Transgenic animals

Transgenic animals open a new horizon in the field of drug discovery. They serve as a unique model for the screening of different drugs.Different types of genes like genes for obesity, diabetes, cancer can be added to produce an animal model. Such type of transgenic animals are known as Knock in animals.

Antiinflammatory property of Macrolides

In addition to their antiinfective properties, some macrolides possess immunomodulatory effects. These macrolides have been used successfully to treat diffuse panbronchiolitis, a progressive inflamatory disease and may be very useful in the treatment of asthma, ,chronic bronchitis, chronic sinusitis, nasal polyps, ottitis media & bronchiectasis.Macrolide antibiotics down-regulate damaging prolonged inflammation as well as increase mucus clearance, decrease bacterial virulence and prevent biofilm formation.

SERM

SERM or selective estrogen receptor modulators are partial estrogen agonist in bone & cardiovascular system but an antagonist in breast & endometrium.The commonly used SERM are Tamoxifen & Raloxifen. They are used in postmenopausal osteoporosis & hormonal treatment of breat cancer. They also improve lipid profile by lowering LDL cholesterol

FINASTERIDE

It act by competetively inhibiting the enzyme 5 alpha reductase. This enzyme 5 alpha reductase is coverting testosterone to dihydrotestosterone which is the active form of testosterone in many tissues like prostate gland & hair follicles. It is relatively selective for 5 alpha reductase type II isoenzyme which predominate in male urogenital tract.It is also used in the treatment of benign prostatic hypertrophy or BPH.finasteride is effective in male pattern baldness.It promote hair growth & prevent further hair loss. Response is slow & benefit is reversed within one year of treatment cessation.Finasteride is effective orally & metabolized in liver.It is well tolerated by most patients. The adverse drug reactions are decreased libido, skin rashes etc.The dose is 1 mg/day for male pattern baldness.

MINOXIDIL

Minoxidil is a vasodilator. It is basically a prodrug. It is converted to an active metabolite in the body which is an opener of potassium channels. It causes relaxation of arteriolar smooth muscles with little effect on venous vessels. It increase hair growth by following mechanism:
Alteration of androgen effect on genetically programmed hair follicle
Enhanced microcirculation around hair follicles
stimulation of resting hair follicles
It is applied topically in different strength ( 2 %, 4%). It is indicated in male pattern baldness & alopecia areata. It should be applied for at lest two months for adequate response. Side effects are headache, dizziness, itching & burning sensation.

ALOPECIA( III)

Surgical treatment of alopecia or baldness

Now a days hair loss can also be treated by hair transplant. In this hair follicles are taken from back or some other body parts & transplanted where required.The problem with hair transplant is that this is costly.The transplanted hair follicles will typically grow hair for a lifetime because they are genetically resistant to going bald. In recent years hair transplantation techniques have evolved from using large plugs and mini grafts to exclusively using large numbers of small grafts that contain from between 1 to 4 hairs.

ALOPECIA (II)

There are various causes for alopecia. The common causes are:
Androgenic
Hereditory
Nutritional
Environmental
Autoimmune diseases
Chemotherapy
Fungal diseases
Chronic stress

Treatment of Alopecia
Alopecia can now be treated by various medical & surgical methods.

General Measures:Take healthy diet. Diet should be rich in protein, vitamins & minerals.

Lifestyle change: Chronic stressful condition may lead to hair loss. So to counteract stress various relaxation techniques, Yoga, exercises should be done.
Proper hygeine should be maintained so as to avoid dandruff & fungal infections. Head should be covered whenever there is long duration exposure in sunlight.Only medically accepted shampoo & hair oils should be used.

Pharmacological Treatment:

Vasodilators: Minoxidil is a vasodilator which improve the microcirculation of hair follicles & prevent further hair loss. The major problem with minoxidil is its side effects & hair fall on stopping the treatment. For effective treatment it has to be applied for a period of two to three months.

Antiandrogens: They will antagonize the action of Dihydrotestosterone on hair follicles.In 1997 FDA has approved the use of Finasteride for the treatment of male pattern baldness. Finasteride act by inhibiting the enzyme 5 alpha reductase which is responsible for the conversion of testosterone to its active form dihydrotestosterone. Finasteride is approved to be taken orally.

ALOPECIA

Alopecia or hair loss is a very common problem. There are a number of etiological factors. The main causes of alopecia are androgenic, hereditory, alopecia areata & environmental. Now a days alopecia can be treated by various methods. Except for few causes, alopecia can now be treated by various pharmacological & nonpharmacological methods

Neonatal tetanus with complete rigidity

Courtesy of centre of disease control & Prevention

Painful muscle contraction from tetanus

Courtesy of Centre for Disease Control & Prevention

TETANUS

First described by Hippocrates
Etiology discovered in 1884 by Carle and Rattone
Passive immunization used for treatment and prophylaxis during World War I
Tetanus toxoid first widely used during World War II
Clostridium tetani
Anaerobic gram-positive, spore-forming bacteria
Spores found in soil, animal feces; may persist for months to years
Multiple toxins produced with growth of bacteria
Pathogenesis
Anaerobic conditions allow germination of spores and production of toxins
Toxin binds in central nervous system
Interferes with neurotransmitter release to block inhibitor impulses
Leads to unopposed muscle contraction and spasm
Clinical features
Incubation period; 8 days (range, 3-21 days)
Generalized tetanus: descending symptoms of trismus (lockjaw), difficulty swallowing, muscle rigidity, spasms
Spasms continue for 3-4 weeks; complete recovery may take months
Fatality rate ~90% w/o treatment
~30% w/ treatment
Neonatal tetanus
Generalized tetanus in newborn infant
Infant born without protective passive immunity
Tetanus complication
Laryngospasm
Fractures
Hypertension
Nosocomial infections
Pulmonary embolism
Aspiration pneumonia
Death
Tetanus toxoid
Formalin-inactivated tetanus toxin
Schedule Three or four doses + booster Booster every 10 years
Efficacy Approximately 100%
Duration Approximately 10 years
Should be administered with diphtheria toxoid as DTaP, DT, Td, or Tdap

WHOOPING COUGH

Caused by Bordetella pertusis
Aerobic, Gram negative coccobacillus
Specific to Humans
Colonizes the respiratory tract
Transmission
Very Contagious
Transmission occurs via respiratory droplets
Toxins:
Pertussis Toxin
Adenylate Cyclase Toxin
Tracheal cytotoxin
Dermonecrotic toxin
Heat-labile toxin
Also known as Pertussis
Outbreaks first described in the 16th Century
Major cause of childhood fatality prior to vaccination
Clinical features:
Incubation period 4-21 days
3 Stages
1st Stage- Catarrhal Stage 1-2 weeks
2nd Stage- Paroxysmal Stage 1-6 weeks
3rd Stage- Covalescent Stage weeks-months
Diagnosis:
Isolation by culture
PCR
Direct fluorescent antibody
Serological testing
Treatment:
Antibiotic therapy
Erythromycin
Azithromycin and clarithromycin
Prevention:
1st Pertussis vaccine- whole cell
Acellular vaccine now used
Combination vaccines

MACROLIDES ANTIBIOTICS

Chemistry : macrocyclic lactone ring with attached sugars
The drugs in this group are
Erythromycin
Roxithromycin
Clarithromycin
Azithromycin
Mechanism of action: act by inhibiting bacterial protein synthesis
Combine with 50 s ribosome subunit & interfere with translocation
Spectrum : overlaps with that of penicillin G
Narrow spectrum, mostly against gram positive
S. pyogenes, S. pneumonae, N. gonorrhoe, Clostridia, C. diptherae, Listeria, Campylobacter, Legionella, B. catarrhalis, Gardenerella & Mycoplasma
PK: erythromycin base is acid labile, given as enteric coated tablets, widely distributed in body but not cross BBB, partly metabolized & excreted primarily in bile
Erythromycin base
Erythromycin stearate
Erythromycin estolate
ADR:
GIT: due to stimulation of motilin receptors in GIT
Hypersensitivity: hepatitis with cholestatic jaundice resembling viral hepatitis occurs with estolate ester after 1-3 weeks, incidence is higher in pregnant women, it clears on discontinuation of drug
Reversible hearing impairment on high dose
Interaction : erythromycin is enzyme inhibitor, it increase the level of theofylline, carbamazapine, valproate & warfain
QT prolongation
Uses: As alternative to penicillin in
Streptococcal infection
Diptheria
Tetanus
Syphilis & gonorrhoea
Leptospirosis
First choice for:
Atypical pneumonia caused by M. pneumonae
Whooping cough caused by B. pertusis
Chancroid caused by H. ducryi
As a second choice in:
Campylobacter enteritis
Legionnares pneumonia
Chlamydia trachomatis
Penicillin resistant staphylococcal infections

DIFFERENCE BETWEEN NORMAL FLU & SWINE FLU

This is also a season for normal flu in india. So it is very important to differentiate between normal viral infections & swine flu. Normally viral infections are manifested by rhinorrhoea, sneezing, coughing, lacrimation, mild to moderate fever, sore throat etc. But in case of swine flu in addition to abovementioned symptoms, following symptoms may occur like high grade fever, chest pain, joint pains, shortness of breath, confusion & persistent vomitting. If patient goes into respiratory failure, ventilatory support is needed.

SWINE FLU UPDATE IN INDIA

Uptill eight casualities had been occured due to swine flu in india.Maximum number of cases occured in Pune.The government had appealed from public not to create panic of swine flu because the disease is totally curable. Adequate number of antiviral drugs like Tamiflu is available in india. Initially swine flu testing facility was available only in government hospitals but now government also give permission for the testing of swine flu in private hospitals which are well equiped for it.Strict screening is going on at various domestic & international airports for the detection of cases. WHO has announced that swine flu vaccine will be available in a month.

HOW TO TACKLE SWINE FLU ??

Prevention is better than cure. So it is better if we avoid infection by following preventive steps
Wash your hands with soap & water whenever you go at public place like shopping malls, movie theatres, markets etc
Wear swine flu H1N1 mask at high risk areas
High risk individuals like doctors, nurses, dentist & paramedical staff should take adequate preventive steps to avoid infection
After use masks should be destroyed either by burning or burrying
If anyone suspect symptoms of swine flu, he or she should immediately visit a hospital where proper facilities are available for diagnosis & treatment of swine flu
Because children, elderly people & those with chronic diseases are more susceptible, so they should be properly monitored

PAIN PHYSIOLOGY

“Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”
Why feel pain?
Gives conscious awareness of tissue damage
Protection:
Remove body from danger
Promote healing by preventing further damage
Avoid noxious stimuli
Elicits behavioural and emotional responses
Nociceptors

free nerve endings in skin respond to noxious stimuli

Nociceptors are special receptors that respond only to noxious stimuli and generate nerve impulses which the brain interprets as "pain".

Nociopectors

Adequate Stimulation
Temperature
Mechanical damage
Chemicals (released from damaged tissue)
Bradykinin, serotonin, histamine, K+, acids, acetylcholine, and proteolytic enzymes can excite the chemical type of pain.
Prostaglandins and substance P enhance the sensitivity of pain endings but do not directly excite them.

Hyperalgesia:
The skin, joints, or muscles that have already been damaged are unusually sensitive. A light touch to a damaged area may elicit excruciating pain;

Primary hyperalgesia occurs within the area of damaged tissue;
Secondary hyperalgesia occurs within the tissues surrounding a damaged area.

. Localization of Pain
Superficial Somatic Pain arises from skin areas
Deep Somatic Pain arises from muscle, joints, tendons & fascia
Visceral Pain arises from receptors in visceral organs
localized damage (cutting) intestines causes no pain
diffuse visceral stimulation can be severe
distension of a bile duct from a gallstone
distension of the ureter from a kidney stone

Fast and Slow Pain
Most pain sensation is a combination of the two types of message.
If you prick your finger you first feel a sharp pain which is conducted by the A fibres,
and this is followed by a dull pain conveyed along C fibres
Fast pain (acute)
occurs rapidly after stimuli (.1 second)
sharp pain like needle puncture or cut
not felt in deeper tissues
larger A nerve fibers
Slow pain (chronic)
begins more slowly & increases in intensity
in both superficial and deeper tissues
smaller C nerve fibers
Impulses transmitted to spinal cord by
Myelinated Aδ nerves: fast pain (80 m/s)
Unmyelinated C nerves: slow pain (0.4 m/s)

Notable features of visceral pain:
Often accompanied by strong autonomic and/or somatic reflexes
Poorly localized;
may be “referred”
Mostly caused by distension of hollow organs or ischemia (localized mechanical trauma may be painless)

Referred Pain
Pain originating from organs perceived as coming from skin

Site of pain may be distant from organ
This type of referred pain occurs because both visceral and somatic afferents often converge on the same interneurons in the pain pathways.

Excitation of the somatic afferent fibers is the more usual source of afferent discharge,

so we “refer” the location of visceral receptor activation to the somatic source even though in the case of visceral pain.

The perception is incorrect.

Pain Gate” Theory

Melzack & Wall (1965)

A gate, where pain impulses can be “gated”

The synaptic junctions between the peripheral nociceptor fiber and the dorsal horn cells in the spinal cord are the sites of considerable plasticity.

A “gate” can stop pain signals arriving at the spinal cord from being passed to the brain

Reduced pain sensation
Natural pain relief (analgesia)
Applications of pain gate
Stimulation of touch fibres for pain relief:
TENS (transcutaneous electrical nerve stimulation)
Acupuncture
Massage

Release of natural opioids
Hypnosis
Natural childbirth techniques
Pain Relief
Aspirin and ibuprofen block formation of prostaglandins that stimulate nociceptors
Novocain blocks conduction of nerve impulses along pain fibers
Morphine lessen the perception of pain in the brain.

SWINE FLU SCREENING AT AIRPORT

Courtesy of CDC

SWINE FLU CARRIER

Courtesy of CDC

ELECTRON MICROSCOPIC IMAGE OF SWINE FLU VIRUS

Courtesy of CDC

ENTERIC FEVER

Salmonella typhi, a Gram-negative bacteria.
Similar but often less severe disease is caused by Salmonella serotype paratyphi A.
Many genes are shared with E. coli and at least 90% with S. typhimurium,
Polysaccharide capsule Vi: present in about 90% of all freshly isolated S. typhi and has a protective effect against the bactericidal action of the serum of infected patients.
The ratio of disease caused by S. typhi to that caused by S. paratyphi is about 10 to 1
Pathogenesis:
Entry in GIT  localisation in Gut associated lymphoid tissue  Lymphatic channel  thoracic duct  circulation  primary silent bacteremia  localisation in macrophages of RES in spleen, liver, bone marrow (incubation period 8-14 days)  secondary bacteremia
Acute non complicated disease:

Characterized by
Prolonged fever,
Disturbances of bowel function Headache, malaise and anorexia.
Bronchitic cough
Exanthem (rose spots), on the chest, abdomen and back.
Complicated disease:
10% of typhoid patients
GIT: occult blood in 10-20% of patients, and malena in up to 3%. Intestinal perforation has also been reported in up to 3% of hospitalized cases.
CNS: Encephalopathy, Typhoid meningitis, encephalomyelitis, Guillain-Barré syndrome, cranial or peripheral neuritis and psychotic symptoms
Others: Hepatitis, myocarditis, pneumonia, disseminated intravascular
Diagnosis:
Culture: blood, bone marrow, bile
Bone marrow aspirate culture is the gold standard for the diagnosis of typhoid fever
Failure to isolate the organism
(i) the limitations of laboratory media
(ii) the presence of antibiotics
(iii) the volume of the specimen cultured
(iv) the time of collection, patients with a history of fever for 7 to 10 days being more likely than others to have a positive blood culture.
Widal Test:
O antibodies appear on days 6-8 and H antibodies on days 10-12
Negative in up to 30% of culture-proven cases of typhoid fever
S. typhi shares O and H antigens with other Salmonella serotypes and has cross-reacting epitopes with other Enterobacteriacae, and this can lead to false-positive results. Such results may also occur in other clinical conditions, e.g. malaria, typhus, bacteraemia caused by other organisms, and cirrhosis
This is acceptable so long as the results are interpreted with care in accordance with appropriate local cut-off values for the determination of positivity.
Oral drugs:
Ofloxacin: 15-20 mg / kg for 7-14 days
Azithromycin:8-10 mg/kg for 7 days
Cefixime: 20 mg /day for 7-14 days
Chloramphenicol: 50-75 mg /kg/day for 14-21 days
Fluoroquinolones:
Optimal for the treatment of typhoid fever
Relatively inexpensive, well tolerated and more rapidly and reliably effective than the former first-line drugs, viz. chloramphenicol, ampicillin, amoxicillin and trimethoprim-sulfamethoxazole.
The majority of isolates are still sensitive.
Attain excellent tissue penetration, kill S. typhi in its intracellular stationary stage in monocytes/macrophages and achieve higher active drug levels in the gall bladder than other drugs.
Rapid therapeutic response, i.e. clearance of fever and symptoms in three to five days, and very low rates of post-treatment carriage.
Chloramphanicol:
The disadvantages of using chloramphenicol include a relatively high rate of relapse (57%), long treatment courses (14 days) and the frequent development of a carrierstate in adults.
The recommended dosage is 50 - 75 mg per kg per day for 14 days divided into four doses per day, or for at least five to seven days after defervescence.
Oral administration gives slightly greater bioavailability than intramuscular (i.m.) or intravenous (i.v.) administration of the succinate salt
Cephalosporins:
Ceftriaxone: 50-75 mg per kg per day one or two doses
Cefotaxime: 40-80 mg per kg per day in two or three doses
Cefoperazone: 50-100 mg per kg per day
Dexamethasone:
Should be immediately be treated with high-dose intravenous dexamethasone in addition to antimicrobials
Initial dose of 3 mg/kg by slow i.v. infusion over 30 minutes
1 mg/kg 6 hourly for 2 days
Mortality can be reduced by some 80-90% in these high-risk patients
live oral vaccine Ty2la
three doses two days apart on an empty stomach.
Protection as from 10-14 days after the third dose.
> 5 years.
Protective efficacy of the enteric-coated capsule formulation seven years after the last dose is still
62% in areas where the disease is endemic;
Antibiotics should be avoided for seven days before or after the immunization
Antibiotic resistance:
MDR is mediated by plasmid
Quinolone resistance is frequently mediated by single point mutations in the quinolone-resistance–determining region of the gyrA gene
Nalidixic acid resistant: MIC of fluoroquinolones for these strains was 10 times that for fully susceptible strains.
The future of typhoid
Cheap,Rapid and reliable serological test
Fluoroquinolone and cephalosporin resistant case
Combination chemotherapy
New drugs

First pass metabolism / presystemic metabolism

Metabolism of drug during its passage from the site of absorption into the systemic circulation
Orally administered drugs are exposed to enzymes in intestinal wall and liver
Also occurs in lungs & skin
Attributes of drugs with high first pass metabolism:
Oral dose is high compared to parenteral dose
Marked individual variation in the oral dose
Oral bioavailability is increased in patients of liver disease

BIOTRANSFORMATION (METABOLISM)

Chemical alteration of drug in the body
Nonpolar compounds (lipid soluble) are converted to polar or lipid insoluble compounds, so that they are not reabsorbed in the renal tubules and excreted
Most hydrophilic drugs are little biotransformed & are excreted unchanged e.g. streptomycin

Biotransformation also help to protect the body from foreign substances or toxins
Sites for drug metabolism are liver (most important), kidney, intestine, lungs & plasma
Biotransformation may lead to :
Inactivation: most of the drugs are rendered inactive or less active e.g. paracetamol
Active metabolite from active drug: e.g. Morphine is converted to morphine-6-glucuronide
Activation of inactive drug: few drugs are inactive & need conversion in the body to active metabolite. Such a drug is called as Prodrug
Advantages of prodrug: more stable, better bioavailability & less side effects
e.g. LevodBiotransformation reactions can be classified into
A. nonsynthetic / phase I/ Functionalization reactions: A functional group is generated: metabolite may be active or inactive
B. Synthetic / Conjugation / Phase II reactions: metabolite is mostly inactive
opa is a prodrug, converted in the body to dopamine, which is active form
Nonsynthetic or Phase I reaction:
Oxidation: addition of oxygen / negatively charged radical or removal of hydrogen / positively charged radical
Most important drug metabolizing reactions
These reactions are carried out by an enzyme K/A monooxygenases in the liver
These reactions require a cytochrome P 450 haemoprotein, NADPH, cytochrome P 450 reductase & molecular oxygen
Importance of cytochrome oxidases: Few cytochrome isoenzymes (CYP3A4, CYP2C19) are important because their synthesis can be induced or inhibited by inducers & inhibitors respectively
Inducers & inhibitors are different for different isoenzymes
Important inducers are rifampicin, barbiturates, anticonvulsant drugs, cigarette smoke, charbroiled meat, polycyclic hydrocarbons etc
Important inhibitors are verapamil, diltiazem, ritonavir, grape fruit juice
Due to these inducers / inhibitors drug interactions may occur
Inducers will reduce the active amount while inhibitors will increase the active amount of drug
The other nonsynReduction
Hydrolysis
Cyclization
Decyclization
thetic reactions are
Synthetic or Phase II reaction:

Glucuronide conjugation
Acetylation
Methylation
Sulfate conjugation
Glycine conjugation
Glutathione conjugation
Ribonucleotide synthesis
Few drugs are metabolised by enzymes of intermediary metabolism e.g.
Alcohol : Alcohol dehydrogenase
Allopurinol: xanthine oxidase
Succinylcholine : plasma cholineesterase
Adrenaline: Monoamine oxidase

Microsomal enzymes:
Located on smooth endoplasmic reticulum, primarily in liver
Also present in kidney, intestine & lungs
Examples are cytochrome P450 (CYP3A4), glucuronyl transferase etc.
They catalyze most of the oxidation, reduction, hydrolysis & glucuronide conjugation
These are inducible by various drugs, diet & other agencies

Nonmicrosomal enzymes:
Present in cytoplasm & mitochondria of hepatocyte as well as in plasma
Not inducible
May show genetic polymorphism e.g. Pseudocholine esterases
Both microsomal & nonmicrosomal are deficient in newborn
Amount & kind of drug metabolising enzymes are controlled genetically
This is onHoffman elimination: inactivation of drug in the body by spontaneous molecular arrangement without the need of enzymes e.g. Atracurium
Inhibition of drug metabolism:
e of the major causes of individual variation in drug response
Mirosomal enzyme induction:
Many drugs, insecticide & carcinogen interact with DNA & increase the synthesis of microsomal enzyme protein e.g. cytochrome P450 & glucuronyl traansferase
As a result metabolism of inducing drug itself as well as of other drugs is increased
Different inducers are relatively selective for certain cytochrome P 450 enzyme families e.g. Anticonvulsant, rifampin: CYP3A4
Isoniazid & chronic alcohol : CYP2E1
Polycyclic hydrocarbons, cigarette smoke, charcoalbroiled meat & industrial pollutant : CYP1A
Induction take 4-14 days to reach its peak& is maintained till the inducing agent is given
Thereafter the enzyme returns to their original level over 1-3 weeks
Results of microsomal enzyme induction:
Decrease in intensity or duration of action of drugs that are inactivated by metabolism e.g. failure of contraception with OCP
Increased intensity of action of drugs that are activated by metabolism e.g. acute paracetamol toxicity
Tolerance if the drug induces its own metabolism
Precipitation of AIP
Intermittent use of inducer may interfere with adjustment of dose of another drug prescribed on regular basis e.g. oral anticoagulant, oral hypoglycemics, antiepileptics, antihypertensives etc
Application of enzyme induction:
Liver disease
Congenital nonhemolytic jaundice, phenobarbitone is given
Cushings syndrome: phenytoin may be given
Chronic poisoning:

ANTICHOLINESTERASE

Agents which inhibit enzyme Cholinesterase
They potentiate cholinergic system
CLASSIFICATION
Reversible & irreversible
Reversible : Carbamate & Acridine
Carbamate: physostigimine, neostigimine, pyridostigimine, edrophonium, rivastigimine, donepezil, galantamine
Acridine: tacrine
Irreversible: organophosphate & carbamate
Organophosphates: Dyflos, Echothiophate, Parathion, Malathion, Diazinon, Tabun, sarin, Soman
Carbamate: Carbaryl, Propoxur
MECHANISM
They inhibit the a/c of enzyme ChE by covalently binding with the esteratic site of enzyme
USES
As miotic
Myasthenia gravis
Postoperative paralytic ileus or urinary retention
Postoperative decurarization
Cobra bite
Belladona poisoning
Other drug overdosages
Alzheimers disease
MANIFESTATIONS
Manifestations :
Iacrimation, salivation, sweating, tracheobronchial secretions, miosis, blurring of vision, colic, involuntry defecation & urination
Fall in BP, bradycardia or tachycardia, cardiac arrythmia & vascular collapse
M. fasciculations, weakness & respiratory paralysis
Excitement, tremor, ataxia, convulsion, coma & death
Death is d/t respiratory failure
Treatment:
Termination of exposure:
ABCD
A AIRWAY
B BREATHING
C CIRCULATION
D DRUGS
Drugs used as antidote are atropine & Pralidoxim (Cholinesterse reactivator)

SWINE FLU DETAILS II

Adults Need Attention If Present With:
Difficulty breathing or shortness of breath
Pain or pressure in the chest or abdomen
Sudden dizziness
Confusion
Severe or persistent vomiting
Diagnosis:
To diagnose swine influenza A infection ,a respiratory specimen (nasopharyngeal swab/aspirate or nasal wash/aspirate, combined nasal swab with an oropharyngeal swab, endotracheal aspirate) would generally need to be collected within the first 4 to 5 days of illness (when an infected person is most likely to be shedding virus).
However, some persons, especially children, may shed virus for 10 days or longer Specimen should be placed into sterile viral transport media (VTM) and immediately placed on ice or cold packs or at 4°C (refrigerator) for transport to the laboratory.
1. Samples to be Collected
 
From Ambulatory patient
Throat Swab and
Nasal / Naso pharyngeal Swab
Blood for serological tests

From an intubated patient
 
Lower respiratory aspirate
Blood for serological tests
. Personal Protective Equipment
Before initiating collection of sample a full complement of PPE should be worn. This includes :
Masks (N-95)
Gloves
Protective eye wear (goggles)
Hair covers
Boot or shoe covers
Protective clothing (gown or apron)
CDC helps in diagnosing cases by performing following test in laboratory

Real-time RT-PCR
Viral culture
Routine serodiagnostic tests in use are based on hemagglutination inhibition (HI) and ELISA.
Drugs effective in swine flu:
Influenza antiviral drugs work best when started soon after illness onset (within two 2 days), but treatment with antiviral drugs should still be considered after 48 hours of symptom onset, particularly for hospitalized patients or people at high risk for influenza-related complications.

There are four different antiviral drugs that are licensed for use for the treatment of influenza:
 Amantidine
 Rimantadine
 Oseltamivir
 Zanamivir

While most swine influenza viruses have been susceptible to all four drugs
Most recent swine influenza viruses isolated from humans are resistant to Amantidine and Rimantadine
CDC recommends the use of Oseltamivir (Tamiflu) or Zanamivir (Relenza) for the treatment and/or prevention of infection with swine influenza viruses.

SWINE FLU DETAILS

Epidemiology:
It is estimated that annual epidemics cause 3–5 million cases of severe illness and 250,000–500,000 deaths worldwide.
The period between epidemic waves of influenza A tends to be 2–3 years; the interepidemic period for type B is longer (3–6 years).
Every 10–40 years, when a new subtype of influenza A appears, a pandemic results.
This happened in 1918 (H1N1), 1957 (H2N2), and 1968 (H3N2).
World Health Organization has reported 70893 laboratory confirmed cases of influenza A/H1N1 infection from 116 countries as on 29th June 2009.
There have been 311 deaths.
No further update is available.
Situation in india:
'A total of 1,549 people have been tested so far, of whom 298 are positive for influenza A(H1N1),' a statement issued here said, adding that 181 people have been discharged from the health facilities.
Pharmaceutical intervention:
Pharmaceutical intervention
As of now, India has a stock of 10 million capsules of oseltamivir.
Some stocks are also committed by pharmaceutical companies for exclusive use by the Government.
This drug is only available through the public health system and its retail sale is banned as indiscriminate use may lead to development of resistance.
If there is widespread infection, MOHFW would review this decision.
Thermoscanner installed in Airport for Entry Screening.
How Swine Flu Spread Among Pigs?
During animal transport
Airborne transmission through aerosols produced by pigs e.g. coughing or sneezing.
The virus usually spreads quickly through a herd, infecting all the pigs within just a few days.

Direct Transmission

Pigs to Human (people are in close proximity to infected pigs, such as in pig barns & livestock exhibits housing pigs at fairs)

Human to Pigs
Human to Human: (via aerosolized respiratory secretions for e.g. coughing ,sneezing of infected person, touching contaminated inanimate objects & then touching nose or mouth)
Swine influenza viruses are not transmitted from eating pork or pork products.
Cooking pork to an internal temperature of 160°F kills the swine flu virus.
Incubation period:
It is usually one to three days.
Pigs begin excreting the virus within 24 hours of infection, and may shed the virus for seven to ten days.
Infectious period:
Defined as “1 day prior to the case’s illness onset to 7 days after onset”.
Younger children, might potentially be contagious for longer periods up to 10 days.
A carrier state can exist for up to 3 months.
The viruses can live 2 hours or longer outside body.
Who are at risk ???
Children aged 6 months up to their 19yrs
Pregnant women
People 50 years of age and older
People of any age with certain medical conditions, such as heart or lung disease (Asthma, COPD, Emphysema ), Diabetes or those with weakened immune systems e.g. HIV.
Pathophysiology:
Influenza viruses enters the respiratory tract bind through Hemagglutinin onto Sialic acid sugars on the surfaces of epithelial cells; typically in the nose, throat and lungs of mammals.

The respiratory tract becomes swollen & inflamed .

From the tract it then enters the blood streams and symptoms begins to show .
Symptoms:

Fever with or without chills
Lethargy
Lack of appetite
Sore throat
Cough
Running nose
Body ache
Headache
Nausea
Vomiting
Diarrhea
Seek Emergency Medical CareIF - in Children
In children emergency warning signs that need urgent medical attention include:

Bluish skin colour
Not drinking enough fluids
Not waking up or not interacting
Being so irritable that the child does not want to be held
Flu-like symptoms improve but then return with fever and worse cough
Fever with a rash

SWINE FLU

Swine influenza, or “Swine Flu” or “Hog Flu” or “H1N1 Influenza” is a highly contagious acute respiratory disease caused by any strain of the influenza virus endemic in pigs (swine) that regularly cause outbreaks of influenza among pigs.

Strains endemic in swine are called swine influenza virus (SIV)
Swine Influenza Virus:
The classical swine flu virus (an influenza type A H1N1 virus) was first isolated from a pig in 1930.
It causes high levels of illness and low death rates in pigs.

Swine influenza viruses may circulate among swine throughout the year,but most outbreaks occur during the late fall & winter months similar to outbreaks in humans.
Classification:
Influenza virus A (common): Influenza type A is antigenically highly variable and is responsible for most cases of epidemic influenza.

Various subtypes H1N1, H1N2,H3N1,H3N2, & H2N3 .

In pigs, three influenza A virus subtypes (H1N1, H3N2, & H1N2) are the most common strains worldwide.
Influenza virus B :
Due to its limited host range and the lack of genetic diversity, this form of influenza does not cause pandemics in humans

Influneza virus C (rare):
Influenza type C is antigenically stable and causes only mild illness in immunocompetent individuals.
Antigenic differences exhibited by two of the internal structural proteins, the nucleocapsid (NP) and matrix (M) proteins, are used to divide influenza viruses into types A, B, and C.
Antigenic variations in the surface glycoproteins, HA and NA, are used to subtype the viruses.
Only type A has designated subtypes.
Four HA (H1–H3, H5) and two NA (N1, N2) subtypes have been recovered from humans.
The standard nomenclature system for influenza virus isolates includes the following information: type, host of origin, geographic origin, strain number, and year of isolation.
The host of origin is not indicated for human isolates, eg, A/Hong Kong/03/68(H3N2), but it is indicated for others, eg, A/swine/Iowa/15/30(H1N1).
Structure & Function of Hemagglutinin
The HA protein of influenza virus binds virus particles to susceptible cells and is the major antigen against which neutralizing (protective) antibodies are directed.
Structure & Function of Neuraminidase:
The NA functions at the end of the viral replication cycle.
It is a sialidase enzyme that removes sialic acid from glycoconjugates.
It facilitates release of virus particles from infected cell surfaces during the budding process and helps prevent self-aggregation of virions by removing sialic acid residues from viral glycoproteins.
Antigenic Drift & Antigenic Shift
The two surface antigens of influenza undergo antigenic variation independent of each other.
Minor antigenic changes are termed antigenic drift.
Antigenic drift is a gradual change in antigenicity due to point mutations that affect major antigenic sites on the glycoprotein.
Major antigenic changes in HA or NA, called antigenic shift, result in the appearance of a new subtype.
Antigenic shift is most likely to result in major epidemics or pandemics.
Antigenic shift is an abrupt change due to genetic reassortment with an unrelated strain.
- Important Properties of Orthomyxoviruses:
Virion: Spherical, pleomorphic, 80–120 nm in diameter (helical nucleocapsid, 9 nm) 
Composition: RNA (1%), protein (73%), lipid (20%), carbohydrate (6%) 
Genome: Single-stranded RNA, segmented (eight molecules), negative-sense, 13.6 kb overall size 
Proteins: Nine structural proteins, one nonstructural