Mechanism of action of antiepileptic drugs

enhancement of GABA action
inhibition of sodium channel function
inhibition of calcium channel function
Newer drugs act by other mechanisms, yet to be elucidated.
Drugs that block glutamate receptors are effective in animal models but are not yet developred for clinical use.
Tonic clonic seizures:
carbamazepine (preferred because of low incidence of side-effects), phenytoin, valproate
use of a single drug is preferred when possible to avoid pharmacokinetic interactions
newer agents (not yet fully assessed) include vigabatrin, lamotrigine, felbamate, gabapentin.
Partial (focal) seizures: carbamazepine, valproate; clonazepam or phenytoin are alternatives.
Absence seizures (petit mal): ethosuximide or valproate
valproate is used when absence seizures coexist with tonic-clonic seizures, since most other drugs used for tonic-clonic seizures can worsen absence seizures.
Myoclonic seizures: diazepam intravenously or (in absence of accessible veins) rectally.
Neuropathic pain, e.g. carbamazepine, gabapentin (see Ch. 40).
To stabilise mood (as an alternative to lithium), e.g. carbamazepine, valproate

Valproate:
chemically unrelated to other antiepileptic drugs
mechanism of action not clear; weak inhibition of GABA transaminase; some effect on sodium channels
related few unwanted effects: baldness, teratogenicity, liver damage (rare, but serious).
Phenytoin:
acts mainly by use-dependent block of sodium channels
effective in many forms of epilepsy, but not absence seizures
metabolism shows saturation kinetics; therefore, plasma concentration can vary widely and monitoring is needed
drug interactions are common
main unwanted effects are confusion, gum hyperplasia, skin rashes, anaemia, teratogenesis
widely used in treatment of epilepsy; also used as antidysrhythmic agent

Carbamazepine:
derivative of tricyclic antidepressants
similar profile of that of phenytoin, but with fewer unwanted effects
effective in most forms of epilepsy (except absence seizures); particularly effective in psychomotor epilepsy; also useful in trigenimal neuralgia
strong enzyme-inducing agent; therefore, many drug interactions
low incidence of unwanted effects; principally sedation, ataxia, mental disturbances, water retention.

Other drugs include:
phenobarbital: highly sedative
various benzodiazepines (e.g. clonazepam); diazepam used in treating status epilepticus.

Clinical features of different epilepsy

Grandmal epilepsy or Generalized tonic clonic epilepsy: It is charecterized by aura followed by tonic contraction of body progressing to rapid jerky clonic movements followed by unconsciousness. There may be respiratory depression followed by an attack of epilepsy

Absense siezures: Suddenly patient may go into black out or momentarily loss of consciousness. This may occur many times per day but the patient is not aware of that

Atonic epilepsy: There is sudden loss of tone of entire body

Myoclonic epilepsy: There is electric current like jerky movements in limbs

simple partial: seizures are localized to a particular group of muscles & patient does not loose consciousness

Complex partial:seizures are localized to a particular group of muscles & patient looses consciousness

EPILEPSY

Epilepsy is a tendency of recurrent fits. It oocurs due to abnormal electrical activity in neurones. The causes of epilepsy are:
Idiopathic
Secondary causes like trauma, tuberculosis, tumour, infection etc
Clinically epilesies can be classified into following groups
Grandmal epilepsy or generalized tonic clonnic
Petitmal epilepsy or absense seizure
Myoclonic epilepsy
Atonic epilepsy
Infantile epilepsy
Simple partial seizures
Complex partial seizures
Epilepsies can also be induced experimentally in animals by giving electric shock or giving some chemicals like PTZ. This is used in the screening of antiepileptic drugs
The drugs used in epilepsies are phenytoin, carbamazepine, sodium valproate, gabapentin, Tiagabin, Vigabatrine, Lamotrigine & benzodiazepines like diazepam, lorazepam & midazolam

Psoriasis

It is a chronic inflammatory skin disorder clinically characterized by erythematous, sharply demarcated papules and rounded plaques, covered by silvery micaceous scale. The skin lesions of psoriasis are variably pruritic. Traumatized areas often develop lesions of psoriasis (Koebner or isomorphic phenomenon). Additionally, other external factors may exacerbate psoriasis including infections, stress, and medications (lithium, beta blockers, and antimalarials
Clinical features
Sharply demarcated, erythematous plaques with mica-like scale; predominantly elbows, knees, and scalp; atypical forms may localize to intertriginous areas; eruptive forms may be associated with infection.
May be aggravated by certain drugs, infection; severe forms seen associated with HIV
he most common variety of psoriasis is called plaque-type. Patients with plaque-type psoriasis will have stable, slowly enlarging plaques, which remain basically unchanged for long periods of time. The most commonly involved areas are the elbows, knees, gluteal cleft, and the scalp. Involvement tends to be symmetric. Plaque psoriasis generally develops slowly and runs an indolent course. It rarely remits spontaneously. Inverse psoriasis affects the intertriginous regions including the axilla, groin, submammary region, and navel; it also tends to affect the scalp, palms, and soleGuttate psoriasis (eruptive psoriasis) is most common in children and young adults. It develops acutely in individuals without psoriasis or in those with chronic plaque psoriasis. Patients present with many small erythematous, scaling papules, frequently after upper respiratory tract infection with -hemolytic streptococci. The differential diagnosis should include pityriasis rosea and secondary syphilis.The other types of psoriasis is pustular psoriasis. About half of all patients with psoriasis have fingernail involvement, appearing as punctate pitting, onycholysis, nail thickening, or subungual hyperkeratosis. About 5–10% of patients with psoriasis have associated arthralgias, and these are most often found in patients with fingernail involvement. Although some have the coincident occurrence of classic rheumatoid arthritis (Chap. 314), many have psoriatic arthritis that falls into one of three types: (1) asymmetric inflammatory arthritis most commonly involving the distal and proximal interphalangeal joints and less commonly the knees, hips, ankles, and wrists; (2) a seronegative rheumatoid arthritis–like disease; a significant portion of these patients go on to develop a severe destructive arthritis; or (3) disease limited to the spine (psoriatic spondylitis).
Treatment:
Treatment of psoriasis depends on the type, location, and extent of disease. All patients should be instructed to avoid excess drying or irritation of their skin and to maintain adequate cutaneous hydration. Most patients with localized, plaque-type psoriasis can be managed with midpotency topical glucocorticoids, although their long-term use is often accompanied by loss of effectiveness (tachyphylaxis) and atrophy of the skin. A topical vitamin D analogue (calcipotriene) and a retinoid (tazarotene) are also efficacious in the treatment of limited psoriasis and have largely replaced other topical agents such as coal tar, salicylic acid, and anthralin.
Ultraviolet light, natural or artificial, is an effective therapy for many patients with widespread psoriasis. Ultraviolet B (UV-B) light, narrowband UV-B, and ultraviolet A (UV-A) spectrum with either oral or topical psoralens (PUVA) are also extremely effective. The long-term use of UV light may be associated with an increased incidence of non-melanoma and melanoma skin cancer. UV light therapy is contraindicated in patients receiving cyclosporine and should be used with great care in all immunocompromised patients due to an increased risk of developing skin cancers.
The FDA approved systemic agents used for psoriasis are methotrexate, Acitretin & Cyclosporine.Etanercept & Infliximab are monoclonal antibodies against TNF alpha which are used in psoriasis

Contact Dermatitis

Contact dermatitis is an inflammatory process in skin caused by an exogenous agent or agents that directly or indirectly injure the skin. This injury may be caused by an inherent characteristic of a compound—irritant contact dermatitis (ICD). An example of ICD would be dermatitis induced by a concentrated acid or base. Agents that cause allergic contact dermatitis (ACD) induce an antigen-specific immune response (poison ivy dermatitis). The clinical lesions of contact dermatitis may be acute (wet and edematous) or chronic (dry, thickened, and scaly), depending on the persistence of the insult
Following types of contact dermatitis is commonly seen in routine practice
Irritant contact dermatitis
Allergic contact dermatitis

Treatment:

If contact dermatitis is suspected and an offending agent is identified and removed, the eruption will resolve. Usually, treatment with high-potency topical glucocorticoids is enough to relieve symptoms while the dermatitis runs its course. For those patients who require systemic therapy, daily oral prednisone beginning at 1 mg/kg, but usually 60 mg/d, is sufficient.
Identification of a contact allergen can be a difficult and time-consuming task. Patients with dermatitis unresponsive to conventional therapy or with an unusual and patterned distribution should be suspected of having ACD. They should be questioned carefully regarding occupational exposures and topical medications. Common sensitizers include preservatives in topical preparations, nickel sulfate, potassium dichromate, thimerosal, neomycin sulfate, fragrances, formaldehyde, and rubber-curing agents. Patch testing is helpful in identifying these agents but should not be attempted on patients with widespread active dermatitis or on those taking systemic glucocorticoids.

ECZEMA & DERMATITIS

Eczema is a type of dermatitis and these terms are often used synonymously (atopic eczema or atopic dermatitis). Eczema is a reaction pattern that presents with variable clinical findings and the common histologic finding of spongiosis (intercellular edema of the epidermis)
Atopic dermatitis (AD) is the cutaneous expression of the atopic state, characterized by a family history of asthma, allergic rhinitis, or eczema. The prevalence of AD is increasing worldwide.

Atopic dermatitis (AD) is clinically charecterized by

1. Pruritus and scratching


2. Course marked by exacerbations and remissions


3. 4. Personal or family history of atopy (asthma, allergic rhinitis, food allergies, or eczema)

4. Lesions typical of eczematous dermatitis

5. Clinical course lasting longer than 6 weeks

6. Lichenification of skin

The etiology of AD is only partially defined, but there is a clear genetic predisposition. When both parents are affected by AD, >80% of their children manifest the disease. When only one parent is affected, the prevalence drops to slightly over 50%. Patients with AD may display a variety of immunoregulatory abnormalities including increased IgE synthesis, increased serum IgE, and impaired delayed-type hypersensitivity reactions.

Treatment


Therapy of AD should include avoidance of cutaneous irritants, adequate moisturizing through the application of emollients, judicious use of topical anti-inflammatory agents, and prompt treatment of secondary infection. Patients should be instructed to bathe no more often than daily using warm or cool water, and to use only mild bath soap. Immediately after bathing while the skin is still moist, a topical anti-inflammatory agent in a cream or ointment base should be applied to areas of dermatitis, and all other skin areas should be lubricated with a moisturizer.
Low- to midpotency topical glucocorticoids are employed in most treatment regimens for AD.

Secondary infection of eczematous skin may lead to exacerbation of AD. Crusted and weeping skin lesions may be infected with S. aureus. When secondary infection is suspected, eczematous lesions should be cultured and patients treated with systemic antibiotics active against S. aureus.

Control of pruritus is essential for treatment, since AD often represents "an itch that rashes." Antihistamines are most often used to control pruritus, and mild sedation may be responsible for their antipruritic action. Sedation may also limit their usefulness; however, when used at bedtime, sedating antihistamines may improve the patient's sleep.

Treatment with systemic glucocorticoids should be limited to severe exacerbations unresponsive to topical therapy

Acne treatment

Patients with moderate to severe acne with a prominent inflammatory component will benefit from the addition of systemic therapy, such as tetracycline in doses of 250–500 mg bid, or doxycycline, 100 mg bid. Minocycline may also be useful. Such antibiotics appear to have an anti-inflammatory effect independent of their antibacterial effect
Female patients who do not respond to oral antibiotics may benefit from hormonal therapy. Women placed on oral contraceptives containing ethinyl estradiol and norgestimate have demonstrated improvement in their acne when compared to a placebo control.
Patients with severe nodulocystic acne unresponsive to the therapies discussed above may benefit from treatment with the synthetic retinoid, isotretinoin. Its dose is based on the patient's weight, and it is given once daily for 5 months. Results are excellent in appropriately selected patients. Its use is highly regulated due to its potential for severe adverse events, primarily teratogenicity.

Acne Vulgaris

Acne vulgaris is a self-limited disorder primarily of teenagers and young adults
The permissive factor for the expression of the disease in adolescence is the increase in sebum production by sebaceous glands after puberty. The activity of bacteria (Proprionobacterium acnes) within the comedones releases free fatty acids from sebum, causes inflammation within the cyst, and results in rupture of the cyst wall. An inflammatory foreign-body reaction develops as result of extrusion of oily and keratinous debris from the cyst.The clinical hallmark of acne vulgaris is the comedone, which may be closed (whitehead) or open (blackhead).
The earliest lesions seen in adolescence are generally mildly inflamed or noninflammatory comedones on the forehead. Subsequently, more typical inflammatory lesions develop on the cheeks, nose, and chin The most common location for acne is the face, but involvement of the chest and back is common. Most disease remains mild and does not lead to scarring. A small number of patients develop large inflammatory cysts and nodules, which may drain and result in significant scarring. Regardless of the severity, acne may affect a patient's quality of life. If adequately treated, this may be a transient effect. In the case of severe, scarring acne, the effects can be permanent and profound. Early therapeutic intervention in severe acne is essential.
Treatment of Acne vulgaris
Treatment of acne vulgaris is directed toward elimination of comedones by normalization of follicular keratinization, decreasing sebaceous gland activity, decreasing the population of P. acnes, and decreasing inflammation. Minimal to moderate, pauci-inflammatory disease may respond adequately to local therapy alone. Although areas affected with acne should be kept clean, overly vigorous scrubbing may aggravate acne due to mechanical rupture of comedones. Topical agents such as retinoic acid, benzoyl peroxide, or salicylic acid may alter the pattern of epidermal desquamation, preventing the formation of comedones and aiding in the resolution of preexisting cysts. Topical antibacterial agents such as azelaic acid, topical erythromycin (with or without zinc), or clindamycin are also useful adjuncts to therapy

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 

MENINGITIS

Meningitis is one of the most terrifying diseases. It can be fatal in hours yet its early symptoms resemble self-limiting conditions like flu and colds…..
Meningitis is an infection of the fluid in the spinal cord and the fluid that surrounds the brain. Meningitis is usually caused by an infection with a virus, with a bacterium or even with fungi.
Common pathogens:
Meningococcus:
common organisms that cause meningitis in children.
caused by bacteria called Neisseria meningitidis.
There are several strains of Neisseria meningitidis.
Strain B causes about 75 percent of the meningococcal cases and has the highest fatality rate.
Haemophilus Influenzae type B (Hib)
is caused by haemophilus bacteria. It was once the most common form of bacterial meningitis,
one of the deadliest childhood diseases.
Pneumococcus
is caused by pneumococcus bacteria, which also cause several diseases of the respiratory system, including pneumonia.
It has a fatality rate of about 20 percent.
It also results in a higher incidence of brain damage than other forms of the disease.
How do people get it?
The most frequent cause of meningitis is the entry of microorganisms from an infection elsewhere in the body through the blood into the cerebrospinal fluid. 

Luckily, it's not easy to get meningitis. The body has natural defenses against infections - and usually even if someone comes across a virus or bacteria that can cause meningitis, the body can fight it off.

However, certain germs may outsmart the body's defenses and spread inside of the body. Some of these germs might then have the ability to infect the central nervous system, invading the meninges and causing meningitis.
Symptoms of meningitis can come on very quickly or take a couple of days to appear. Most cases of meningitis occur in the first 5 years of life, with the peak incidence between 3 and 5 months of age.
This varies with the organism and the underlying cause of the meningitis, but once the organisms have entered the cerebrospinal fluid, the body defenses cannot control their rapid growth as well as they could when the organisms were only in the bloodstream.

Once bacteria have entered the spinal fluid, the child usually shows symptoms fairly rapidly.
Complications Young children:
Babyish behavior
Forgetting recently learned skills
Reverting to bed-wetting
Babyish behavior
of MOne of the most common problems resulting from meningitis is hearing loss. Anyone who has had meningitis should take a hearing test.
Older people:
Lethargy
Recurring headaches
Difficulty in concentration
Short-term memory loss
Clumsiness
Balance problems
Depression
Other serious complications can include:

Brain damage

Epilepsy 
Changes in eye sight
Bacterial meningitis can be treated with a number of effective antibiotics. It is important, however, that treatment be started early in the course of the disease. Appropriate antibiotic treatment of most common types of bacterial meningitis should reduce the risk of dying from meningitis to below 15%, although the risk is higher among the elderly.

Knowing whether meningitis is caused by a virus or a bacterium is important because of differences in the seriousness of the illness and the treatment needed.
Investigations:
Examinations of CSF by lumber puncture
blood cultures
neuroimaging studies (CT or MRI)
detection of bacterial nucleic acid by polymerase chain reaction (PCR) assay.

OTHER FLUOROQUINOLONES

Pefloxacin:
Methyl derivative of Norfloxacin
Preferred for meningeal infections
Ofloxacin:
More potent than ciprofloxacin for gram +ve & anaerobes
Also inhibit M. tuberculosis & M.leprae
Levofloxacin:
Levoisomer of of ofloxacin
Improved activity against S. pneumonae & other gram positive bacteria
Oral BA is 100 %
Indications are CA pneumonia, exacerbation of chronic bronchitis & ENT infections
Lomefloxacin:
Second generation FQ, more active against gram positive
Long half life
Sparfloxacin:
Second generation FQ
Indications are pneumonia, exacerbations of bronchitis, ENT infections, chlamydial infections
Good efficacy in TB, MAC infections in AIDS pts & leprosy
Phototoxic reactions, slight prolongations of QTc interval
Gatifloxacin:
2nd generation FQ
Indications are pneumonia, exacerbations of bronchitis, URTI & LRTI
ADR: Tachycardia, prolong QTc interval, Torsades de pointes
Discontinued in USA & UK
Drugs that prolong QTc interval are cisapride, TCA, phenothiazines class IA & III antiarrhythmics
Moxifloxacin:
2n d generation FQ
Most potent FQ against M. tuberculosis
Also prolong QTc interval
Indications are same as that of other 2nd gen. FQ

NORFLOXACIN

Primarily used for urinary, GIT & genital infection
Good for bacterial diarrhea because high conc. Are present in gut & anaerobic flora is not disturberd

CIPROFLOXACIN

Most potent first generation FQ
Broad spectrum
Spectrum: Highly susceptible bacteria are E.coli, K. pneumonae, Enterobacter, S. typhi, Shigella, proteus, N. gonorrhoea, N. meningitidis, H. influenzae, H.ducreyi, C. jejuni, Y. enterocolitica, V. cholerae
Moderately susceptible are P. aeruginosa, S. aureus, S. epidermidis, Legionella, Brucella, Listeria, B. anthracis & M. tuberculosis
Remarkable microbiological feature of FQ are:
Rapidly bactericidal activity & high potency
Long postantibiotic effect
Low chances of resistance
Protective intestinal streptococci & anaerobes are spared
Active against many beta lactam & aminoglycoside resistant bacteria
Less active at acidic pH
PK: absorbed orally, high tissue penetration is most important feature, conc. In lung, sputum, muscle, bone, prostate & phagocyte exceed that in plasma but CSF levels are lower, excreted in urine, urinary & biliary conc. Are higher than plasma
ADR:

TGI upset tendonitis & Tendon rupture: few cases have been reported. FQ caused cartilage damage in immature pups. FQ are C/I in children & during pregnancy
CNS: seizures occur at high dose d/t GABA antagonistic action
Hypersensitivity Rx:
INTERACTIONS:
Ciprofloxacin is cytochrome enzyme inhibitor, so plasma conc. of theofylline, warfarin are increased
NSAIDS may cause seizures CNS toxicity
USES:
UTI
Typhoid
Bone, soft tissue, gynecological & wound infection
Respiratory infections
Gonorrhea
Chancroid
Bacterial gastroenteritis
Gram negative septicemias
Meningitis
Tuberculosis
Prophylaxis
Conjunctivitis

FLUOROQUINOLONES (MECHANISM)

FQ inhibit the enzyme DNA gyrase
DNA gyrase enzyme nick the ds DNA, introduces negative supercoils & then reseal the nicked ends
This is necessary to prevent excessive positive supercoiling
DNA gyrase consist of two A & two B subunits
A subunit carries out nicking of DNA, B subunit introduce negative supercoils & then A subunit reseal the strands
FQ bind to A subunit & interfere with its strand cutting & resealing function
In gram +ve bacteria, the major target of FQ action is a similar enzyme k/a Topoisomerase IV
Mammalian cell posses an enzyme k/a Topoisomerase II which has very low affinity for FQ, hence low toxicity to host cells
Mechanism of Resistance: Resistance to FQ is slow to develop
Mutation leading to production of DNA gyrase with reduced affinity to FQ

FLUOROQUINOLONES

Quinolone antimicrobials having one or more fluorine substitutions
First generation FQ have one fluoro substitution while second generation FQ have additional fluoro substitution
Second generation FQ have extended spectrum & longer half life

CARBAPENEM

Includes imipenem, Meropenem & Faropenem
Imipenem: Extremely potent & broad spectrum beta lactam antibiotic
Spectrum: gram positive coci, enterobacteriacae, P.aeruginosa, Listeria, as well as anaerobes like B. fragilis, cl. difficile
Resistant to most beta lactamases
It undergo rapid hydrolysis by the enzyme dehydropeptidase I located on the brush border of renal tubular cells
So it is combined with Cilastatin, a reversible inhibitor of dehydropeptidase I
ADR: GI upset, rashes & seizures at high dose
Indications: serious hospital acquired infections in neutropenic, cancer & AIDS pts
Meropenem: newer carbapenem
Not hydrolysed by renal dehydropeptidase I
Spectrum: broad spectrum similar to Imipenem
Indication: reserve drug for serious nosocomial infections caused by cephalosporin resistant bacteria
Less likely to cause seizures

MONOBACTAM

Aztreonam: Beta lactam antibiotic in which the other ring is missing
Antibacterial spectrum: gram negative enteric bacilli, H.influenzae, Pseudomonas
It does not inhibit gram positive cocci or anaerobes (spectrum resembling aminoglycoside)
Resistant to gram negative beta lactamases
Lack of cross sensitivity with other beta lactam antibiotic is important feature
So aztreonam can be used in pts allergic to Pn or cephalosporin
ADR: Rashes & rise in serum transaminase
Use : Hospital acquired infections originating from biliary, gastrointestinal & urinary tracts

TREATMENT OF TYPHOID FEVER OR ENTERIC FEVER

Typhoid fever is a systemic disease characterized by fever and abdominal pain and caused by dissemination of S. Typhi or S. Paratyphi
Diseases was initially called typhoid fever because of its clinical similarity to typhus
Typhoid fever was clearly defined pathologically as a unique illness on the basis of its association with enlarged Peyer's patches and mesenteric lymph nodes
Empirical treatment:
Ceftriaxone 1-2 g/d iv for 7-14 days
Azithromycin 1 g/d orally for 5 days
Ceftriaxone is to be preferred over FQ in children, pregnant women & in areas with FQ resistance
Fully susceptible cases:
Ciprofloxacin (First line) 500 mg BD for 5-7 days
Amoxycillin 1g TDS for 14 days
Cotrimoxazole 160/800 mg BD for 14 days
Multidrug-Resistant
Ciprofloxacin 500 mg BD (PO) for 5–7 days
Ceftriaxone 2–3 g/d (IV) for 7–14 days
Azithromycin 1 g/d (PO) for 5 days

PROPERTIES OF CEPHALOSPORINS

Bactericidal
Same mechanism of action as Penicillin, but they bind to different proteins than those which bind penicillin
Aquired resistance occurs by three mechanism
Drug tolerant e.g. alteration in PBP
Drug impermeable
Drug destroying e.g. beta lactamases or cephalosporinase
Individual cephalosporin differ in
Antibacterial spectrum
Susceptibility to beta lactamases
Pharmacokinetic properties
Local irritancy on I.m. injection
ADR
Pain after i.m. injection
Diarrhea
HT reactions
Nephrotoxicity e.g. cephaloridine
Bleeding d/t hypoprothrombinemia e.g. cefoperazone & ceftriaxone
Neutropenia & thrombocytopenia are rare side effects
Disulfiram like reaction with alcohol e.g. cefoperazone
Uses
As alternative to PnG
Respiratory, urinary & soft tissue infections
Penicillinase producing staph. Infections
Septicemia caused by gram negative organism, an aminoglycoside may be combined
Surgical prophylaxis e.g. cefazolin
Meningitis:for empical therapy, iv ceftriaxone + ampicillin or vancomycin is given, for pseudomonas meningitis, ceftazidime +gentamycin is used
PPNG: ceftriaxone is DOC for single dose therapy of PPNG
Typhoid: ceftriaxone & cefoperazone are used
Mixed aerobic anaerobic infections
Hospital acquired infections
Prophylaxis & treatment of infections in neutropenic patients

Cephalosporins

Group of semisynthetic antibiotics derived from cephalosprin -C obtained from fungus Cephalosporium
Chemically related to Pn, the nucleus consist of beta lactam ring fused to dihydrothiazine ring
Divided into four generation on the basis of chronological sequence, potency & antibacterial spectrum
First generation cephalosporins
Developed in 1960s
High activity against gram positive but weaker against gram negative bacteria
Mainly used for surgical prophylaxis
Oral: Cephalexin, Cephradine, Cefadroxil
Parenteral: Cefazolin, Cephalothin
Second generation cephalosporins
Developed subsequent to first generation
More active against gram negative organism, some members active against anaerobes but none inhibit P.aeruginosa
Oral: Cefaclor, Cefuroxim axetil
Parenteral: Cefuroxim, Cefoxitin
Third generation cephalosporins
Augmented activity against gram negative enterobacteriacae, some inhibit Pseudomonas as well
Highly resistant to beta lactamases from gram negative bacteria
Oral: Cefixime, Cefdinir,
Parenteral: Ceftriaxone, Cefotaxim, Cefoperazone,
Fourth generation cephalosporins
Developed in 1990s, antibacterial spectrum similar to 3rd generation , but is highly resistant to beta lactamases
Active against P. aeruginosa & S. aureus
Used for serious hospital acquired infections
Only parenteral
Cefepime
Cefpirome
Properties

AMOXYCILLIN

Close congener of ampicillin, similar to it in all aspects except:
Oral absorption is better, food does not interfere with absorption
Incidence of diarrhea is less
Less active against H.influenzae & Shigella
CARBOXYPENICILLINS
Carbenicillin: special feature is its activity against Pseudomonas aeruginosa & indole positive proteus which are not inhibited by PnG
PK: niether acid resistant nor penicillinase resistant, inactive orally, given by im or iv route
Use : serious infections caused by pseudomonas or proteus e.g. burn, UTI, septicemia etc
ANTIPSEUDOMONAS PENICILLINS
Carbenicillin
Ticarcillin
Piperacillin
Mezlocillin
BETA LACTAMASES INHIBITOR
Beta lactamase are family of enzymes, produced by many gram positive & negative bacteria that inactivate beta lactam antibiotic
Clavulanic acid: obtained from S. clavuligerus
It has a beta lactam ring but no antibacterial activity of its own
It inhibits a wide variety of beta lactamases
Progressive inhibitor of beta lactamases
Suicide inhibitor
It inhibits the periplasmically located Beta Lactamases enzyme in gram –ve bacteria
PK: rapid oral absorption, it is used with amoxycillin (coamoxyclav),
Uses: addition of clavulanic acid reestablishes the activity of amoxycillin against PP S. aureus but not MRSA that have altered PBP
Skin & soft tissue infections
Gonorrhea:(PPNG) Single dose amoxycillin 3g +clavulanic acid 0.5g + probenecid 1g is highly active
Sulbactam: semisynthetic beta lactamase inhibitor
Related chemically as well as in activity to clavulanic acid
Also a progressive inhibitor of beta lactamases
Less potent than clavulanic acid
Sulbactam does not induce chromosomal beta lactamases while clavulanic acid can induce some of them
Sulbactam is given parenterally
It is combined with ampicillin ( sultamicillin tosylate)
Uses: PPNG gonorrhoea
Mixed aerobic anaerobic infections
ADR: thrombophlibitis of injected vein, rashes, diarrhoea etc
TAZOBACTAM
Beta lactamase inhibitor, which is similar to sulbactam
Combined with piperacillin
Use : severe infections like peritonitis, pelvic & respiratory infections produced by beta lactamase producing bacilli

SEMISYNTHETIC PENICILLINS

Produced by chemically combining specific side chains in place of benzyl side chain of PnG
Procaine Pn & benzathine Pn are salts of PnG & not semisynthetic Pn
The aim is to overcome the shortcomings of PnG which are:
Poor oral efficacy
Susceptibility to beta lactamase
Narrow spectrum
Hypersensitivity reactions
CLASSIFICATION
Acid resistant alternative to PnG: Phenoxy methyl Pn / PnV
Penicillinase/ beta lactamase resistant Pn: Methicillin, Cloxacillin
Extended spectrum Pn
1. Amino Pn: Ampicillin, Bacampicillin, Amoxycillin
2. CarboxyPn: Carbenicillin, Ticarcillin
3.UreidoPn: Piperacillin, Mezlocillin
ANTI-staphylococcal penicillins
“semi-synthetic”
Add bulky side chains to provide
STERIC HINDRANCE
(Methicillin) - renal toxicity
Nafcillin
Oxacillin
Cloxacillin (di-clox) - oral drugs
Beta lactamases inhibitors: Clavulanic acid, Sulbactam, Tazobactam
Ampicillin:
Spectrum: all organism which are sensitive to PnG + H. influenzae, E.coli, proteus, Salmonella & Shigella
PK: not degraded by gastric juice so given orally, partly excreted in bile & reabsorbed, enterohepatic circulation occurs, primary channel of excretion is kidney
USES
UTI
RTI
Meningitis
Gonorrhoea
Typhoid fever
Bacillary desentry d/t Shigella
Cholecystitis
SABE
Septicemia & Mixed infection

Penicillin G / Benzyl Penicillin

Spectrum: narrow spectrum antibiotic, primarily against gram positive bacteria
Cocci: Streptococci (except viridans or enterococci), pneumococci,N. gonorrhoea, N. meningitidis
Bacilli: B. anthracis, C.diptherae, Clostridia, Listeria, T. pallidum, Leptospira
Pharmacokinetics: PnG is acid labile as well as thermolabile, absorption from i.m. site is rapid, reaches most body fluids, but penetration in serous cavities & CSF is poor,
nearly 60 % plasma protein bound, plasma half life is 30 min. Tubular secretion of PnG can be blocked by probenecid, higher conc. can be achieved

Local : pain, nausea, thrombophlebitis
Systemic: mental confusion, m. twitchings, convulsion & coma at high dose, bleeding d/t interference with platelet fxs,
Hypersensitivity reactions: PnG is the most common drug implicated in drug allergy
Rash, fever, itching, urticaria, wheezing, angionerotic edema, exfoliative dermatitis, anaphylaxis (rare)
HT is more common after parenteral than oral administration
Partial cross sensitivity b/w different Pn
Procaine Pn is also allergenic
A scratch or intradermal test
If a pt is aiiergic to Pn, use alternative antibiotic
Superinfections: rare with PnG
Jarisch herxheimer reaction: seen after injection of Pn in syphilitic pt. Manifestations are fever, shivering, myalgia, & vascular collapse. This is d/t release of spirochital lytic products. It does not reoccur & does not need interruption of therapy. Aspirin & sedation may be given for symptomatic relief
Uses: Streptococcal infections
Pneumococcal infections
Meningococcal infections
Gonorrhoea
Syphilis
Diptheria
Tetanus
Gas gangrene
Rare infections like leptospirosis, anthrax, actinomycois, trench mouth, ratbite fever, listeria & pasturella
Streptococcal infections
Pneumococcal infections
Meningococcal infections
Gonorrhoea
Syphilis
Diptheria
Tetanus
Gas gangrene
Rare infections like leptospirosis, anthrax, actinomycois, trench mouth, ratbite fever, listeria & pasturella

BETA LACTAM ANTIBIOTICS

Antibiotics having beta lactam ring
These include penicillins, cephalosporin, monobactam & carbapenem
Penicillin nucleus consist of fused thiazolidine & beta lactam rings to which side chains are attached through an amide linkage
Penicillin G (PnG) having a benzyl side chain is the original penicillin used clinically
The side chain of natural Pn can be split of by an amidase to produce 6 amino penicillanic acid. Other side chains can be attached to it resulting in different type of semisynthetic Pn
Mechanism of action: Beta lactam antibiotic interfere with the synthesis of bacterial cell wall
Bacterial cell wall is made up of Peptidoglycan
Peptidoglycan is composed of N acetylmuramic acid (NAM) & acetylglucosamine (NAG) which are cross linked with each other
This cross linking occurs with the help of enzyme transpeptidase
Beta lactam antibiotic inhibit the enzyme transpeptidase so that cross linking does not occur
This enzyme transpeptidase & other related proteins constitute the penicillin binding protein
This cross linking occurs with the help of enzyme transpeptidase
Beta lactam antibiotic inhibit the enzyme transpeptidase so that cross linking does not occur
This enzyme transpeptidase & other related proteins constitute the penicillin binding protein
This cross linking occurs with the help of enzyme transpeptidase
Beta lactam antibiotic inhibit the enzyme transpeptidase so that cross linking does not occur
This enzyme transpeptidase & other related proteins constitute the penicillin binding protein
This cross linking occurs with the help of enzyme transpeptidase
Beta lactam antibiotic inhibit the enzyme transpeptidase so that cross linking does not occur
This enzyme transpeptidase & other related proteins constitute the penicillin binding protein

Failure of antimicrobial therapy

Improper selection of drug, dose, route or duration
Lack of adjuvant measures e.g. drainage of abscess, removal of renal stones, other foreign body or infected gall bladder, control of diabetes or adjustment of urinary pH in case of UTI
Late treatment
Poor host defence
Infecting organism present behind barriers

SUPERINFECTIONS

Superinfections refers to appearance of new infections as a result of antimicrobial therapy
Due to alteration in the normal microbial flora
It occurs in immunocompromised host e.g. Corticosteroid therapy, diabetes, Leukemias, malignancies, AIDS
Commonly associated with the use of broad spectrum AMA e.g. Tetracyclines

PREVENTION OF DUG RESISTANCE

No indiscriminate or prolonged use of antibiotic
Prefer rapidly acting & narrow spectrum AMA whenever possible
Use combination of AMA whenever prolonged therapy is undertaken e.g. TB, SABE
Infection by organism notorious for developing resistance e.g. S. aureus, E. coli, M. tuberculosis, Proteus must be treated intensively

NOBEL PRIZE IN THE FIELD OF MALARIA

In 1902, Sir Ronald Ross was awarded Nobel Prize for his pioneer work in the field of Malaria. He discovered that malaria was caused by the bite of female anopheles mosquito. He also discovered various life cycle stages of malaria parasite Plasmodium vivax

NOBEL PRIZE WINNER IN THE FIELD OF TUBERCULOSIS

Robert Koch was awarded Nobel prize in 1905 for his discoveries about tuberculosis

NOBEL PRIZE WINNERS IN FIELD OF CHEMOTHERAPY

Robert Koch was awarded Nobel Prize in Medicine in 1905 for his investigations & discoveries in relation to Tuberculosis

NOBEL PRIZE WINNERS IN MEDICINE

1928: Alexander Fleming noticed that a mould (penicillium notatum) produced a compound that inhibits bacterial growth.

1940: Florey and Chain showed that an injection of extract cured infections in mice and later in humans.

1945: Fleming, Florey and Chain were awarded a Nobel Prize for Medicine.

PROBLEMS ARISING WITH THE USE OF ANTIMICROBIALS

Toxicity A. Local B. Systemic
Hypersensitivity Reactions: It may be in the form of rashes, urticaria, fever, itching, exfoliative dermatitis, angioneurotic edema or rarely anaphylactic shock
Drug resistance: Natural or Acquired
Acquired resistance may be developed by mutation or gene transfer
Mutation is stable and heritable genetic change that occurs spontaneously and randomly among microorganisms

Mutation may be single step or mutistep
Gene transfer: from one organism to other organism occur by
Conjugation
Transduction
Transformation
Resistant organism may be of following types
Drug tolerant means that the organism has altered binding proteins so that an antimicrobial may not reach at the site of action e.g. Methicillin resistant Staphylococcus aureus (MRSA)
Drug destroying means organism is producing some enzyme that inactivate the antibiotic e.g. production of beta lactamases various bacterias
Drug impermeable means that bacteria have altered porin channels through which antibiotic enter into bacterial cell

SOURCES OF ANTIMICROBIALS

Fungi: Pn, Cephalosporin
Bacteria: Polymyxin B, Bacitracin
Actinomycetes: Aminoglycosides, Macrolides

TERMS RELATED TO ANTIMICROBIALS

Broad Spectrum: Agents which are active against more than one group or classes of microbes e.g. Tetracyclines which inhibit both gram positive as well as gram negative bacterias
Narrow Spectrum: Agents which are ative against only one group of microbes e.g. Penicillin G which is active only against gram positive bacteria
Bactericidal: Agents that kill the pathogenic microbes
Bacteriostatic: Agents which only inhibit the pathogenic microbes

MECHANISM OF ACTION

Agents that inhibit synthesis of bacterial cell walls e.g. Penicillins & Cephalosporin
Agents that act directly on the cell membrane of the microorganism, increasing permeability and leading to leakage of intracellular compounds, including detergents such as polymyxin; polyene antifungal agents (e.g., nystatin and amphotericin B) which bind to cell-wall sterols; and the lipopeptide daptomycin
Agents that disrupt function of 30S or 50S ribosomal subunits to reversibly inhibit protein synthesis, which generally are bacteriostatic (e.g., chloramphenicol, the tetracyclines, erythromycin, clindamycin, streptogramins, and linezolid)
Agents that bind to the 30S ribosomal subunit and alter protein synthesis, which generally are bactericidal (e.g., the aminoglycosides)


Agents that affect bacterial nucleic acid metabolism, such as the rifamycins (e.g., rifampin and rifabutin), which inhibit RNA polymerase, and the quinolones, which inhibit topoisomerases
Antimetabolites, including trimethoprim and the sulfonamides, which block essential enzymes of folate metabolism. There are several classes of antiviral agents
nucleic acid analogs, such as acyclovir or ganciclovir, which selectively inhibit viral DNA polymerase, and zidovudine or lamivudine, which inhibit HIV reverse transcriptase
non-nucleoside HIV reverse transcriptase inhibitors, such as nevirapine or efavirenz;
inhibitors of other essential viral enzymes, e.g., inhibitors of HIV protease or influenza neuraminidase;
fusion inhibitors such as enfuvirtide

CHEMICAL CLASSES OF ANTIMICROBIALS

Sulfonamides e.g. Dapsone
Diaminopyrimidines e.g. Trimethoprim
Quinolones e.g. Ciprofloxacin
Beta lactam antibiotic e.g. Penicillins, Cefalosporins
Tetracyclines e.g. Doxycyclines
Nitrobenzene derivative e.g. Chloramphanicol
Aminoglycosides e.g. Gentamycin
Macrolides: Erythromycin
Lincosamide: Clindamycin
Glycopeptide: Vancomycin
Oxazolidinone: Linezolid
Polypeptide : Polymyxin
Nitrofuran: Furazolidone
Nicotinic acid derivative: Isoniazid
Polyene: Nystatin
Azole: Ketoconazole
Others: Rifampin

Ideal Antibiotic

It must be able to reach the part of the human body where the infection is occurring
It should not cause the development of resistant forms of parasites

It should not produce undesirable side effects in the host such as allergic reaction, nerve damage or irritation of the kidneys and gastrointestinal tract


It should be given orally without inactivation by stomach acid, or by injection (parenterally) without binding to the blood proteins

Finally, it should have a high level of solubility in the body fluids and be possible to achieve concentrations in the tissue or blood, which are sufficiently high to inhibit or kill the infectious agent.

Antimicrobial Agents

Antimicrobial agents are among the most commonly used and misused of all drugs.
Antibiotics are antibacterial substances produced by various species of microorganisms (bacteria, fungi, and actinomycetes) that suppress the growth of other microorganisms.
The term Antimicrobial agent (AMA) is used to designate synthetic as well as naturally obtained drugs that attenuate microorganism
Chemotherapy is the treatment of systemic infections with specific drugs that selectively suppress the infecting microorganism without significantly affecting the host
Due to analogy b/w the malignant cell & the pathogenic microbes, T/t of neoplastic diseases with drugs is also called chemotherapy