Immunomodulators

Immunomodulators include both immunosuppressants as well as immunostimulants.
The important group of immunosuppressants are glucocorticoids, calcineurin inhibitors, antiproliferative and antimetabolic agents and antibodies.
Among the group of immunostimulants, the main drugs are Levamisole, thalidomide, BCG vaccine, recombinant cytokines, interferons & interleukin-2.
Clinical role of Immunosuppressants
Glucocorticoids:
1. To prevent and treat transplant rejection
2. autoimmune disorders like rheumatoid and other arthritides, systemic lupus erythematosus, systemic dermatomyositis, psoriasis and other skin conditions
3. Treatment of graft-versus-host disease in bone-marrow transplantation. asthma and other allergic disorders
4. inflammatory bowel disease,
5. inflammatory ophthalmic diseases
6. autoimmune hematologic disorders
7. acute exacerbations of multiple sclerosis
Calcineurin inhibitors
Cyclosporine suppresses some humoral immunity, but is more effective against T-cell-dependent immune mechanisms such as those underlying transplant rejection and some forms of autoimmunity
Therapeutic uses:
1. kidney, liver, heart, and other organ transplantation
2. Rheumatoid arthritis
3. Psoriasis
4. Behcet’s acute ocular syndrome
5. endogenous uveitis,
6. atopic dermatitis,
7. inflammatory bowel disease, and
8. Nephrotic syndrome, when standard therapies have failed
Antiproliferative agents
Sirolimus is an antiproliferative agent.
Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus
Sirolimus inhibits T-lymphocyte activation and proliferation downstream of the IL-2 and other T-cell growth factor receptors
Sirolimus is indicated for prophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and glucocorticoids
Azathioprine is a purine antimetabolites
Azathioprine was first introduced as an immunosuppressive agent in 1961, helping to make allogeneic kidney transplantation possible
Severe rheumatoid arthritis
Other antiproliferative & cytotoxic agents
Many of the cytotoxic and antimetabolic agents used in cancer chemotherapy are immunosuppressive due to their action on lymphocytes and other cells of the immune system. Other cytotoxic drugs that have been used as immunosuppressive agents include methotrexate, cyclophosphamide thalidomide, and chlorambucil
Methotrexate is used for treatment of graft-versus-host disease, rheumatoid arthritis, and psoriasis, as well as in anticancer therapy
Cyclophosphamide and chlorambucil are used in treating childhood nephrotic syndrome and a variety of malignancies

Antibody
Both polyclonal and monoclonal antibodies against lymphocyte cell-surface antigens are widely used for prevention and treatment of organ transplant rejection
The advent of hybridoma technology to produce monoclonal antibodies was a major advance in immunology
Both polyclonal and monoclonal products have a place in immunosuppressive therapy.
The important antibodies which are used in immunosuppression are
Antithymocyte Globulin: used for treatment of acute renal transplant rejection
Anti-CD3 Monoclonal Antibodies: (Muromonab-CD3) is indicated for treatment of acute organ transplant rejection
Anti-TNF Reagents.
Infliximab Infliximab is a chimeric anti-TNF-? monoclonal antibody used in rheumatoid arthritis

Immunostimulants:
Levamisole. Levamisole was synthesized originally as an anthelmintic but appears to “restore” depressed immune function of B lymphocytes, T lymphocytes, monocytes, and macrophages.
Its only clinical indication is as adjuvant therapy with 5-fluorouracil after surgical resection in patients with Dukes’ stage C colon cancer where it occasionally has been associated with fatal agranulocytosis

Thalidomide. Thalidomide is best known for the severe, life-threatening birth defects it caused when administered to pregnant women
Thalidomide should never be taken by women who are pregnant or who could become pregnant while taking the drug.
Nevertheless, it is indicated for the treatment of patients with erythema nodosum leprosum and also is used in conditions such as multiple myeloma.
Its mechanism of action is unclear
Alternatively, it has been suggested that the drug affects angiogenesis
The anti-TNF-? effect has led to its evaluation as a treatment for severe, refractory rheumatoid arthritis

Bacillus Calmette-Guerin (BCG)
It is live attenuated vaccine for tuberculosis.
By unclear mechanisms, this preparation is active against tumors and is indicated for treatment and prophylaxis of carcinoma in situ of the urinary bladder
Interferons.Although interferons (alpha, beta, and gamma) initially were identified by their antiviral activity, these agents also have important immunomodulatory activities
Interleukin-2: Human recombinant interleukin-2 (aldesleukin) is indicated for the treatment of adults with metastatic renal cell carcinoma and melanoma
(Reference: Goodman & Gillman’s, The Pharmacological Basis of Therapeutics 11th edition)

Drugs used in epilepsy

Antiepileptic drugs are
Hydantoin e.g. Phenytoin
Iminostilbene e.g. Carbamazepine
Aliphatic carboxylic acide e.g. Valproate
Barbiturates e.g. Phenobarbitone
Deoxybarbiturates e.g. Primidone
Succinimide e.g. Ethosuximide
Benzodiazepines e.g. Clonazepam, Diazepam, Lorazepam
Phenyltriazine e.g. Lamotrigene
GABA analogue e.g. Gabapentin
Newer drugs e.g. Vigabatrin, Levetiracetam, Topiramate, Tiagabine

Antidepressant drugs

I. Tricyclic antidepressants :
A. Predominately Noradrenaline reuptake inhibitor : Desipramine, Nortriptyline
B. Noradrenaline + Serotonin reuptake inhibitor : Imipramine, Amitryptyline, Doxepin, Clomipramine
II. Selective serotonin reuptake inhibitor (SSRI) : Fluoxetine, Fluvoxamine, Sertraline, Citalopram, Paroxetine
III. Atypical antidepressants: Trazodone, Mianserin, Venlafaxine, Bupropion
IV. Reversible inhibitor of MAO-A (mono amine oxidase A): Clorgyline, Moclobemide

Osteoporosis

Osteoporosis, which comes from Greek meaning porous bone, is a condition or disease process that is marked by structural deterioration of bone tissue and low bone mass. Low bone mass can lead to bone fragility and increase risk of fractures
Clinical Features
a "silent disease" (i.e., there are frequently no symptoms) until a fracture has occurred. As the disease progresses, symptoms may include
back pain,
fractures,
loss of height,
skeletal deformity (kyphosis or kyphoscoliosis),
neck strain (due to an exaggerated cervical lordosis),
midabdominal pain (caused from the ribs resting on the iliac crest),
alterations in bowel function,
Risk factors
Postmenopausal women
Elderly age
Personal Medical History and Family History
Hormonal abnormalities, such as hyperthyroidism, and hyperparathyroidism can impair the bone-making process
Individuals with a history of neoplastic disorders, such as multiple myeloma,
Nutritional deficiencies,inadequate calcium or vitamin D intake,
Lifestyle Factors
Pharmacologic Risk Factors
Phenytoin sodium (Dilantin)
Glucocorticoids
Medroxyprogesterone acetate (Depo-Provera)
Nonpharmacologic Interventions

Lifestyle modification
Weight-bearing exercises
Nutrition

Pharmacological interventions
hormone replacement therapy
bisphosphonates,
calcitonin,
selective estrogen receptor modulators,
fluoride supplementation

ERT/HRT
ERT/HRT has been shown to prevent osteoporosis by decreasing the bone loss that is common after menopause,
new studies have indicated that although ERT/HRT may prevent bone loss, there is no concrete evidence to support its use as a treatment modality because of unacceptable increased incidence of breast cancer noted in the women who used HRT
women with osteoporosis, other pharmacologic interventions may be preferred
Bisphosphonates
Alendronate,Etidronate,Pamidronate

Mechanism of action:
Inhibits bone resorption by binding to hydroxyapatite crystals
Accelerated apoptosis of osteoclasts
Disruption of cytoskeleton and ruffled border of osteoclasts
Inhibits osteoclasts differentiation by suppressing IL-6

Precaution needed with BPN Prevent conatct with oesophageal mucosa

Second/third generation BPN Zolendronate,Risedronate

Enfavirtide

It is fusion inhibitor, used in HIV.
It is an antiretroviral drug(for HIV/HTLV-3 virus)
It act by binding to HIV-1 envelope glycoprotein (gp41) & prevent the fusion of viral & cellular membranes.
Entry of virus into cell is blocked.
It is not active against HIV-2.
It is given by s.c. route
It is used as add on drug.

Selective estrogen receptor modulators (SERM)

Nonsteroidal synthetic agents
Selective estrogen receptor modulators, which are sometimes referred to as partial estrogen agonist/antagonists
Modulates activity of estrogen receptors
Unique profile of aginistic/antagonistic actions(agonist in bone and CVS but antagonist in endometrium and breast)
statistically significant improvement in bone mineral density
extreme caution for perimenopausal because the drug is contraindicated in pregnancy

good choice of therapy for women with a history of breast or uterine cancer or for women with concerns about taking estrogen
Adverse effects are vasomotor symptoms
Other side effects of leg cramps and venous thrombohemolytic events have been reported.
It may also be a better choice of therapy for women with severe gastrointestinal symptoms and for those who have difficulty tolerating the bisphosphonates.

New emerging therapies of osteoporosis

Statins:
great interest in actions of statins unrelated to their main effect of lowering LDL
Promotes osteoclasts apoptosis
Increase osteoblast activity
Increase gene expression for BMP-2
r-PTH(recombinant PTH Teriparatide)
PTH in low and intermittent doses increase bone formation without stimulating bone resorption
Subcutaneous route 25 mg/day

Cephalosporins

The first-generation cephalosporins, epitomized by cephalothin and cefazolin, have good activity against gram-positive bacteria and relatively modest activity against gram-negative microorganisms.
The second-generation cephalosporins have somewhat increased activity against gram-negative microorganisms but are much less active than the third-generation agents
Third-generation cephalosporins generally are less active than first-generation agents against gram-positive cocci, but they are much more active against the Enterobacteriaceae, including b-lactamase-producing strains
Fourth-generation cephalosporins, such as cefepime, have an extended spectrum of activity compared with the third generation and have increased stability from hydrolysis by plasmid and chromosomally mediated b-lactamases
The first-generation cephalosporins are excellent agents for skin and soft tissue infections owing to S. aureus and S. pyogenes
The second-generation cephalosporins generally have been displaced by third-generation agents. They have inferior activity against penicillin-resistant S. pneumoniae compared with either the third-generation agents or ampicillin and therefore should not be used for empirical treatment of meningitis or pneumonia. The oral second-generation cephalosporins can be used to treat respiratory tract infections
The third-generation cephalosporins, with or without aminoglycosides, have been considered to be the drugs of choice for serious infections caused by Klebsiella, Enterobacter, Proteus, Providencia, Serratia, and Haemophilus spp
The fourth-generation cephalosporins are indicated for the empirical treatment of nosocomial infections where antibiotic resistance owing to extended-spectrum b-lactamases or chromosomally induced b-lactamases are anticipated.

Patient-Controlled Analgesia (PCA)

With this modality, the patient has limited control of the dosing of opioid from an infusion pump within tightly mandated parameters.
PCA can be used for intravenous or epidural infusion.
This technique avoids any delays in administration and permits greater dosing flexibility than other regimens, better adapting to individual differences in responsiveness to pain and to opioids.
It also gives the patient a greater sense of control.
With shorter-acting opioids, serious toxicity or excessive use rarely occurs.
An early concern that self-administration of opioids would increase the probability of addiction has not materialized.
PCA is suitable for adults and children, and it is preferred over intramuscular injections for postoperative pain control

Hematological Toxicity of Chloramphanicol

Dr. Ahmad Najmi, Index Medical College, Indore
The most important adverse effect of chloramphenicol is on the bone marrow. Chloramphenicol affects the hematopoietic system in two ways: a dose-related toxicity that presents as anemia, leukopenia, or thrombocytopenia; and an idiosyncratic response manifested by aplastic anemia, leading in many cases to fatal pancytopenia.
Pancytopenia seems to occur more commonly in individuals who undergo prolonged therapy and especially in those who are exposed to the drug on more than one occasion.
A genetic predisposition is suggested by the occurrence of pancytopenia in identical twins. Although the incidence of the reaction is low¾1 in approximately 30,000 or more courses of therapy¾the fatality rate is high when bone-marrow aplasia is complete, and there is an increased incidence of acute leukemia in those who recover.
Aplastic anemia accounts for approximately 70% of cases of blood dyscrasias due to chloramphenicol, while hypoplastic anemia, agranulocytosis, and thrombocytopenia make up the remainder.
The exact biochemical mechanism has not yet been elucidated but is hypothesized to involve conversion of the nitro group to a toxic intermediate by intestinal bacteria.

The risk of aplastic anemia does not contraindicate the use of chloramphenicol in situations in which it may be life-saving. The drug should never be used, however, in undefined situations or in diseases readily, safely, and effectively treatable with other antimicrobial agents.

Dose-related, reversible erythroid suppression probably reflects an inhibitory action of chloramphenicol on mitochondrial protein synthesis in erythroid precursors, which in turn impairs iron incorporation into heme.
Leukopenia and thrombocytopenia also may occur. Bone marrow suppression occurs regularly when plasma concentrations are 25 mg/ml or higher and is observed with the use of large doses of chloramphenicol, prolonged treatment, or both. Dose-related suppression of the bone marrow may progress to fatal aplasia if treatment is continued, but most cases of bone marrow aplasia develop suddenly, without prior dose-related marrow suppression.
Some patients who developed chronic bone marrow hypoplasia after chloramphenicol treatment subsequently developed acute myeloblastic leukemia.

The administration of chloramphenicol in the presence of hepatic disease frequently depresses erythropoiesis. About one-third of patients with severe renal insufficiency exhibit the same reaction.
Reference: Goodman & Gillmans Pharmacological Basis of Therapeutics , 11th edition

Daptomycin

By Dr. Ahmad Najmi, Index Medical College, Indore
Daptomycin is a cyclic lipopeptide antibiotic derived from Streptomyces roseosporus It is bactericidal effective against vancomycin-resistant gram-positive bacteria. Also active against aerobic, facultative, and anaerobic gram-positive bacteria
Daptomycin binds to bacterial membranes resulting in depolarization, loss of membrane potential, and cell death
Daptomycin is poorly absorbed orally and should only be administered intravenously
Daptomycin is indicated for treatment of complicated skin and skin-structure infections caused by methicillin-susceptible and methicillin-resistant strains of S. aureus, hemolytic streptococci, and vancomycin-susceptible E. faecalis
Skeletal muscle damage occurs in dogs given daptomycin at doses above 10 mg/kg. Peripheral neuropathic effects with axonal degeneration occurred at higher doses
Reference: Goodman & Gillmans Pharmacological Basis of Therapeutics, 11th edition

Gray baby syndrome

by Dr. Ahmad Najmi, Index Medical College, Indore
Neonates, especially if premature, may develop a serious illness termed gray baby syndrome if exposed to excessive doses of chloramphenicol
This syndrome usually begins 2 to 9 days (average of 4 days) after treatment is started
Within the first 24 hours, vomiting, refusal to suck, irregular and rapid respiration, abdominal distention, periods of cyanosis, and passage of loose, green stools occur
The children all are severely ill by the end of the first day, and in the next 24 hours turn an ashen-gray color and become flaccid and hypothermic
A similar "gray syndrome" has been reported in adults who were accidentally overdosed with the drug
Death occurs in about 40% of patients within 2 days of initial symptoms.
Those who recover usually exhibit no sequelae.

Two mechanisms apparently are responsible for chloramphenicol toxicity in neonates: (1) a developmental deficiency of glucuronyl transferase, the hepatic enzyme that metabolizes chloramphenicol, in the first 3 to 4 weeks of life; and
(2) inadequate renal excretion of unconjugated drug. At the onset of the clinical syndrome, chloramphenicol concentrations in plasma usually exceed 100 mg/ml, although they may be as low as 75 mg/ml.
Children 2 weeks of age or younger should receive chloramphenicol in a daily dose no larger than 25 mg/kg of body weight; after this age, full-term infants may be given daily quantities up to 50 mg/kg.
Toxic effects have not been observed in the newborns when as much as 1 g of the antibiotic has been given every 2 hours to the mothers during labor.
Chloramphenicol is removed only minimally from the blood by either peritoneal dialysis or traditional hemodialysis.
Thus, exchange transfusion and charcoal hemoperfusion have been used to treat overdose with chloramphenicol in infants
Reference: Goodman & Gillmans Pharmacological Basis of Therapeutics 11th edition

QUINUPRISTIN/DALFOPRISTIN

By Dr. Ahmad Najmi, Index Medical College, Indore
Quinupristin/dalfopristin is a combination of quinupristin, a streptogramin B, with dalfopristin, a streptogramin A, in a 30:70 ratio
These compounds are semisynthetic derivatives of naturally occurring pristinamycins, produced by Streptomyces pristinaespiralis
Quinupristin/dalfopristin is active against gram-positive cocci, including S. pneumoniae, beta- and alpha-hemolytic strains of streptococci, E. faecium (but not E. faecalis), and coagulase-positive and coagulase-negative strains of staphylococci
Quinupristin and dalfopristin are protein synthesis inhibitors that bind the 50S ribosomal subunit
The combination of quinupristin/dalfopristin is administered only by intravenous infusion over at least 1 hour. It is incompatible with saline and heparin and should be dissolved in 5% dextrose in water
Quinupristin/dalfopristin is approved in the United States for treatment of infections caused by vancomycin-resistant strains of E. faecium and complicated skin and skin-structure infections caused by methicillin-susceptible strains of S. aureus or S. pyogenes
Quinupristin/dalfopristin should be reserved for treatment of serious infections caused by multiple-drug-resistant gram-positive organisms such as vancomycin-resistant E. faecium
The most common side effects are infusion-related events, such as pain and phlebitis at the infusion site and arthralgias and myalgias
Quinupristin/dalfopristin inhibits CYP3A4
(Reference Goodman & Gillmans, The Pharmacological Basis of Therapeutics, 11th edition)

Mechanism of resistance in macrolide antibiotics

Resistance to macrolides usually results from one of four mechanisms: (1) drug efflux by an active pump mechanism (encoded by mrsA, mefA, or mefE in staphylococci, group A streptococci, or S. pneumoniae, respectively);
(2) ribosomal protection by inducible or constitutive production of methylase enzymes, mediated by expression of ermA, ermB, and ermC, which modify the ribosomal target and decrease drug binding;
(3) macrolide hydrolysis by esterases produced by Enterobacteriaceae
(4) chromosomal mutations that alter a 50S ribosomal protein (found in B. subtilis, Campylobacter spp., mycobacteria, and gram-positive cocci).

The MLSB (macrolide-lincosamide-streptogramin B) phenotype is conferred by erm genes, which encode methylases that modify the macrolide binding of the ribosome. Because macrolides, lincosamides, and type B streptogramins share the same ribosomal binding site, constitutive expression of erm confers cross-resistance to all three drug classes

KETOLIDES (TELITHROMYCIN)

Ketolides and macrolides have very similar antibacterial properties
Ketolides and macrolides have the same ribosomal target site
The principal difference between the two is that structural modifications within ketolides neutralize the common resistance mechanisms that make macrolides ineffective
Introduction of the 3-keto function converts a methylase-inducing macrolide into a noninducing ketolide
This moiety also prevents drug efflux, probably because it generates a less-desirable substrate

Types of beta lactamase enzyme

Bacteria also can destroy beta-lactam antibiotics enzymatically.
b-Lactamases are capable of inactivating certain of these antibiotics and may be present in large quantities
Different microorganisms elaborate a number of distinct beta-lactamases, although most bacteria produce only one form of the enzyme. The substrate specificities of some of these enzymes are relatively narrow, and these often are described as either penicillinases or cephalosporinases.
Other "extended spectrum" enzymes are less discriminant and can hydrolyze a variety of b-lactam antibiotics.
b-Lactamases are grouped into four classes: A through D.
Class A b-lactamases include the extended-spectrum b-lactamases (ESBLs) and degrade penicillins, some cephalosporins, and, in some instances, carbapenems
Class A and D enzymes are inhibited by the commercially available b-lactamase inhibitors, such as clavulanate and tazobactam
Class B b-lactamases are Zn2+-dependent enzymes that destroy all b-lactams except aztreonam,
class C b-lactamases are active against cephalosporins
Class D includes cloxacillin-degrading enzymes (Bush, 2001)

Adverse effects of morphine (MBBS DAV April 2010 paper)

Dr. Ahmad Najmi, Index Medical College, Indore
Respiratory depression
Nausea & vomiting
Dizziness
Mental clouding
Dysphoria,
Pruritus,
Constipation
Increased pressure in the biliary tract
Urinary retention
Hypotension
Morphine causes histamine release, which can cause bronchoconstriction and vasodilation
Morphine and related opioids must be used cautiously in patients with compromised respiratory function
Anaphylactoid reactions

Drugs for acne vulgaris

Acne vulgaris is a self-limited disorder primarily of teenagers and young adults. It occurs due to increase in sebum production by sebaceous glands after puberty. Small cysts, called comedones , form in hair follicles due to blockage of the follicular orifice by retention of keratinous material and sebum. The activity of bacteria (Proprionobacterium acnes) within the comedones releases free fatty acids from sebum, causes inflammation within the cyst.
The drugs can be given by either topical route or by systemic route
Topical therapy includes Benzyl benzoate, retinoic acid, Adapalene, topical antibiotics & azelaic acid
Benzyl benzoate:
It gradually liberate oxygen which kills bacteria
Keratolytic
Comedolytic
Induce mild desquamation
Adverse effects: Burning & stinging sensation, dryness of skin, scaling, erythema etc
Avoid contact with eyes, lips & mucous membranes
It is used in the form of cream, gel or lotion
Retinoic acid:
Comedolytic
Keratolytic
epidermal cell turn over is stimulated resulted in peeling
response is delayed
Adverse effects are warmth, stinging, redness, crusting & edema
used in form of cream or gel
It is teratogenic, so should be avoided during pregnancy
retinoic acid & benzoyl peroxide should not be applied together because benzyl peroxide promote degradation of retinoic acid

Adapalene: It is newer synthetic tretinoin like drug
It act by binding to nuclear retinoic acid receptor
Comedolytic
Keratolytic
Antiinflammatory
less irritating as compared to tretinoin
can be combined along with benzyl peroxide

Topical Antibiotics: Clindamycin, erythromycin & tetracyclines can be used topically in the form of cream, gel or lotion. Nadifloxacin is a newer topical quinolone broad spectrum antibiotic which can be used in inflammed acne & folliculitis
Azelaic acid:
Natural product from Pityorosporum ovale
Many Aerobic, anaerobic organism & P. acnes are inhibited
reduces bacterial density
reduces free fatty acid content of skin
reduces proliferation of keratinocytes
used in the form of cream
response is delayed
also used in melasma

Systemic therapy:
Indicated in severe cases with cyst & pustules
Antibiotics: Tetracycline, doxycyclines, Minocyclines & erythromycin are used
Isotretinoin or cis retinoic acid:
It is an orally administered retinoid
decrease production of sebum
correct abnormal keratinization
Adverse effects are dryness of skin, eyes, nose , mouth, chelitis, epistaxis, pruritus, rise in serum lipids & intracranial tension.
It is highly teratogenic, strictly contraindicated during pregnancy & one month after

Unwanted effects and pharmacokinetics of local anaesthetics (LAs)

LAs are either esters or amides. Esters are rapidly hydrolysed by plasma cholinesterase, and amides are metabolised in the liver. Plasma half-lives are generally short, about 1-2 hours.
Unwanted effects result mainly from escape of LAs into systemic circulation.
Main unwanted effects are:
CNS effects, agitation, confusion, tremors progressing to convulsions and respiratory depression
cardiovascular effects, namely myocardial depression and vasodilatation, leading to fall in blood pressure
occasional hypersensitivity reactions.
LAs vary in the rapidity with which they penetrate tissues, and in their duration of action. Lidocaine penetrates tissues readily and is suitable for surface application; bupivacaine has a particularly long duration of action.

Mechanism of action of local anaesthetics

Action of local anaesthetics (LAs)
LAs block action potential generation by blocking sodium channels.
LAs are amphiphilic molecules, with a hydrophobic aromatic group and a basic amine group.
LAs probably act in their cationic form but must reach their site of action by penetrating the nerve sheath and axonal membrane as unionised species; they, therefore, have to be weak bases.
Many LAs show use-dependence (depth of block increases with action potential frequency). This arises:
because anaesthetic molecules gain access to the channel more readily when the channel is open
because anaesthetic molecules have higher affinity for inactivated than for resting channels.
Use-dependence is mainly of importance in relation to antidysrhythmic and antiepileptic effects of sodium channel blockers.
LAs block conduction in the following order: small myelinated axons, non-myelinated axons, large myelinated axons. Nociceptive and sympathetic transmission is thus blocked first.

Therapeutic uses of NSAIDS

As an analgesic
As antipyretic
As an anti-inflammatory
Rheumatic fever
Prophylaxis & treatment of MI & DVT
PDA
Bartters syndrome
High risk pregnancy to reduce the risk of preeclampsia & PIH
Prophylaxis of Ca colon & rectum
Radiation induced diarrhoea
Niacin induced flushing
ACEI induced cough
Systemic mastocytosis
Hypercalcemia of some tumours
Alzheimers disease

Selective COX 2 Inhibitors

Parecoxib, Rofecoxib, Celecoxib, Valdecoxib
They do not depress TXA 2 production by platelets (COXI dependent), but reduce PGI2 production by vascular endothelium (COX2 dependant)
Only in patients at high risk of peptic ulcer, perforation or bleeds
They should be given in lowest dose for shortest period of time
Avoided in patients of cardiovascular risk factors

What is centchroman / Saheli ?

Dr. Ahmad Najmi, Index Medical College, Indore
•Non-steroidal oral contraceptive (CDRI, Lucknow)
•Oestrogen antagonist
•Anti-implantation agent
•Safer free from OCS side effects; menstrual cycle not disturbed – may be lengthened in 6-10% women
•For all age group of women
•Failure rate: 1 – 3 %
•Side effects: enlargement of ovary
•C/I: polycystic ovarian disease, cervical hyperplasia,

renal or hepatic disease, tuberculosis & lactating mother
•Dose: 30mg tablet twice a week; 30mg once a week till needed

Dr. Ahmad Najmi, Index Medical College, Indore

What is the mechanism of action of oral contraceptive pills ?

1. Decrease Gonadotropin release from pituitary leading to absence of FSH & LH peaks

2. Decrease Follicular development & ovulation

3. Thick cervical mucus hostile to sperms

4. Decrease Implantation of blastocyst in endometrium

5. Contractions of uterus & Fallopian tubes are modified

Dr. Ahmad Najmi, Index Medical College, Indore

Types of OCP's

Types of methods
A-Oral
1-Combined pill-contain estrogen(ethinyl estradiol) and progestin(norgestrel)

2-Sequential pill-
3-Phased regime-initial phase(proliferative) estrogen

then in secretory(luteal) phaseesrtrogen plus progesterone-recommended for women over 35 years age

4-Mini pill-progesterone only pill-where estrogen is contraindicted

5-Post-coital pill-emergency pill-

1-levonorgestrel plus ethinyl estradiol

2 tablets within 72 hour of unprotected intercourse

2-levonorgestrel alone 2 tablets within 72 hours

3-mifepristone alone within 72 hours
B-Injectable

1-Long acting
a-progest. alone-DMPA-150 mg at 3 monthly interawal

b-Norethindrone enanthate-200mg-at 2 months interwa

2-Long acting
progest. + Oestrog.
C-Implants:
Norplant-levonorgestrel 6 capsules subcutaneous

Dr. Ahmad Najmi, Index Medical College, Indore

Adverse effects of OCP"s

Most serious:
A-CVS side effects:
1-Thrmobophlebitis (due to O & P)
2-Thromboembolism ( due to oestrogen)
3-Hypertension
4-Cerebral & coronary thrombosis
5-Increased incidence of M.I. and stroke

B-Cancer: Ca. breast, vagina and cervix ?
Benign hepatoma:
Gall stones: biliary cholesterol secretion
C-Less serious:
Weight. gain
Pigmentation of cheeks, nose and forehood
Pruritus vulvae
Diabetes,
Mood swings, abdominal discomfort
D-Non- serious:
Nausea, vomiting
Breakthrough bleeding
Breast discomfort
Suppression of lactation (very rare)
(Dr. Ahmad Najmi, Index Medical College, Indore)

Benefits of OCP's other than contraception

Dr. Ahmad Najmi, Index Medical College, Indore
There is reduced risk of :

* Ovarian cysts

* Ovarian & endometrial cancer

* Benign breast diseases

* Lower incidence of ectopic pregnancy

There is less common chances of

* iron deficiency
* rheumatoid arthritis
* Pre-menstrual tension
* Dysmenorrhea
* Endometriosis
* Acne
* Hirsutism

Sildenafil

(By Dr. Ahmad Najmi, Index Medical College, Indore)


1.It is used in erectile dysfunction
2. Inhibits (phosphodiesterase -5 ) PDE5 in the corpus cavernosa of the penis, thus increasing the level of c-AMP
3. 50mg, per orally 1 h before sexual activity
4. potentiate nitrate’s hypotension activity
5. ketoconazole & erythromycin increases its level
6. renal & hepatic disease increases its level
7. Side effects:

headache, flushing, dyspepsia, myalgia

Therapeutic uses of testosterone

(By Dr. Ahmad Najmi, Index Medical College, Indore)

1. Testicular failure: Primary & Secondary
2.Osteoporosis
3. Burns
4. Chronic illness
5. Long term corticosteroid therapy
6. Pituitary dwarfism
7. Carcinoma of breast
8. Hereditary angioneurotic oedema
9. Anaemia (refractory)
10. Menopausal syndrome

Why Linezolid Should not be used with tyramine containing food like cheese etc ?

Linezolid belongs to glycopeptide group of antibiotics. It is available for the treatment of VRSA, VRE & many other resistant type of organisms. Because linezolid inhibit the enzyme monoamine oxidase (MAOI), interaction with adrenergic, serotonergic & tyramine containing food may occur.

By Dr. Ahmad Najmi, Asst. prof. Index Medical College, Indore

Mneumonics- Antiarrythmic drugs classification-MBA College

In order of class I to IV:
Membrane stabilizers (class I)
Beta blockers(Class11)
Action potential widening agents(Class 111)
Calcium channel blockers (IV)
By Dr. Ahmad Najmi, IMCHRC, Indore

Mnemonics

Hepatic necrosis: drugs causing focal to massive necrosis
“Very Angry Hepatocytes”:
Valproic acid
Acetaminophen
Halothane
Adrenoceptors: vasomotor function of alpha vs. beta
ABCD:
Alpha = Constrict.
Beta = Dilate.
Amiodarone: action, side effects
6 P’s:
Prolongs action potential duration
Photosensitivity
Pigmentation of skin
Peripheral neuropathy
Pulmonary alveolitis and fibrosis
Peripheral conversion of T4 to T3 is inhibited -> hypothyroidism
Antiarrhythmics: class III members
BIAS:
Bretylium
Ibutilide
Amiodarone
Sotalol
By Dr. Ahmad Najmi,Asst. prof., Index Medical College, Indore

Ivabradine

(By Dr. Ahmad Najmi, Index Medical College, Indore)
It is new drug for the treatment of chronic angina which is resistant to conventional drugs.
It reduce cardiac work load by selectively reducing heart rate.
It is selective sinus node channel inhibitor.
It has got no negative inotropic effect

WHO analgesic ladder

By Dr. Ahmad Najmi, Index Medical College, Indore)
WHO has formulated certain guidelines for the use of analgesic drugs in various painful conditions. These guidelines are known as WHO analgesic ladder. According to these guidelines :
1. For mild degree pain, simple nonopioid analgesic drugs like paracetamol or acetamenophen should be used
2. For moderate degree of pain weak opioid analgesic like codeine should be used with or without NSAIDS
3. For severe degree of pain, strong opioid should be used for e.g. morphine with or without non opioids

Actions of Morphine

(By Dr. Ahmad Najmi, Index Medical College, Indore)
The main pharmacological effects are:

* analgesia

* euphoria and sedation

* respiratory depression-can lead to respiratory failure-apnoea.
* suppression of cough-is used as cough suppressent

* nausea and vomiting-Due to CTZ stimulation

* pupillary constriction-pinpoint pupil

* reduced gastrointestinal motility, causing constipation

* histamine release, causing bronchoconstriction-contraindicated in astmatics and hypotension.

* The most troublesome unwanted effects are constipation and respiratory depression.

* Morphine may be given by injection (intravenous or intramuscular) or by mouth, often as slow-release tablets.

* Acute overdosage with morphine produces coma and respiratory depression.- is treated by naloxone- antidote

* Morphine is metabolised to morphine 6-glucuronide (M6G), which is more potent as an analgesic.

* Morphine and M6G, are the active metabolites of diamorphine and codein

Explain why morphine is contraindicated in head injury ?

Head injury is a traumatic , painful condition requiring analgesic.

Morphine in opoid analgesic.

1-It depresses respiratory drive.slowing of respiration leads to retention of co2

which will lead to increased intracranial tension.Head injury itself increases intracranial tension.

2-Raised intracranial tension leads to vomiting. Morphine also stimulates CTZ , LEADING TO nausea and vomiting.

3–Head injury assessment is done by pupillary constriction /dilataion.

Morphiune interferes wih this assessment/prognosis because it causes pupillary miosis- constriction of pupil.

Adverse Drug Reaction

According to WHO, response to a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function
excludes therapeutic failures, overdose, drug abuse, noncompliance, and medication errors
Adverse drug effects are classified on the basis of type, severity & onset
According to onset they are classified into
Onset of event:
Acute
within 60 minutes
Sub-acute
1 to 24 hours
Latent
> 2 days


According to severity
Severity of reaction:
Mild
bothersome but requires no change in therapy
Moderate
requires change in therapy, additional treatment, hospitalization
Severe
disabling or life-threatening
FDA Serious ADR
Result in death
Life-threatening
Require hospitalization
Prolong hospitalization
Cause disability
Cause congenital anomalies
Require intervention to prevent permanent injury
According to type

Type A
extension of pharmacologic effect
often predictable and dose dependent
responsible for at least two-thirds of ADRs
e.g., propranolol and heart block, anticholinergics and dry mouth

Type B
idiosyncratic or immunologic reactions
rare and unpredictable
e.g., chloramphenicol and aplastic anemia

Type C
associated with long-term use
involves dose accumulation
e.g., phenacetin and interstitial nephritis or antimalarials and ocular toxicity

Type D
delayed effects (dose independent)
Carcinogenicity (e.g., immunosuppressants)
Teratogenicity (e.g., fetal hydantoin syndrome)

Types of allergic reactions
Type I – immediate, anaphylactic (IgE)
e.g., anaphylaxis with penicillins
Type II – cytotoxic antibody (IgG, IgM)
e.g., methyldopa and hemolytic anemia
Type III – serum sickness (IgG, IgM)
antigen-antibody complex
e.g., procainamide-induced lupus
Type IV – delayed hypersensitivity (T cell)
e.g., contact dermatitis

Common causes of ADR
Antibiotics
Antineoplastics*
Anticoagulants
Cardiovascular drugs*
Hypoglycemics
Antihypertensives
NSAID/Analgesics
Diagnostic agents
CNS drugs*
*account for 69% of fatal ADRs

By Dr. Ahmad Najmi

Define briefly drug antagonism ?

(By Dr. Ahmad Najmi, Index Medical College, Indore)
When one drug decrease the action of another drug, they are k/a antagonist.Depending on mechanism involved antagonism may be
1. Physical e.g. charcoal adsorb alkaloids
2. Chemical e.g. Chelating agents complex toxic metals
3. Physiological e.g. Glucagon & insulin on blood sugar
4. Receptor is further divided into competetive & noncompetetive
In competetive type of antagonism, antagonist is chemically similar to agonist & bind to the same site.
In noncompetetive type of antagonism, the antagonist is chemically unrelated to the agonist, bind to a different allosteric site.

Antiandrogens

Danazol
Cyproterone acetate
Flutamide
Finasteride

Finasteride

5-alpha reductase inhibitor

Orally active
used in BPH
Dose 5 mg/day
Decrease prostate volume
Decrease symptom score
Decrease DHT level in prostate
Also used for androgenic alopecia
ADR: loss of libido & impotense in 5 % patients

Adverse effects of corticosteroids

Iatrogenic Cushing’s syndrome
Hyperglycaemia, glycosuria, diabetes
Myopathy (negative nitrogen balance)
Osteoporosis (vertebral compression fracture)
Retardation of growth (children)
Hypertension, oedema,CCF
Avascular necrosis of femur
HPA axis suppression
Behavioral toxicity: Euphoria, psychomotor reactions, suicidal tendency
Ocular toxicity: steroid induced glaucoma,posterior subcapsular cataract.
Others:
Superinfections
Delayed wound healing
Steroid arthropathy
Peptic ulcer
Live vaccines are dangerous
By Dr. Ahmad Najmi, Index Medical College, Indore

Contraindications of corticosteroids

Infections
Hypertension with CCF
Psychosis
Peptic ulcer
Diabetes mellitus
Osteoporosis
Glaucoma
Pregnancy : (prednisolone preferred)

Therapeutic uses of corticosteroids

(By Dr. Ahmad Najmi, Index Medical College, Indore)

1. Endocrine Disorders
Acute adrenal insufficiency
Primary adrenocortical insufficiency
Ad. Insufficiency second. to Ant. Pituitary
Congenital adrenal hyperplasia
2. Rheumatic carditis
Not responding to salicylates
Severely ill pts.
Prednisolone 40mg in divided doses
Salicylates given concurrently to prevent reactivation
3. Arthritis
Not the drug of first choice
Prednisolone 5 or 7.5 mg
Intra-articular injection
4. Renal diseases (Nephrotic syndrome)
Prednisolone 60 mg in divided doses for 3 – 4 weeks
If remission occurs continue for 1 year
Do not modify the course of disease; Some may benefit
5. Collagen diseases
DLE, pemphigus vulgaris, polyarteritis nodosa
Defect in connective tissue proteins in joints, various organs and deeper layer of skin
6. Allergic diseases
Anaphylactic shock, blood transfusion reaction, hay fever
Prednisolone (short course)
7. Bronchial asthma
Not routinely used except in Status asthmaticus
Methyl prednisolone sodium i.v. given followed by oral prednisolone
Inhaled steroids (Minimal HPA axis suppression
8. Ocular diseases
Outer eye & anterior segment: local application
Posterior segment: systemic use
Caution: bacterial, viral & fungal conjunctivitis
9. Dermatological conditions
Pempigus: Life saving therapy is steroids
Eczema, dermatitis & psoriasis: respond well
10. . Diseases of intestinal Tract
Ulcerative colitis: cortisol retention enema
11. Cerebral oedema
Questionable value in cerebral oedema following trauma, cerebrovascular oedema
Valuable in oedema associated with neoplasm and parasites
13. Malignancy
Part of multi drug regimens for acute lymphatic leukaemia (children), chronic lymphatic leukaemia (adult)

Prednisolone 1mg/Kg start; gradually reduce the dose

Guidelines for topical steroids

Penetration differs at different sites:
High: axilla, groin, face, scalp, scrotum
Medium: limbs, trunk
Low: palm, sole, elbow, knee
Occlusive dressing enhance absorption (10 fold)
Absorption is greater in infants & Children
Absorption depends on nature of lesion:
High: atopic & exfoliative dermatitis
Low: hyperkeratinized & plaque forming lesions
More than 3 applications a day is not needed
Choice of vehicle is important
Lotions & creams: for exudative lesions
Sprays & gels: for hairy regions
Ointments: for chronic scaly lesions
(By Dr. Ahmad Najmi, Index Medical College, Indore)