROQUINOLONES
The quinolones were fluorinated to get fluoroquinolones with wider
specturm of activity,fewer side effects,lesser chances of resistance
development,and better tissue penetration when compared to
quinolones.The fluroquinolones (FQs) include norfloxacin, ciprofloxacin,
pefloxacin, ofloxacin, levofloxacin, lomefloxacin and sparfloxacin-many more
 are being added.The newer agents include travofloxavin, gatifloxacin,
moxifloxacin, and clinafloxacin.

Mechanism of Action
Fluroquinolones are bactericidal.They inhibit the bacterial enzyme DNA
gyrase which is requried for DNA replication and transcription.
Fluoroquinolones

DNA gyrase Topoisomerase IV

Intreface with seperation of daughter

Correction of cells
Positive supercoiling

Damaged DNA Stops multiplication

Bactericidal

USES :
Ofloxacin is used in the treatment of bacterial infections such as:

 Acute bacterial exacerbations of COPD

 Community-acquired pneumonia
 Uncomplicated skin and skin structure infections
 Nongonococcal urethritis and cervicitis
 Epididymitis
 Mixed Infections of the urethra and cervix
 Acute pelvic inflammatory disease
 Uncomplicated cystitis
 Complicated urinary tract infections
 Prostatitis
 Outer ear infections (swimmer's ear or ear canal infections) and
 middle ear infections..
 Urinary tract infections: very effective in uti even when caused by multidrug resistant
bacteria-norfloxacin is generally used (400 mg bd for 5-10 days)
 Typhoid: ciprofloxacin is the drug of choice (500 mg bd for 10 days)-it also eradicates
the carrier state.
 Diarrhea: due to shigella, E. coli and campylobacter respond.
 Gonorrhea: single does 250 mg ciprofloxacin is curative. Ciprofloxacin is used for 3
days.
  chancroid as an alternative to cotrimoxazole-ciprofloxacin is used for 3
days.chlamydial urethritis,cervicitis,ciprofloxacin or sparfloxacin can be used as
alternatives to tetracyclines.
 respiratory tract infections-due to H.influenzae,legionella and micoplasma and be
treated with fluoroquinolones.
 bone,joint,soft tissue and intra-abdominal infections-osteomyelitis and joint
infections requrie prolonged treatment.soft tissue infections is due to sensitive
bacteria and can be treated with fluoroquinolones.
 Tuberculosis: ciprofloxacin in one of the drugs a multidrug regiments use for
resistant tuberculosis.it is also useful in atypical my cobacterial infections.
 Bacterial prostatis and crvicitis-FQs are useful.
 .Eye infections- ciprofloxacin and ofloxacin may be used topically in the treatment of
eye infections.
 Anthrax-also response to fluoroquinolones.
SIDE EFFECTS

 Mild irritation/discomfort in the ear,

 dizziness,
 headache,
 earache,
 changes in taste may occur.
 tingling/numbness.
 hearing changes.

3. ANTI-THYROID AGENTS.

Antithyroid Agents

 Antithyroid agents are drugs used to block the production of thyroid

hormone and treat hyperthyroidism.
 This include thioamides and iodide solutions. These groups of drugs are
not chemically related but they both block the formation of thyroid
hormones within the thyroid gland.

Therapeutic Action
The desired and beneficial action of antithyroid agents:

 Thioamides lower thyroid hormones by preventing the formation of

thyroid hormone in the thyroid cells. They also partially inhibit the
conversion of T4 to T3 at cellular level. Thioamides
include propylthiouracil (PTU) and methimazole.
  Iodine solutions in high doses block thyroid function. They cause the cells
to become oversaturated with iodine and stop producing hormones

Indications:

Antithyroid agents are indicated for the following medical conditions:

 Treatment of hyperthyroidism
 Thyroid blocking in a radiation emergency

Pharmacokinetics:

Here are the characteristic interactions of thioamides and the body in terms of
absorption, distribution, metabolism, and excretion:

Route Onset Peak Duration

PO 30-60 min – 2-4 h

T1/2: 6-13 h
Metabolism: –
Excretion: urine

Here are the characteristic interactions of iodine solutions and the body in terms of
absorption, distribution, metabolism, and excretion:

Route Onset Peak Duration

PO 24 h 10-15 d 6 wk

T1/2: unknown
Metabolism: liver
Excretion: urine

Contraindications

The following are contraindications and cautions for the use of antithyroid agents:

 Allergy to any component of the drug. To prevent hypersensitivity

reactions.
 Pregnancy. Development of cretinism. PTU is the drug of choice for
pregnant women.
  Lactation. Risk of antithyroid activity in the infant (neonatal goiter)
 Pulmonary edema or tuberculosis. Contraindicated with strong iodine
products.

Adverse Effects:

Use of antithyroid agents may result to these adverse effects:

 Thioamides: drowsiness, lethargy, bradycardia, nausea, skin rash

 PTU: nausea, vomiting, GI complaints, severe liver toxicity
 Methimazole: bone marrow suppression
 Iodine solution: hypothyroidism; metallic taste and burning sensation in
the mouth, sore teeth and gums, diarrhea; staining of teeth, skin rash, and
development of goiter. I131 is only for patients over 30 years old because of
adverse effects associated with radioactivity.

Interactions:

The following are drug-drug interactions involved in the use of antithyroid agents:

 Thioamides: increased bleeding with oral anticoagulants and PTU

 Iodine solutions: changes in the metabolism and level of anticoagulants,
theophylline, digoxin, metoprolol, and propranolol

Nursing Considerations

Here are important nursing considerations when administering antithyroid agents:

Nursing Assessment

These are the important things the nurse should include in conducting assessment,
history taking, and examination:

 Assess for contraindications or cautions (e.g. history of allergy, renal stone,

pregnancy, etc.) to avoid adverse effects.
 Assess skin lesions; orientation and affect; liver evaluation; serum calcium,
magnesium, and alkaline phosphate levels; and radiographs of bones as
appropriate, to determine baseline status before beginning therapy and
for any potential adverse effects.
 Give iodine solution through a straw to decrease staining of teeth; tables
can be crushed.
 Provide comfort measures to help patient cope with drug effects.
  Provide patient education about drug effects and warning signs to report
to enhance patient knowledge and to promote compliance.
III. Short Answer Questions: (4 x 2 = 8)
1. MENTION TWO USES OF ADRENALINE
Epinephrine, also known as adrenaline,
 It is a hormone and neurotransmitter and produced by the adrenal glands
that can also be used as a drug due to its various important functions
 Dosage delivery routes for epinephrine include intravenous, inhalation,
nebulization, intramuscular injection, and subcutaneous injection.
 This medication is used in emergencies to treat very serious allergic reactions
to insect stings/bites, foods, drugs, or other substances.
 Epinephrine acts quickly to improve breathing, stimulate the heart, raise a
dropping blood pressure, reverse hives, and reduce swelling of the face, lips, and
throat.

2. DEFINE DEPENDENCE WITH EXAMPLE.

Drug dependence, is an adaptive state that develops from
repeated drug administration, and which results in withdrawal upon cessation
of drug use. ... Compulsive and repetitive use may result in tolerance to the effect of
the drug and withdrawal symptoms when use is reduced or stopped.
Drugs of dependence are prescription medicines with a recognised therapeutic use
but also a higher potential for misuse, abuse and dependence. ... These medicines
have important therapeutic uses such as: treatment of severe pain. management of
attention deficit hyperactivity disorder (ADHD)
Eg: tramadol
3. MENTION THE USES OF ACIDIFIERS WITH EXAMPLE
Antacids are indicated for the following:

 Symptomatic relief of GI hyperacidity, treatment of hyperphosphatemia,

prevention of formation of phosphate urinary stones.
 Treatment of calcium deficiency, prevention of hypocalcemia.
 Prophylaxis of stress ulcers, relief of constipation.

4. NAME TWO ANTI-EMETIC DRUGS.

Ondansetron
promethazine
Phenergan
 metoclopramide
SECTION - B
(PATHOLOGY AND GENETICS)
PATHOLOGY
I. ELABORATE ON: (1 X 15 = 15)
1. WHAT IS INFLAMMATION? WRITE A DETAILED ACCOUNT ON THE CELLULAR EVENTS OF
INFLAMMATION AND ITS MEDIATORS

Definition:
Inflammation is a local response (reaction) of living vasculaized tissues to
endogenous and exogenous stimuli. The term is derived from the Latin "inflammare"
meaning to burn. Inflammation is fundamentally destined to localize and eliminate
the causative agent and to limit tissue injury.

Thus, inflammation is a physiologic (protective) response to injury, an observation

made by Sir John Hunter in 1794 concluded: “inflammation is itself not to be
considered as a disease but as a salutary operation consequent either to some
violence or to some diseases”.
Causes:
Causes of inflammation are apparently causes of diseases such as
1, physical agents - mechanical injuries, alteration in temperatures and pressure,
radiation injuries.
2. chemical agents- including the ever increasing lists of drugs and toxins.
3. biologic agents (infectious)- bacteria,viruses,fungi, parasites
4, immunologic disorders- hypersensitivity reactions, autoimmunity,
immunodeficiency states etc
5. genetic/metabolic disorders- examples gout, diabetes mellitus etc…
Acute inflammation is categorized into an early vascular and a late cellular
responses.

1) The Vascular response has the following steps:

a) Immediate (momentary) vasoconstriction in seconds due to neurogenic or

chemical stimuli.
b) Vasodilatation of arterioles and venules resulting in increased blood flow.
c) After the phase of increased blood flow there is a slowing of blood flow & stasis
due to increased vascular permeability that is most remarkably seen in the post-
capillary venules. The increased vascular permeability oozes protein-rich fluid into
extravascular tissues. Due to this, the already dilated blood vessels are now packed
with red blood cells resulting in stasis. The protein-rich fluid which is now found in
the extravascular space is called exudate. The presence of the exudates clinically
appears as swelling. Chemical mediators mediate the vascular events of acute
inflammation.

2) Cellular response

The cellular response has the following stages:

A. Migration, rolling, pavementing, & adhesion of leukocytes

B. Transmigration of leukocytes
C. Chemotaxis
D. Phagocytosis

-Normally blood cells particularly erythrocytes in venules are confined to the central
(axial) zone and plasma assumes the peripheral zone. As a result of increased
vascular permeability (See vascular events above), more and more neutrophils
accumulate along the endothelial surfaces (peripheral zone).

A) Migration, rolling, pavementing, and adhesion of leukocytes

- Margination is a peripheral positioning of white cells along the endothelial cells.

- Subsequently, rows of leukocytes tumble slowly along the endothelium in a process
known as rolling
- In time, the endothelium can be virtually lined by white cells. This appearance is
called pavementing
- Thereafter, the binding of leukocytes with endothelial cells is facilitated by cell
adhesion molecules such as selectins, immunoglobulins, integrins, etc which result in
adhesion of leukocytes with the endothelium.

B). Transmigration of leukocytes

- Leukocytes escape from venules and small veins but only occasionally from
capillaries. The movement of leukocytes by extending pseudopodia through the
vascular wall occurs by a process called diapedesis.
- The most important mechanism of leukocyte emigration is via widening of
interendothelial junctions after endothelial cells contractions. The basement
membrane is disrupted and resealed thereafter immediately.

C). Chemotaxis:

- A unidirectional attraction of leukocytes from vascular channels towards the site of

inflammation within the tissue space guided by chemical gradients (including
bacteria and cellular debris) is called chemotaxis.
- The most important chemotactic factors for neutrophils are components of the
complement system (C5a), bacterial and mitochondrial products of arachidonic acid
metabolism such as leukotriene B4 and cytokines (IL-8). All granulocytes, monocytes
and to lesser extent lymphocytes respond to chemotactic stimuli.
- How do leukocytes "see" or "smell" the chemotactic agent? This is because
receptors on cell membrane of the leukocytes react with the chemoattractants
resulting in the activation of phospholipase C that ultimately leads to release of
cytocolic calcium ions and these ions trigger cell movement towards the stimulus.

D) Phagocytosis

- Phagocytosis is the process of engulfment and internalization by specialized cells

of particulate material, which includes invading microorganisms, damaged cells,
and tissue debris.
- These phagocytic cells include polymorphonuclear leukocytes (particularly
neutrophiles), monocytes and tissue macrophages. Phagocytosis involves three
distinct but interrelated steps.

1). Recognition and attachment of the particle to be ingested by the leukocytes:

Phagocytosis is enhanced if the material to be phagocytosed is coated with certain

plasma proteins called opsonins. These opsonins promote the adhesion between the
particulate material and the phagocyte’s cell membrane. The three major opsonins
are: the Fc fragment of the immunoglobulin, components of the complement system
C3b and C3bi, and the carbohydrate-binding proteins – lectins.

Thus, IgG binds to receptors for the Fc piece of the immunoglobulin (FcR) whereas
3cb and 3bi are ligands for complement receptors CR1 and CR2 respectively.

2). Engulfment:

During engulfment, extension of the cytoplasm (pseudopods) flow around the object
to be engulfed, eventually resulting in complete enclosure of the particle within the
phagosome created by the cytoplasmic membrane of the phagocytic cell.
As a result of fusion between the phagosome and lysosome, a phagolysosome is
formed and the engulfed particle is exposed to the degradative lysosomal enzymes.

3) Killing or degradation

The ultimate step in phagocytosis of bacteria is killing and degradation. There are
two
forms of bacterial killing

a). Oxygen-independent mechanism:

- This is mediate by some of the constituents of the primary and secondary granules
of polymorphonuclear leukocytes. These include: Bactericidal permeability
increasing protein (BPI)

Lysozymes
Lactoferrin
Major basic protein
Defenses

- It is probable that bacterial killing by lysosomal enzymes is inefficient and relatively

unimportant compared with the oxygen dependent mechanisms. The lysosomal
enzymes are, however, essential for the degradation of dead organisms within
phagosomes.

b) Oxygen-dependent mechanism:

There are two types of oxygen- dependent killing mechanisms

i) Non-myeloperoxidase dependent

- The oxygen - dependent killing of microorganisms is due to formation of reactive

oxygen species such as hydrogen peroxide (H2O2), super oxide (O2) and hydroxyl ion
(HO-) and possibly single oxygen (1O2). These species have single unpaired electrons
in their outer orbits that react with molecules in cell membrane or nucleus to cause
damages. The destructive effects of H2O2 in the body are gauged by the action of
the glutathione peroxidase and catalase.

ii) Myloperoxidase–dependent
- The bactericidal activity of H2O2 involves the lysosomal enzyme myeloperoxidase,
which in the presence of halide ions converts H2O2 to hypochlorous acid (HOCI). This
H2O2 – halide - myecloperoxidease system is the most efficient bactericidal system
in neutrophils. A similar mechanism is also effective against fungi, viruses, protozoa
and helminths. Like the vascular events, the cellular events (i.e. the adhesion, the
transmigration, the chemotaxis, & the phagocytosis) are initiated or activated by
chemical mediators.
Next, we will focus on the sources of these mediators.

Chemical mediators of inflammation

Chemical mediators account for the events of inflammation. Inflammation has the
following
sequence:

Cell injury > Chemical mediators > Acute inflammation (i.e. the vascular & cellular
events).

Sources of mediators:

The chemical meditors of inflammation can be derived from plasma or cells.

a) Plasma-derived mediators:

i) Complement activation

- increases vascular permeability (C3a,C5a)

- activates chemotaxis (C5a)
 - opsoninization (C3b,C3bi)

ii) Factor XII (Hegman factor) activation

Its activation results in recruitment of four systems: the kinin, the clotting, the
fibrinolytic and the compliment systems.

b) Cell-derived chemical mediatos:

Cell-derived chemical mediators include:

Most mediators perform their biologic activities by initially binding to specific

receptors on target cells. Once activated and released from the cells, most of these
mediators are short lived. Most mediators have the potential to cause harmful
effects.
II. WRITE NOTES ON: (2 X 5 = 10)
1. BRONCHITIS.
Chronic bronchitis is a common condition defined clinically as persistent cough with
expectoration on most days for at least three months of the year for two or more
consecutive years. The cough is caused by oversecretion of mucus.

 In spite of its name, chronic inflammation of the bronchi is not a prominent

feature. The condition is more common in middle-aged males than females;
approximately 20% of adult men and 5% of adult women have chronic
bronchitis, but only a minority of them develop serious disabling COPD or cor
pulmonale.
 Quite frequently, chronic bronchitis is associated with emphysema.

ETIOPATHOGENESIS.:

The two most important etiologic factors responsible for majority of cases of chronic
bronchitis are:

 cigarette smoking and atmospheric pollution.

 Other contributory factors are occupation, infection, familial and genetic factors.
1. Smoking. :
The most commonly identified factor implicated in causation of chronic
bronchitis and in emphysema is heavy smoking. Heavy cigarette smokers have
4 to 10 times higher proneness to develop chronic bronchitis. Prolonged
cigarette smoking appears to act on the lungs in a number of ways:

i) It impairs ciliary movement.

ii) It inhibits the function of alveolar macrophages.

iii) It leads to hypertrophy and hyperplasia of mucussecreting glands

iv) It causes considerable obstruction of small airways.

 v) It stimulates the vagus and causes bronchoconstriction.

2. Atmospheric pollution.

The incidence of chronic bronchitis is higher in industrialised urban areas where air is
polluted. Some of the atmospheric pollutants which increase the risk of developing
chronic bronchitis are sulfur dioxide, nitrogen dioxide, particulate dust and toxic
fumes.

3. Occupation.

Workers engaged in certain occupations such as in cotton mills (byssinosis), plastic

factories etc. are exposed to various organic or inorganic dusts which contribute to
disabling chronic bronchitis in such individuals.
4. Infection.
Bacterial, viral and mycoplasmal infections do not initiate chronic bronchitis but
usually occur secondary to bronchitis. Cigarette smoke, however, predisposes to
infection responsible for acute exacerbation in chronic bronchitis.
5. Familial and genetic factors.
There appears to be a poorly-defined familial tendency and genetic predisposition to
develop disabling chronic bronchitis. However, it is more likely that nonsmoker
family members who remain in the air-pollution of home are significantly exposed to
smoke (passive smoking) and hence have increased blood levels of carbon monoxide.
MORPHOLOGIC FEATURES.
Grossly, the bronchial wall is thickened, hyperaemic and oedematous. Lumina of the
bronchi and bronchioles may contain mucus plugs and purulent exudate.
Microscopically, just as there is clinical definition, there is histologic definition of
chronic bronchitis by increased Reid index. Reid index is the ratio between thickness
of the submucosal mucus glands (i.e. hypertrophy and hyperplasia) in the cartilage-
containing large airways to that of the total bronchial wall (Fig. 17.16). The increase
in thickness can be quantitatively assessed by micrometer lens. The bronchial
epithelium may show squamous metaplasia and dysplasia. There is little chronic
inflammatory cell infiltrate. The non-cartilage containing small airways show goblet
cell hyperplasia and intraluminal and peribronchial fibrosis.
CLINICAL FEATURES.
There is considerable overlap of clinical features of chronic bronchitis and
pulmonary emphysema (discussed below) as quite often the two coexist.. Some
important features of ‘predominant bronchitis’ are as under:
 Persistent cough with copious expectoration of long duration; initially beginning in a
heavy smoker with ‘morning catarrh’ or ‘throat clearing’ which worsens in winter.
 Recurrent respiratory infections are common.
  Dyspnoea is generally not prominent at rest but is more on exertion.
 Patients are called ‘blue bloaters’ due to cyanosis and oedema.
 Features of right heart failure (cor pulmonale) are common
 Chest X-ray shows enlarged heart with prominent vessels.

2. CIRRHOSIS LIVER.
Cirrhosis of the liver is one of the ten leading causes of death in the Western world. It
represents the irreversible end-stage of several diffuse diseases causing hepatocellular
injury and is characterised by the following 4 features:
 It involves the entire liver.
 The normal lobular architecture of hepatic parenchyma is disorganised.
 There is formation of nodules separated from one another by irregular bands of
fibrosis.
 It occurs following hepatocellular necrosis of varying etiology so that there are
alternate areas of necrosis and regenerative nodules.
However, regenerative nodules are not essential for diagnosis of cirrhosis since biliary
cirrhosis and cirrhosis in haemochromatosis have little regeneration.
PATHOGENESIS
Irrespective of the etiology, cirrhosis in general is initiated by hepatocellular
necrosis. Continued destruction of hepatocytes causes collapse of normal lobular
hepatic parenchyma followed by fibrosis around necrotic liver cells and proliferated
ductules and there is formation of compensatory regenerative nodules.
FIBROGENESIS.
Fibrosis in the liver lobules may be portalcentral, portal-portal, or both. The
mechanism of fibrosis is by increased synthesis of all types of collagen and increase
in the number of collagen-producing cells. In cirrhosis, there is proliferation of fat-
storing Ito cells underlying the sinusoidal epithelium which become transformed into
myofibroblasts and fibrocytes. Besides collagen, two glycoproteins, fibronectin and
laminin, are deposited in excessive amounts in area of liver cell damage. The nature
of factors acting as stimulants for fibrosis is not clearly known, but possible
candidate mediators are lymphokines and monokines
. REGENERATIVE NODULE.
The cause of compensatory proliferation of hepatocytes to form regenerative
nodules is obscure. Possibly, growth factors, chalones and hormonal imbalance, play
a role in regeneration.
CLASSIFICATION
Cirrhosis can be classified on the basis of morphology and etiology
A. MORPHOLOGIC CLASSIFICATION.
 There are 3 morphologic types of cirrhosis—
 micronodular,
 macronodular and
 mixed.
Each of these forms may have an active and inactive form. An active form is
characterised by continuing hepatocellular necrosis and inflammatory reaction, a
process that closely resembles chronic hepatitis. An inactive form, on the other
hand, has no evidence of continuing hepatocellular necrosis and has sharply-defined
nodules of surviving hepatic parenchyma without any significant inflammation.
1. Micronodular cirrhosis.
In micronodular cirrhosis, the nodules are usually regular and small, less than 3
mm in diameter. There is diffuse involvement of all the hepatic lobules forming
nodules by thick fibrous septa which may be portal-portal, portal-central, or
both. The micronodular cirrhosis includes etiologic type of alcoholic cirrhosis (or
nutritional cirrhosis or Laennec’s cirrhosis) and represents impaired capacity for
regrowth as seen in alcoholism, malnutrition, severe anaemia and old age.

2. Macronodular cirrhosis. In this type, the nodules are of variable size and are
generally larger than 3 mm in diameter. The pattern of involvement is more irregular
than in micronodular cirrhosis, sparing some portal tracts and central veins, and
more marked evidence of regeneration. Macronodular cirrhosis corresponds to post-
necrotic (or posthepatitis) cirrhosis of the etiologic classification
3. Mixed cirrhosis. In mixed type, some parts of the liver show micronodular
appearance while other parts show macronodular patternAll the portal tracts and
central veins are not involved by fibrosis but instead some of them are spared.
Mixed pattern is a kind of incomplete expression of micronodular cirrhosis.
B. ETIOLOGIC CLASSIFICATION. Based on the etiologic agent for cirrhosis, various categories
of cirrhosis are described as given in
 Alcoholic cirrhosis (nodules less than 3 mm) (the most common, 60-70%) II.
Macronodular
 Post-necrotic cirrhosis (10%) (nodules more than 3 mm)
 Biliary cirrhosis (5-10%) III. Mixed
 Pigment cirrhosis in haemochromatosis (5%)
 Cirrhosis in Wilson’s disease
 Cirrhosis in α-1-antitrypsin deficiency
 Cardiac cirrhosis
 Indian childhood cirrhosis (ICC)
 Cirrhosis in autoimmune hepatitis
 Cirrhosis in non-alcoholic steatohepatitis
 Miscellaneous forms of cirrhosis (metabolic, infectious, GI, infiltrative)
diseases
 Cryptogenic cirrhosis
LABORATORY DIAGNOSIS.
The clinical manifestations and complications of cirrhosis in general are described on
The laboratory findings in the course of alcoholic liver disease may be quite variable
and liver biopsy is necessary in doubtful cases. Progressive form of the disease,
however, generally presents the following biochemical and haematological
alterations:
o Elevated transaminases: increase in SGOT (AST) is more than that of SGPT
(ALT).
o Rise in serum γ-glutamyl transpeptidase (γ-GT).
o Elevation in serum alkaline phosphatase.
o Hyperbilirubinemia.
o Hypoproteinaemia with reversal of albumin-globulin ratio.
o Prolonged prothrombin time and partial thromboplastin time.
o Anaemia.

CLINICAL MANIFESTATIONS AND

The range of clinical features in cirrhosis varies widely, from an asymptomatic state to
progressive liver failure and death.. These include
 weakness,
 fatiguability,
 weight loss,
 anorexia,
 muscle wasting, and
 low-grade fever due to hepatocellular necrosis or some latent infection.
COMPLICATIONS OF CIRRHOSIS
 Portal hypertension and its major effects such as ascites, splenomegaly and
development of collaterals (e.g. oesophageal varices, spider naevi etc) as
discussed below.
 Progressive hepatic failure and its manifestations as described already (page
602).
 Development of hepatocellular carcinoma, more often in post-necrotic
cirrhosis (HBV and HCV more often) than following alcoholic cirrhosis (page
634).
 Chronic relapsing pancreatitis, especially in alcoholic liver disease (page 646).
 Steatorrhoea due to reduced hepatic bile secretion.
 Gallstones usually of pigment type, are seen twice more frequently in
patients with cirrhosis than in general population.
 Infections are more frequent in patients with cirrhosis due to impaired
phagocytic activity of reticuloendothelial system.
 Haematologic derangements such as bleeding disorders and anaemia due to
impaired hepatic synthesis of coagulation factors and hypoalbuminaemia are
present.
  Cardiovascular complications such as atherosclerosis of coronaries and aorta
and myocardial infarction are more frequent in cirrhotic patients
o

GENETICS
I. Write notes on: (2 x 5 = 10)
1. Pre-natal screening for developmental delay.
Prenatal diagnosis
procedures which are used to detect genetic disorders during early stages of pregnancy.
Indications ;
1. To identify fetal disease when abortion is being considered.
2. Advanced maternal age
3. Previous offspring with chromosomal anomalies
4. Positive maternal screening test
5. Mother having disease or being exposed to drug, medication, or infections known to
be associated with congenital malformation.
6. Molecular DNA diagnosis (cystic fibrosis, fragile X).
7. Direct fetal treatment
Methods of prenatal diagnosis
o Imaging- Ultrasound MRI
o Fluid analysis- Amniocentesis Cordocentesis
o Fetal tissue analysis- Chorionic villus sampling
o Maternal serum tests- α-feto protein Triple test Quad test
o Maternal cervix- Fetal fibronectin Fluid Bacterial culture

Non invasive methods

 Imaging- USG, MRI

 Maternal serum analysis Maternal cervical fluid analysis Invasive methods
 Fluid analysis- Amniocentesis, Cordocentesis,
 Fetal tissue analysis- Chorionic villus sampling
Imaging Ultrasound USG
• In the 1st trimester most reliable method to know gestational age.
• Fetal growth abnormalities- by biometric measurement of biparietal diameter, femoral
length, or head or abdominal circumference.
• Fetal anomalies eg. Hydrocephalus, NTDs, duodenal atresia, diaphragmatic hernia, renal
agenesis, limb anomalies, omphalocele, gastroschisis, hydrops.
Fluid Analysis Chorionic Villous Sampling
Transvcervical or transabdominal chorionic villous biopsy, which provides fetal cells. The
placenta contains tissue that is genetically identical to fetus.
Timing:In first trimester, shouldn’t be performed before 10wk, commonly performed
between 11 and 13 wks.
Indications: for karyotype, enzyme assay, molecular DNA genetic analysis
Method of CVS: two ways to perform a CVS, transabdominally (TA) and transcervically (TC),
depends on the location of the villi in the uterus. Transabdominal approach- When the villi
are anterior, under all aseptic precautions ultrasound guided needle is passed through
abdominal wall and the uterus to reach the villi. A syringe attached to the needle is used to
suction out a small amount of villi
Transcervical (TC) approach-
When the villi are in the lower part of the uterus and posterior, TC approach is used.
A thin flexible plastic catheter is carefully guided through the cervix under ultrasound
guidance to the villi. A syringe attached to the catheter is used to suction out a small
amount of villi as the catheter is withdrawn. O The CVS procedure collects larger samples
and provides faster results than amniocentesis. O Different from amniocentesis in that it
does not allow for testing for neural tube defects. 11/03/2016 22
Complications:
1.miscarriage/ fetal loss (1% - 2%).
2. Oromandibular limb hypoplasia.
3.Isolated limb reduction defect-
• Increased risk is associated with decreased gestational age at the time of CVS, highest
susceptibility when CVS if performed before 9 wks.
• Mechanism: thromboembolization or fetal hypoperfusion through hypovolemia or
vasoconstriction (based on assumption that caused by some form of vascular disruption).
The limbs and mandible are susceptible to such disruption before 10 weeks’ gestation.
• Overall risk for transverse limb deficiency from CVS is 0.03%–0.10% 4.Rh-
isoimmunization.
Amnicentesis :
USG guided percutaneous withdrawal of amniotic fluid for diagnostic purpose. O Timing-
between 14- 16wks.
Indications:
• Karyotype (advanced maternal age)
• Fetal maturity (L:S ratio, phosphatidylcholine or phosphatidylglycerol)
• Biochemical enzyme/amino acid/hormone analysis.
• Molecular genetic DNA diagnosis.
• α- fetoprotein(for NTDs) and 17-ketosteroid (for adrenogenital syndrome) determination
Method of amniocentesis:
Performed transabdominally (TA). During the procedure, a needle is passed through the
abdomen and into the amniotic sac under continuous ultrasound guidance. The needle
stilette is removed once the needle is in the correct position. A small sample of amniotic
fluid (10–20ml) is then removed using a syringe attached to the needle.
Complications of amniocentesis:
1.Miscarriage (risk about 1%). Before 14 weeks of gestation (early amniocentesis) has a
higher fetal loss rate.
2.Preterm labor (stimulation of uterine contraction) or PROM.
3.Injury to fetus
4.Placental puncture and bleeding with secondary damage to fetus.
5.Infection
6. Maternal sensitization to fetal blood (Rh- isoimmunization) :- Anti D immunoglobulin to
be given to Rh –ve mother.
28. Cordocentesis O Cordocentesis, or PUBS (Percutaneous Umbilical Blood Sampling), is the
sampling of blood from the umbilical cord.
Objective:
(a) prenatal diagnosis and
(b) fetal therapy.
Timing: can be performed as early as 16 wks of gestation but commonly performed between
18-22 wks of gestation for prenatal diagnosis
Indication of cordocentesis:
(a) Prenatal diagnosis:
Detection of anemia, hemoglobinopathies, thrombocytopenia, acidosis, hypoxia,
polycythemia
• Immunoglobuline M antibody response to infection
• Rapid karyotype and molecular DNA genetic diagnosis.
(b) Fetal therapy
: • Transfusion or administration of drugs.
30. O Method of cordocentesis: Under ultrasound guidance needle is inserted in the
umbilical vein within the umbilical cord at its placental end or fetal end. Upon entering the
umbilical cord, the stylet is removed and fetal blood is withdrawn into a syringe attached to
the hub of the needle. The needle is withdrawn, then the puncture site is monitored for
bleeding, and the fetal heart rate is assessed. After this procedure, the fetal heart rate and
uterine contraction are monitored for 1-2 hours.
Complications of cordocentesis:

 Pregnancy loss, overall fetal loss risk of 1- 2%

 Transient fetal bradycardia, manifestations of a vasovagal response caused by local
vasospasm, more with umbilical artery puncture.
 Bleeding from the puncture site, cord hematoma.
 Fetomaternalhemorrhage
 Premature labor
 Infection
 Rh iso- immunization
 Maternal serum test (A) α- feto protein: Incresed Decreased
 Twins Trisomies
 NTDs Aneuploidy
 Intestinal atresia
 Fetal demise (B) Triple test: can detect 70% of Down syndrome
 Unconjugated estriol ↓ed
 α- feto protein ↓ed
 β-HCG ↑ed (C) Quad test: can detect 80% of Down syndrome.
 Unconjugated estriol ↓
Down syndrome screening:
(A) 1st trimester: • Fetal nuchal translucency (NT) thickness alone ≤70%
(B) NT with β-HCG & PAPP-A 87% (PAPP-A = Pregnancy Associated Plasma Protein- A)
(B) 2nd trimester:
(C) Triple test 70%
(D) Quad test 80% (C) Integrated screen: 1st trimester screen + 2nd trimester screen
detect 95%

2. Gene therapy.

Gene therapy involves replacement of a defective/ abnormal gene into the cells
of a patient who is deficient of the normal gene product. The technical basis of
gene therapy is gene delivery.i e , introducting the desired gene into the
 appropriate cells of the patient. The current wave of gene therapy research has
gathered momentum because highly effective gene delivery systems have
been developed. In particular those based on the use of retroviral vectors.
GENE DELIVERY
 Gene therapy requires introduction of foreign DNA sequences with stable
integration,gene expression and an appropriate regulation in the target tissue.
The newly introduced gene can replace a missing gene.
 There are two strategies used to deliver genes-
(1) ex vivo and
(2) in vivo transfer.
 In ex vivo transfer, cells are removed from the patient, an appropriate
gene (DNA sequences) is introduced in these cells and then these
genetically engineered cells are transplanted back into the patient’s
body.
 In in vivo approach, the desired gene is directly introduced into the
target tissue.
GENE TRANSFER TECHNIQUES
 Transfer of gene can be accomplished by following the methods:
(1) physical or
(2) biological (viral victors).

PHYSICAL TRANSFECTION METHODS

These include
1. Liposome- mediated DNA transfer
2. Receptor-mediated endocytosis

LIPOSOME-MEDIATED DNA TRANSFER:

It involves complexing plasmid DNA (with foreign DNA) with liposomes and introducing it
into the target cell
ADVANTAGES:
o Using this technique, one can introduce larger amount of DNA into the target cells
than what is possible with viral vector systems.
o This can be as large as an artificially constructed minichromosome, which includes
elements for regulation of gene expression apart from the particular structural
gene.
o These elements regulate gene expression in physiologically controlled manner.
Disadvantage: The gene expression is transient; therefore, the treatmenthas to be
repeated.
VIRAL VECTORS ( BIOLOGICAL TRANSFECTION METHOD ):

 In biological transfection methods, viral vectors form an efficient mode of

gene delivery into the target cells).
 Various viruses used include retroviruses, adenoviruses, herpes virus,
adeno- associated virus, parvovirus, etc.
 The viruses are rendered replication deficient by removing
encapsidation( ,psi) gene sequences.
Retroviruses:
 The retroviruses are rendered incapable of replication by removing
encapsidationsequences,which are essential for viral replication.
 Retroviruses integrate into the host DNA and make copy of their genome
using reverse transcriptase enzyme.
 T he provirus thus formed serves as a template for the production of mRNAs
for various viral gene products as well as the new genomic RNA of the virus.
The retroviruses used in gene therapy need a couple of elements
(1) packaging cell line and
(2) helper virus.
1. Packaging cell line :
It is the cell line that has been infected with the retrovirus that is
genetically engineered to lack regionofproviral DNA called packaging
sequence.
2. Helper virus/ vector:
It consists of a retroviral provirus with its more than 90% of viral genomic
material removed, leaving only minimal sequences essential to produce
copies of the virual RNA along with the sequences necessary for packaging of
the virual genomic RNA. This is a vector backbone in which foreign gene(DNA
sequence) can be inserted. It this helper virus is introduced into the
packaging cell line that contains provirus in which packaging sequences are
missing, then RNA produced by the victor provirus can be packaged into
viruses. These virions can be used to infect or more precisely called
transducer the target cells.

Disadvantages: Demerits of retroviruses as vectors in gene therapy are as follow.

 Only smaller DNA sequences (less than 7 kb usually) can be introduced,

e.g. dystrophin gene to be used in gene therapy in case of Duchennr
muscular dystrophy.
 Retrovial vector can transduce only dividing cells and hence central
nervous system disorders are not amenable to it.
 The retroviruses can only be used in vitro.
 Another demerit of retroviruses is that they are unstable.
 they cannot be purified for use in gene therapy without reducing their
capability to transduce target cells.
  Controlling the levels of the introduced gene is yet another difficult task.
DISEASES AMENABLE TO GENE THERAPY
Cancer
Gene therapy for cancer involves the introduction of tumor suppressor gene or
inactivating an oncogene or use of immune cells and so on.Potential strategies for gene
therapy in the cancer treatment are as under
1. Tumor suppressor gene: Inserting a wild- type tumer suppressor gene, e.g., p53 or
the gene involved in Wilmstumer.
2. Blocking oncogene: Blocking expression of an oncogene, e.g., by introducing the
gene that encodes antisense K-RAS message.
3. Suicide gene: Insertion of a sensitive or suicide gene into the tumor, e.g.,
introducting gene that encodes thymidine kinase gene of herpes simplex virus
(HSVTK).
4. Promoting immunogenicity of tumor.
5. Protecting stem cells from the toxic effects of chemotherapy by introducing the gene
that confers multiple drug resistance-1 (MDR-1).
Other diseases amenable to gene therapy are as under
. Peripheral Vascular Disease
. Coronary Artery Disease
. Acquired Immunodeficiency Syndrome (AIDS)
severe combined immunodefi- ciency (SCID) was given transfusion of her own
peripheral blood T-Lymphocytes that had been transduced ex vivo using
retroviral-mediated gene transfer with the normal human ADA gene.
Future Prospects: Injections of gene transfer vectors directly , to develop
safe and cost effective gene delivery that responds to physiological and
metabolic changes in blood.

II. Short answers on: (1 x 2 = 2)

1. Name two autosomal recessive disorders.
 Cystic fibrosis (CF)
 Sickle cell anemia
 Tay Sachs disease.