antibiotics, analgesic,anti-inflammatory drugs

Padmashree Dr. D.Y.Patil College of Ayurveda

& Research Institute.

Shalya Tantra Department

Presented By: Vaibhav Revnath Devkar.

Antibiotics, Analgesic and Anti-inflammatory.

Brief history

Erlich: formulate the hypothesis of selective toxicity for drugs against bacteria

1909 - Salvarsane for syphilis treatment (arsenic compound)

1928- Fleming descovered penicillin

1940 - Florey and Chain – industrial production of penicillin

The photo (courtesy of Merck & Co., Inc.) shows how the growth of bacteria on the agar in a culture dish has been inhibited by the three circular colonies of the fungus Penicillium notatum.

The antibiotic penicillin, diffusing outward from the colonies, is responsible for this effect. Today, penicillin is made from cultures of Penicillium chrysogenum that has been specially adapted for high yields.


Definitions

An antibiotic is a substance produced by a microorganism, which, in minute amounts, is able to inhibit other microorganisms. Therefore, this term is properly applied only to compounds directly derived from microorganisms.

An antibacterial agent is any compound – natural, synthetic or semisynthetic – that is clinically useful in the treatment of bacterial infections.

Bacteriostatic vs. bactericidal

Bacteriostatic agents (ex. sulfonamides, chloramphenicol) inhibit bacterial growth.

Bactericidal agents (ex. penicillin, streptomycin) significantly reduce (99.9%) the number of viable bacteria in the culture (killing effect).

Bactericidal effect in vivo is obtained in cooperation with host’s defense mecha-nisms.

Narrow versus broad spectrum

Narrow spectrum antibacterial agents are preferentially active against either gram-negative or gram-positive bacteria.

Broad-spectrum antibacterial agents are active against both gram-positive and gram-negative bacteria.

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Concentration versus time dependent antibacterial agents

Concentration dependent antibacterial agents – the antibacterial effect depends on the achievement of high concentra-tions;


It doesn’t matter for how long this concentration lasts (e.g., gentamycin).

Time dependent antibacterial agents – the antibacterial effect depends on the achievement of active concentrations according with period of time when active concentration > MIC (minimum inhibitory concentration);

the raise of the dose doesn’t improve the antibacterial effect (e.g., beta-lactam antibiotics).

Qualities of the ideal antimicrobial drug

ü selective toxicity;

ü broad antimicrobial spectrum;

ü good diffusion in the tissues;

ü good persistence in active form;

ü it should not produce hypersensitivity reactions (allergy or anaphylactic shock*);

ü bacteria should not develop resistance;

ü cheap.

Skin test (+), and an anaphylactic reaction (dyspnea, hypotension, urticaria)


General criteria for effective antibiotic activity

1. Microorganism2. Antibacterial agent3. Host

1.Microorganism

An unique and vital target (specific protein or nucleic acid), that is susceptible to low concentration of the antibacterial agent, must exist in the organism;

this target must be sufficiently different from the host’s target in order to minimize side effects (ex. peptidoglycan).

2.Antibacterial agent

The antibacterial agent must be able to penetrate the bacterial surface and reach the target in its active form.

The antibacterial agent needs to reach the infected tissue. (e.g., the treatment of bacterial meningitis is difficult because many common antibacterial agents do not effectively cross the blood-brain barrier).

Infections with intracellular organisms or facultative intracellular organisms are difficult to be treated because many antibacterial agents do not diffuse well into mammalian cells.

Tetracyclines, however, are usually effective against intracellular bacteria.

3.Host

Intact immune system.


The immune system of the host must be able to collaborate effectively in the fight against the invading organism.

The integrity of the phagocytes is particularly important.

Bacterial infections are difficult to be treated in neutropenic patients and in those with primary or secondary immune-deficiencies.

Host - Irrigation and drainage.

Impaired blood supply or drainage of the infected area usually diminishes the efficiency of the antibacterial therapy.

Bacterial endocarditis, osteomyelitis, and abscesses are associated with minimal irrigation of the infected tissue.

Bronchiectasia (lung disease), kidney stones, and gallbladder stones impair drainage of bronchial secretions, urine and bile, respectively;

this may be the cause to extremely difficult to treat bacterial infections, unless the obstruction or anatomical abnormality is surgically removed.


Principles of effective antibacterial therapy

Selective use .

Antibacterial treatment should be given only when necessary, for the treatment of confirmed bacterial infections.

The empirical use of broad-spectrum antibiotics increases, by selection, the prevalence of bacteria resistant to several antibiotics.

Collection of clinical specimens useful for the identification of the etiological agent ALWAYS before the start of the antibacterial therapy.

(Culture)

Criteria for the choice of the antibacterial agent:

Clinical criteria: e.g., scarlet fever, erysipelas, are produced only by Streptococcus pyogenes that remains sensitive to penicillin.

Epidemiological criteria, showing the prevalence of resistant strains among bacteria isolated in that specific area.

Bacteriological criteria:

e.g., microscopic examination, antigenic detection (immediate results) offer some indication (Gram positive cocci, etc)

Susceptibility tests (results in 48 hours from the collection of the specimen).


Other criteria:

The site of infection (the drug has to realize active concentrations in the site of infection);

According to the patient: age, pregnancy and immune-depression.

Early treatment: when antibacterial therapy is indeed necessary, it should be promptly initiated.

Administration: dose, way, duration.

Inadequate use of antibacterial (e.g., doses that are too low; therapy is ended prematurely) is a major factor for the selection of resistant strains.

Special situations:

Infections in poorly irrigated tissues should be treated with bactericidal antibacterial agents.

When abscesses have formed or the infection is associated with obstruction or foreign bodies, surgery is essential to correct the conditions that promote bacterial survival.


CLASSIFICATION

Antibiotics mainly effective against gram-positive bacteria:

For systemic infections-Penicillins, macrolides, vancomycin, lincomycin.

For topical use-eg. Bacitracin.

Antibiotics mainly effective against gram negative bacteria:

For systemic infections-Streptomycin and other amino glycosides

For local use in intestines eg.Neomycin.

Antibiotics mainly effective against both gram-positive and gram negative bacteria:

For systemic infections-amoxycillin, ampicillin, cephalosporin, carbencillin, rifamycins.

For topical use –Neomycin

Antibiotics mainly effective against acid fast bacilli:

Streptomycin and other amino glycosides, rifamycin. viomycin and Quinolones.

Antibiotics mainly effective against fungi:

Amphotericin-B, Griseofluvin


CLASSIFICATION

A.Antibacterial agents that inhibit the cell wall synthesis

B.Antibacterial agents that alter the function of the cytoplasmic membrane

C. Antibacterial agents that inhibit the protein synthesis

D.Antibacterial that inhibit the nucleic acid synthesis


A) Antibacterial agents that inhibit the cell wall synthesis

Beta-lactam antibacterial agents

Glycopeptides

Phosphomycine

Cicloserine

Bacitracine

Penicillins

Cephalosporines

Carbapenemes

Monobactam


Penicillins

penicillins are compounds produced and released by fungi from genus Penicillium.

Chemistry. All penicillins are derived from 6-aminopenicillanic acid.

The antibacterial and pharmacolo-gical properties of different penicillins depend on the side chain attached to the nucleus.

Penicillin - Mechanism of action.

The bacterial targets of penicillins are known as penicillin binding proteins (PBP): transpeptidase, carboxy-peptidase, autolytic enzymes.

The inactivation of transpeptidases and the activation of autolysins result in the rapid destruction of peptidoglycan and dissolution of the cell wall, which leads to bacterial lysis.

Penicillin and b acterial resistance


Some bacteria produce enzymes that inactivate beta-lactams, known as beta-lactamases.

Penicillin classification

Natural

Semi-synthetic penicillins

Antibacterial spectrum

Natural penicillins are narrow spectrum antibiotics that are primarily active against gram-positive bacteria (enterococci are only inhibited), gram-negative cocci, Treponema pallidum and most anaerobes (except Bacteroides fragilis

Penicilinase resistant penicillins (group M penicillins): methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin.

Penicilinase resistant penicillins are preferred for the treatment of Staphylo-coccus aureus infections, which have a high frequency of beta-lactamase positive isolates.

Otherwise, these penicillins have the same spectrum of bacterial susceptibility as the natural penicillins.

Extended spectrum penicillins - This group includes:

aminopenicillins (ampicillin, amoxicillin);

carboxypenicillins (carbenicillin, ticarcillin);

ureidopenicillins (azlocillin, mezlocillin, piperacillin);

amidinopenicillins (mecilinam).

Extended spectrum penicillins

They are effective against a great variety of gram-positive and gram-negative bacteria.


Some of these broad-spectrum penicillins, such as carbenicillin, piperacillin, are active against Pseudomonas.

Broad-spectrum penicillins are penicillinase susceptible.

The concomitant use of beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) can reduce this susceptibility.

Preparation and dosage

Benzylpenicillin (penicilin G) injection 5,00,000 units per ml.

Dose: 6-12 lakh units daily IM.

Benzylpenicillin tablet contains 50,000 to 5,00,000 units.

Dosage:2-4 lakh units 4 hrly.

Beta-lactamase inhibitors

They don’t have important antibacterial effect, but they block the beta-lactamase activity, excepting chromosomal cephalosporinases.

E.g., clavulanic acid, sulbactam, tazobactam.

Associations:

• amoxicillin + clavulanic acid;

• ticarcillin + clavulanic acid;

• ampicillin + sulbactam.

Toxicity


Because the bacterial target of penicillins are enzymes unique to bacteria, generally, the penicillins have very limited toxicity.

The most severe side effects are allergic reactions, which depend on individual predisposition (anaphylactic shock,skin rashes,serum sickness like syndrome)

Cephalosporines


C lassification

• The cephalosporines are classified into 4 generations, roughly parallel to their chronological development.

• First generation cephalosporines. E.g., cephazolin, cephalotin (injectable), cephalexin (oral).

• Second generation cephalosporines. E.g., cephamandole, cephuroxime, cefoxitine (injectable), cefaclor (oral).

Third generation cephalosporines. E.g., cephotaxime, ceftriaxone (injectable), cephixime (oral).

Fourth generation cephalosporines. E.g., cefepime, cefpirome.

Dosage

First generation cephalosporines.Cefadroxil (PO)

Adult:0.5-1 gm BD-QDS

Child: 30 mg/kg/d in 2 doses.

Contra indication: impaired renal function, h/o GI disease esp. Collitis.

Cephalexin (PO)

Adult: 0.25-0.5gm QDS

Child: 2550 mg/kg/d in 4 doses.

Contra indication: renal failure, collitis, hypersensitivity to penicillin

Cefazolin (IV)

Adult: 0.5-2 gm q8h

Child : 25-100 mg/kg/d in 3-4 doses.


Contra indication: renal failure, concomitant use of diuretics.

Second generation cephalosporines.

Cefuroxime (IV)

Adult: 0.75-1.5 gm q8h

Child: 50-100 mg/kg/d in 3-4 doses.

Contra indication: renal failure, hypersensitivity to penicillin

Cefoxitin (IV)

Adult: 1-2 gm q6-8h


Cefuroxime axetil (PO)

Adult: 0.25-0.5gm bd

Child: 0.125-0.250 gm bd

Contra indication: renal failure, hypersensitivity to penicillin, elderly.

Third generation cephalosporines.

Cefotaxime (IV)

Adult: 1-2 gm q6-12 h


Contra indication: impaired renal function, hypersensitivity.

Ceftriaxone (IV)


Adult: 1-4 gm q24h


Contra indication: impaired renal function, hypersensitivity

Fourth generation cephalosporines.

Cefpirome (IV)

Adult: 1-2 gm q12 h

Contra indication: hypersensitivity, pregnancy and lactation.

Cefepime (IV)

Adult: 0.5-1 gm q12 h.

Contra indication: hypersensitivity and lactation.

Cephalosporines – antibacterial spectrum


Cephalosporines are active against a wide variety of bacteria and are considered wide spectrum antibacterials.

Most cephalosporines are resistant to staphylococcal penicillinases.

Second and third generation cephalosporines are resistant to most beta-lactamases produced by gram-negative bacteria

Only some second-generation cephalosporines are active against anaerobes (e.g., cefoxitine, cefotetane).

Some third and fourth generation cephalosporines are active on Pseudomonas aeruginosa (e.g., ceftazidime, cefoperazone, cefepime, cefpirome).

Toxicity

Because the structures of cephalosporines and penicillins are similar, 10-15% of the patients allergic to penicillin may be allergic to cephalosporines, too.

Cephalosporines are more toxic than penicillins; the most toxic are the first generation cephalosporines.

Other beta-lactam antibacterial agents


Carbapenem (Imipenem, Meropenem). These agents have a very broad antibacterial spectrum (gram-positive and

negative, aerobic and anaerobic organisms).

They are resistant to beta-lactamases.

They are not active on methicillin-resistant staphylococci.

Imipenem (IV)

Adult: 0.25-0.5 gm q 6-8 h

Meropenem (IV)

Adult: 0.5-1 gm q8h

Child: 10-40 mg/kg 8 hrly.

Contra indication: h/o hypersensitivity to penicillin, carbapenem or other beta lactum and lactation.

Monobactams

Monobactams (Aztreonam) are effective against a narrow spectrum of aerobic gram-negative bacteria, including Pseudomonas.

They are resistant to beta-lactamases.

Aztreonam (IV or IM )

0.5-1 gm q6-8 h in UTI

2 gm 8 hrly in severe infections.

Contra indication: h/o hypersensitivity to beta lactum, renal and hepatic impairment and lactation.

Cycloserine


Mechanism of action: inhibits incorporation of D-alanine into an oligopeptide in the cytoplasm.

Cycloserine is rarely used, as a second line antimycobacterial drug.

It is ototoxic (particularly when given parenterally) and should not be used unless absolutely necessary.

Glicopeptides (vancomycin, teichoplanin)

Mechanism of action: they block incorporation of new subunits in the peptidoglycan molecule.

Vancomycin (IV)

Adult : 30mg /kg/d in 2-3 doses.

Child : 40 mg /kg/d im 3-4 doses

Oral : 0.125-0.25 gm 6 hrly.

Contra indication: hypersensitivity to the drug.

Antibacterial spectrum and administration:

Vancomycin is the first choice antibiotic in infections produced by methicillin resistant staphylococci (MRSA) and penicillinase producing enterococci.

Glicopeptides are macromolecules and can’t cross the gram-negative membrane.

They must be given parenterally in the treatment of systemic infections because it is poorly absorbed by the intestinal mucosa.

They realize active concentrations in CSF. Vancomycin can be given orally for the local treatment of intestinal infections (e.g., pseudomembranous colitis produced by Clostridium difficile).

Toxicity.


Vancomycin is more toxic than penicillins, especially for kidneys

Bacitracin

Inhibits peptidoglycan synthesis by interfering with the recycling of the phosphorilated lipid carrier.

It is active against gram-positive bacteria.

Bacitracin 500 units/g in ointment base(neomycin) is used for suppression of mixed bacterial flora in wounds , lesion of skin.

Solution of Bacitracin 100-200 units/ml of saline is used for irrigation of wounds , joints or pleural cavity.

Bacitracin is nephrotoxic and ototoxic when given parenterally; therefore it is mainly used in topical ointments (only local).

Def: Ototoxicity is damage of the ear (oto), specifically the cochlea or auditory nerve and sometimes the vestibulum, by a toxin (often medication like antibiotics).

Vancomycin and beta- lactams like penicllin interfere with cell wall synthesis (1)


B) Antibacterial agents that alter the function of the cytoplasmic membrane

Polymyxines are polypeptides with big molecular weight.

E.g., polymixine B, polymixine E (colistine).

Mechanism of action:

They modify the structure of the cytoplasmic membrane, which disturb the active transport of some molecules through it.

They are bactericidal.


Gram-negative bacilli and cocobacilli (aerobic or facultative anaerobic).

Administration:

Orally in enteritis; parenterally in urinary tract infections.

They don’t penetrate the blood-brain barrier (not efficient in meningitis).

15,000-25,000 units/kg daily IV or IM.

Local- 0.1% solution or ointment.

Toxicity:

Nephrotoxic, neurotoxic.


C) Antibacterial agents that inhibit the protein synthesis

1. Aminoglycosides

2. Tetracyclines

3. Chloramphenicol

4. Macrolides – lincosamides – streptogramines (MLS group)


Aminoglycosides

Natural Aminoglycosides

© produced by Streptomyces: streptomycin, neomycin, kanamycin, tobramycin, spectinomycin;

© produced by Micromonospora: gentamycin, sisomycin.

Semisynthesis aminoglycosides:

- kanamycin derived: amikacin;

- sisomycin derived: netilmycin.

Mechanism of action:

Aminoglycosides bind the 30S ribosomal subunit, which disturbs the protein synthesis and produce non-functional proteins.

Antibacterial spectrum.

Aminoglycosides are bactericidal.

They are active on facultative anaerobic gram-negative bacilli and on staphylococci. Gentamycin, tobramycin, amikacin and netilmycin are also active on Pseudomonas aeruginosa.

Streptomycin is particularly active on mycobacteria, Yersinia pestis and Brucella.

Spectinomycin is given in gonococci infection with beta-lactamase producing strains.

Neomycin is mostly used in topical ointments and in oral preparations.

Aminoglycosides in association with penicillins or vancomycin are synergistic against enterococci and viridans streptococci.


Administration:

Aminoglycosides are not absorbed from the digestive tract; thus, they are given parenterally. They may be given locally in meningitis.

Toxicity:

Ototoxic, nephrotoxic, except spectinomycin.

Gentamycin, tobramycin, amikacin, netilmycin have lower toxicity levels.

Aminoglycosides realize concentrations very close to the toxic ones (their serum concentrations have to be checked).

Streptomycin

Streptomycin sulfate inj.0.5-1gm daily deep intramuscular.

It is drug of choice in plague.

Dose: 30mg/kg/d IM BD for 10 days.

Contra indication: Ear disease, myasthenia gravis.

Neomycin

Neomycin Sulphate Dose : 0.25-1gm QDS

Contra-indication: Hypersensitivity to aminoglycosides, Renal impairement, Pregnancy, Lactation.

Amikacin

Dose: IM/IV Adults: 15mg/kg/day 2-3times a day

max: 1.5g/day

Neo-nates: 10mg/kg followed by 7.5mg/kg 12hrly

Contra-indication: Hypersensitivity to amino glycosides, Renal impairment, Pregnancy, Lactation.


Tobramycin Sulphate:

Dose: Adult: 3-5mg/kg/day TDS

Children: 6-7.5mg/kg/day 3-4equal doses

Neo-nates: upto 4mg/kg/day BD

Gentamycin:

Dose: IM/IV 3-5mg/kg daily in 3divided doses for

7-10days.

Contra-indication: Uremia, severe renal impairment, Pregnancy & Neo-nates.

Kanamycin:

Dose: adults: 250mg QIDS or 500mg BD IM

Max.: 1.5mg/day

Children: 10-15mg/kg/day IM 2-3times a day.

Contra-indication: Pregnancy, Lactation.


Tetracycline

Natural tetracyclines: chlortetracycline, oxytetracycline.

Semisynthesis tetracyclines: tetracycline, doxycycline, minocycline.

Tetracyclines - Mechanism of action

Tetracyclines are bacteriostatic.

They fix on the 30S ribosomal subunit, blocking the binding of tRNA on the complex mRNA-ribosom; thus, they stop peptide elongation.

Antibiotics that act at the level of the elongation phase of protein synthesis

How antibiotics work

For example vancomycin and b- lactams like penicllin interfere with cell wall synthesis .

Erythromycin and tetracyclin disrupt protein synthesis at the ribosome .

Quinolones inhibit enzymes involved in DNA synthesis and sulfonamides also interfere with DNA synthesis by mimicking naturally-occurring building materials.

Erythromycin and tetracycline disrupt protein synthesis at the ribosome.


Tetracyclines are broad-spectrum antibacterial, active on gram-positive and gram-negative, aerobic and anaerobic organisms.

They are also active on: spirochete, mycoplasmas, Chlamydia, rickettsia.

They are not active on Pseudomonas aeruginosa.


Administration

When given orally, they are well absorbed. They don’t realize active concentrations in CSF.

They are not eliminated by urine, so, they are not effective in urinary tract infections.

Doxycycline, minocycline are long acting tetracyclines and require less frequent administration.

Tetracycline- administration

Drug of choice in infection with mycoplasma pneumoniae,chylamydiae,rickettsiae.

Commonly used to treat Gastric & duodenal ulcer caused by H.Pylori

Used in Chlamydial infection like STD’s.

Tetracycline dose:

Oral :

Adult: 0.25-0.5 gm qds

Child below 8yrs: 20-40mg/kg/d

Contra-indication : Hypersensitivity, later half of Pregnancy & Lactation.

Drug of choice- Doxycycline OD.

Parental :

IV -0.1-0.5 gm 6-12 hrly.

Doxycycline -100-200mg 12-24 hrly.

Contra-indication : Hypersensitivity.


Minocycline:

Dose: 100mg daily

In V.D.: 100mg twice daily

Contra-indication: Hypersensitivity & hepatic & renal dysfunction, pregnancy , lactation & pediatrics below 8yrs 0f age.

Tetracycline - Side effects

They produce brownish staining of the teeth and they affect the growth of long bones in children.

That’s why they are counter-indicated in children less than 8 years old and in pregnant women.

Tetracycline administration encourages candidiasis as a result of the loss of the normal flora.

Adverse reaction

GI: nausea, vomitting and diarrhoea.

Hepatic toxicity.

Renal toxicity.


Chloramphenicol

Chloramphenicol is the first antimicrobial compound synthesized in the laboratory.

Tianphenicol is a less toxic derivative.

Mechanism of action: it blocks protein synthesis by fixing on the 50S ribosomal subunit and inhibiting the peptidiltransferase.

Chloramphenicol - Antibacterial spectrum.

Chloramphenicol is bacteriostatic against most bacteria, but it is bactericidal against Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae.

Antibacterial spectrum .

The antibacterial spectrum is similar to that of tetracyclines.

It is active against intracellular bacteria (it is the first choice antibacterial in the treatment of typhoid fever, Rocky Mountain spotted fever).

It is also useful in H. influenzae meningitis because it penetrates the blood-brain barrier.

It is effective against anaerobes.

Also effective against Rickettese but not Chlamydiae.

Administration

Chloramphenicol can be given orally or in injections, realizing good concentrations in tissues, even in CSF.

It is conjugated in the liver, the resulted inactive compound being eliminated by urine.


Indication and dosage

Due to toxicity, bacterial resistance and availability of other effective drugs Chloranphenicol is OBOSLETE as systemic drug.

It is used for T/t of Rickettesial infection like typhus.

Topically used for treatment of eye infections.

Dose : 50-100 mg /kg/d in 4 doses.

Contra-indication:

Hypersensitivity, Pregnancy, Lactation, prophylaxis & concomitant use of penencillin.

Adverse reaction :

Nausea, vomitting and diarrhea.

Oral and vaginal Candiasis due to alteration of normal microbial flora.

Dose of 50 mg/kg/d for 1-2 wks causes suppression of RBC production.

Aplastic Anaemia.

Toxicity .

In newborn or premature, chloramphenicol produces gray baby syndrome because the liver is incapable to conjugate the compound.

In adults, there is a dose-dependent toxic effect on the bone marrow, which is reversible.

In a very low number of patients (1: 25000), a dose independent toxic effect may appear – the irreversible, lethal bone marrow aplasia.


Macrolides Erythromycin

Roxitromycin

Clarithromycin

Azithromycin

Spiramycin

Josamycin

Mechanism of action :

Macrolides bind to the 50S ribosomal subunit, immobilize peptidyl tRNA and cause premature peptide chain termination.

Antibacterial spectrum:

Erythromycin is active against gram-positive cocci and bacilli, including anaerobes, Legionella pneumophila*, Bordetella pertussis*, Campylobacter jejuni* (* = Gram negative bacilli), mycoplasmas, chlamydia.

Erythromycin is the alternative to penicillin in the treatment of group A streptococcal infections.

The new macrolides (clarithromycin, azithromycin) are also active on gram-negative bacteria: Moraxella catarrhalis, Haemophilus influenzae.

Clarythromycin is active in the treatment of Helicobacter pylori gastritis and in infections with Mycobacterium avium-intracellulare.


Administration :

Macrolides are given orally and realize good concentrations in tissues, but not in CSF. They are eliminated predominantly by bile.

Toxicity :

Macrolides have low toxicity. They may cause gastric intolerance.

Azithromycin

Dose: Adult – 500mg OD for 3 days.

Child - >6 yrs 10 mg/kg/d once daily for 3 days.

Contra-indication : Hypersensitivity.

Erythromycin

Dose: Adult – 1 gm daily in BD/ TDS dose.

Max. Upto 4 gm /day.

Prophylactic dose- 250 mg 6hrly.

Child – 30-50 mg /kg/day in 3-4 doses.

Contra-indication: Hypersensitivity and h/o Jaundice.

Roxitromycin

Dose: Adult-150-300 mg BD 30 min before meals for 7 days.

Child: 2.5-5 mg/kg BD


Contra-indication: Hypersensitivity, lactation, pregnancy, liver cirrhosis.

Clarithromycin

Dose: Adult – 250-500 mg BD for 7-14 days.

Child – 7.5 mg/kg BD.

Contra-indication: Hypersensitivity, lactation, pregnancy,

Children, renal impairment. Patient receiving Terfenadine/Astemizole.

Spiramycin

Dose: Adult – 6-9 million IU/day in 2-3 divide doses for 5 days.

Child – 3-5 million IU/day

Contra-indication: Hyper sensitivity, meningitis.

Lincosamides


Ex: Lincomycin

Clindamycin

Antibacterial spectrum:

Lincosamides are active against staphylococci, gram-positive and gram-negative anaerobes, including Bacteroides fragilis.

Adverse effects:

Lincosamides encourage, more than other antibacterials, the pseudomembranous colitis with Clostridium difficile.

Lincomycin

Dose: Oral –Adult – 500 mg TDS

Child – 30 mg/kg/day TDS

Parental: Adult - IV / IM - 600 mg twice daily.

Child - IV / IM – 10 mg/kg twice daily.

Contra-indication: Hyper sensitivity, meningitis, neonates.

Clindamycin

Dose: Adult – IM /IV 600-1200 mg/day in 2-4 doses.

Child – IM /IV 20-40 mg/kg/day in 3-4 doses.

Neonates - IM /IV 15-20 mg/kg/day in 3-4 doses.

Contra-indication: Hyper sensitivity, Lactation.

Streptogramines

Ex.: Pristinamycin


Virginamycin


Streptogramines are active against staphylococci, including methicilin resistant strains (MRSA).

Antibacterials that inhibit the nucleic acid synthesis

1. Sulfonamides

- Sulfizoxazole

- Sulfamethoxazole etc.

Sulfonamides

Mechanism of action .

Sulfonamides are bacteriostatic. They inhibit the folic acid synthesis by inhibiting dihidropteroate synthetase.


Sulfonamides are active on:Gram-positive and gram-negative bacteria, except Pseudomonas aeruginosa;

Actinomyces israelii, but not other anaerobes; Chlamydia.

Administration:

Orally resulting in good concentrations in tissues. Elimination by urine.

Adverse effects :

ü hypersensitivity reactions, especially after local administration;


ü acute hemolytic anemia in patients with G6PD deficiency;

ü increased concentrations of non-conjugated bilirubine in newborn.

ü Steven Johnson syndrome.

Sulfamethoxazole:

Therapeutic Uses- Azo-Gantanol

Combined with phenazopyridine (an analgesic-anesthetic that affects the mucosa of the urinary tract).

Used to treat urinary tract infections (UTIs) and to reduce the pain associated with UTIs.

Bactrim (Cotrimoxazole)

Combined with trimethoprim.

Used to treat UTIs, Pneumocystis Carinii, pneumonia, ear infections, bronchitis, gonorrhea, etc.

Sulfizoxazole

Therapeutic Uses- Azo-Gantrisin

Combined with phenazopyridine

Used for UTIs

Pediazole

Combined with erythromycin


Used to treat otitis media

Dosage:1-2 gm initially ,then 0.5-1gm

Trimethoprim

Mechanism of action. Bacteriostatic. It inhibits folic acid synthesis by blocking dihidrofolate reductase.

Antibacterial spectrum. Similar to sulfonamides.

Adverse effects. It may produce skin rash or bone marrow depression.

Dosage: 200mg tablet 12 hrly.

Cotrimoxazole

Trimethoprim (80mg)+ sulfamethoxazole(400mg) (5/1) = cotrimoxazol, a synergistic combination. Each component is bacteriostatic, but the combination is bactericidal.

It is particularly useful in the treatment of genitourinary tract infections, bacterial gastro-enteritis and it is frequently used in the long-term prophylaxis of bacterial infections in immune-compromised hosts.

Dosage:

Oral-2 tab BD for 10-14 days.

IM or IV - 960 mg 12 hrly.

Paediatric tab- Trimethoprim (20mg)+ sulfamethoxazole(100mg)

Suspension - Trimethoprim (40mg)+ sulfamethoxazole(200mg) per 5ml.

Quinolones

First generation:


Nalidixic acid

Pipemidic acid etc.

Second generation (Fluoroquinolones):-

- Norfloxacin

- Pefloxacin

- Ofloxacin

- Ciprofloxacin

- Sparfloxacin

Mechanism of action .

Bactericidal; they inhibit DNA gyrase.


First generation quinolones are active only on Enterobacteriaceae.

Fluoroquinolones have extended spectrum, being also active on Ps. aeruginosa, staphylococci, gram-negative cocci and coccobacilli, Legionella pneumophila, chlamydia and mycoplasmas.

They are inactive on streptococci and anaerobic bacteria.

Administration .

Nalidixic acid is given orally, but it realizes active concentrations only in the kidneys. Fluoroquinolones are systemic quinolones, which, after oral


administration, realize active concentrations in tissues and CSF, having good penetration in the cells. They are eliminated predominantly urinary.

Adverse effects .

Fluoroquinolones determine photosensitivity after exposure to the sunlight. They have limited applications in children.

Nalidixic acid

Dose: Adult – 1 gm QDS for 1-2 wks.

Child – 60 mg/kg daily in 4 doses.

Contra indication: Hypersensitivity, h/o convulsive disorders, lactation and infants < 3 months.

Norfloxacin

Dose : Adult – 400 mg BD.

Contra indication: Hypersensitivity, Convulsion, Children, lactation.

Ofloxacin

Dose: Adult – orally 200-800 mg/ day.

IV 200 mg Infusion BD.

Contra indication: Hypersensitivity, Convulsion, Children, lactation

Ciprofloxacin

Dose: Oral – 250-500 BD

IV – 200-400 mg BD over 60 min.

Contra indication: Hypersensitivity, Children below 12 yrs lactation.


Gatifloxacin

Dose: Oral/ IV – 400 mg OD.

Contra indication: Hypersensitivity, Children below 18 yrs, patients on Antiarrhytmics.

Sparfloxacin

Dose: usually 400 mg on day 1; followed by 200 mg OD.

Contra indication: Hypersensitivity, Children, pregnancy.

Metronidazole

Mechanism of action.


After penetration in the bacterial cell, intermediate metabolism compounds interact with DNA.


Protozoa, anaerobic and microaerophilic bacteria.

Administration.

After oral administration, it realizes active concentrations in tissues and CSF. Urinary elimination.

Adverse effects.

They are, generally, well tolerated.

Dose: Oral - 7.5 mg/kg QDS max. 4 gm/day.

IV – 15 mg/kg infused over 30 min. 1hr before surgery.

Afterwards 7.5 mg/kg 6 and 12 hrs.

Contra indication: blood dyscrasis, CNS disease, alcohol and serious hepatic failure.

Rules for the association of the antibiotics


It is avoided the association of aminoglycosides or with polymixines (the toxic effects are summed).

It is avoided the association of a bacteriostatic by inhibition of the protein synthesis (tetracyclines, macrolides) with a bactericidal antibiotic (penicillins, aminoglycosides) (antagonistic effect).

It is indicated the association of antibiotics that block successive steps of a metabolic pathway (e.g., trimetoprim + sulfamethoxazole).

Rules for the association of the antibiotics

It is indicated the association of an antibiotic with another one that encourages its penetration in the bacterium (e.g., penicillin + aminoglycosides against enterococci).

It is indicated the association in which one antibiotic is protected from enzymatic effects by the other one (e.g., ampicillin + sulbactam).


General biochemistry and immunology& finally the drug NSAIDs

Prostanoids synthesis Mechanism of action of prostanoids


Cyclooxygenase structure and functionsNonsteroidal anti-inflammatory drugsTherapeutic uses and contraindications and untoward effects

Synthesis:

Membrane bound phospholipids is enzymatically acted by cytosolic phospholipase_A2 yielding arachidonic acid.

Finally arachidonic acid is converted to short life prostaglandin i.e. PGG2.


This PGG2 is converted to PGH2

by the help of enzyme cyclooxygenase.

PGH2 is the major prostaglandin through which series of other prostanoids i.e.(prostaglandin,prostacycline,thromboxane) are synthesized

Cyclooxygenase

Cyclooxygenase is a complex enzyme which is responsible for synthesis of prostaglandin.

Cycloxygenase is a dimmers(formed by two monomers) of identical subunits. Each monomer consists of two different active sites.

Hence altogether total subunits contains four active sites.


Active sites of a monomer consists of one , perooxidase while the other one is cyclooxygenase

Here two identical subunits is being demarcated by a red line. Unit in left of red line is one subunit while on right is another subunit And each subunit consists of two active sites. One site is perooxidase while other is cyclooxygenase


The monomer hence contains two active sites one is heme containing site , having perooxidase activity while the other site is cyclooxygenase.

The cyclooxygenase is responsible for oxidizing arachidonic acid by abstracting hydrogen atom from arachidonic acid.

tyrosine radical generated by peroxidase active site is responsible for abstraction of this hydrogen. hence yielding hydroperoxy endoperoxide prostaglandin G2.

This is converted to PGG2 by imparting two oxygen molecules . Now the perooxidase is responsible for conversion of PGG2 to PGH2.


Cyclooxygenase-1

Isoenzyme 1 (COX-1) is involved in the control of many constantly occurring processes and it is constitutively expressed in all kinds of healthy tissue as part of the usual cell functions, in other words it is continuously produced. This also means, that this isoenzyme occurs in all cell-types of the body and it is abundant and available everywhere. High levels of COX-1 are particularly found in the stomach walls, as well as in kidney. Concentrations of COX-1 remain largely unaffected by inflammation.

Common every day effects of COX-1 are for instance the stimulation of prostaglandin-synthesis which helps protecting the

gastric mucosa from aggressive acids the regulation of haemostasis, i.e. the blood circulation in the tissue by

vascular dilatation and vascular constriction of blood vessels and the regulation of muscle contractions. In addition COX-1 contributes to the synthesis of the prostaglandin-like

thromboxane which is produced in the platelets (thrombocytes) and which improves the process of blood coagulation

Cyclooxygenase-2

Isoenzyme 2 (COX-2) is also involved in prostaglandin synthesis It catalyses the synthesis of a prostaglandin with inflammatory and pain increasing properties, and which thereby has a protective function in the defense mechanism of the body. However, in contrast to COX-1 the COX-2 in many cell types is only found in small amounts or even not found at all. It is produced in large amounts on demand, initiated by specific stimulation like proinflammatory cytocins, liposaccharides, mutagens and oncogens, grows factors, as well as changes of the water-electrolyte-balance. The subsequent inhibition of the COX-2 expression occurs by glucocorticoids and anti-inflammatory cytocins

COX-2, because of its expression-characteristics, belongs to the class of Immediate-Response-Genes, a gene family, in which the induction of gene transcription is characteristically fast. The increase of the expression of these genes is possible in a few minutes. On the other hand this protein has


a relative short half-life of about 5 to 30 minutes in most cell types, so that the cellular concentration of COX-2 decreases comparatively fast after the stimuli has ceased and the prostaglandin release goes back to physiological level .

Because of these results the hypothesis was derived that COX-1 is responsible for maintaining prostaglandins in a physiologically necessary concentration, while those prostaglandins responsible for pain, fever and inflammation are catalysed by COX-2.


PROSTAGLANDIN AND THROMBOXANE MECHANISM OF ACTION

There are currently nine known prostaglandin receptors on various cell types. Prostaglandins ligate a subfamily of cell surface seven- transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2).

These varied receptors mean that Prostaglandins thus act on a variety of cells, and have a wide variety of actions:

cause constriction or dilatation in vascular smooth muscle cells cause aggregation or disaggregation of platelets e.g. thromboxane is an

clotting factor responsible for platelets aggregation. If platelet is not let to form by NSAIDs then how come it be possible to platelet aggregation .

sensitize spinal neurons to pain decrease intraocular pressure regulate inflammatory mediation regulate calcium movement control hormone regulation control cell growth Prostaglandins are potent but have a short half-life before being inactivated

and excreted. Therefore, they exert only a paracrine (locally active) or autocrine (acting on the same cell from which it is synthesized) function.


Non-steroidal anti-inflammatory drugs

Aspirin IbubrufenKetoprofenNaproxen & FenoprofenDiclofenac NaPiroxicam Indometacin

Aspirin

Indication –

As analgesic,anti-inflammatory and anti pyretic-

Dosage:

Adult -300-900mg every 4-6 hrly up to 4gm/day

In children with Juvenile R.A-50-80mg/kg /day

Ibubrufen

Indication:

Musculoskeletal pains of all types including trauma, RA, OA.Acute Gout and dysmenorrhoea.

In children with Juvenile R.A.

Dosage:

Adult: 200-600mg QDS up to 1.2-1.80gm/day preferably after food.


SR tablets can be given BD

Children: 20-40mg/day in divided doses but not below 7yrs of age.

Ketoprofen : It is propionic acid derivative.

Indication:

Musculoskeletal pains ,RA,OA.Acute Gout and capsulitis of the shoulder

Dosage:

Adult: oral 25-50mg 6-8 hrly

IM-50-100mg for 3 days

Children: Not Recommended.

Naproxen

Indication:

RA, OA. Dysmenorrhoea, anklylosing spondylitis and Acute Gout.

Dosage:

Adult: 250mg twice daily

In c/o Acute Gout =

750mg stat initially followed by 250mg 8 hrly.

Diclofenac Na

Indication:

Musculoskeletal pains of all types including trauma, inflammatory and degenerative arthritis, RA,OA,Acute Gout, dental pain , post operative pain.


Dosage:

Oral: Adult-50mg bd/tds

Children ->1yr: 1-3mg/kg/day in divided doses.

IM: Adult- 75mg BD by deep intragluteal injection.

Children: Not Recommended

Piroxicam

It belongs to oxicam group of NSAIDs; has longer T-half life and given in OD dosage.

Indication:

RA, OA. Dysmenorrhoea, anklylosing spondylitis and Acute Gout.

Dosage:

Oral:Adult:10-30 mg daily

Acute Gout -40 mg daily for 7-14days.

IM : 20mg once a day

Indometacin

Indole derivative.

One of most potent inhibitor of PG.

Indication:

RA,OA. anklylosing spondylitis and Acute Gout .

Given IV in premature children with patent ductus arterious.


Dosage:

Adult: 25 mg BD/TDS

75 mg SR capsules OD

Mefenamic Acid

Indication:

Musculoskeletal pains of all types including trauma, RA, OA.Acute Gout and dysmenorrhoea.

In children with Juvenile R.A.

Dosage:

Adult: Acute pain 500mg stat followed by

250 mg 4-6hrly with food.

Other conditions: 500 mg TDS.

Chronic Juvenile Arthritis: 25mg/kg in divided doses.

Children: Antipyretic-4mg/kg .


Mechanism of action of NSAIDs

Non-steroidal anti-inflammatory drugs are responsible for binding with cyclo-oxygenase enzyme . In case of cyclooxygenase1 , it`s active acetyl group binds with serine side chain of the enzyme.

Hence ,causing inhibition of formation of prostaglandin. This results in anti-inflammatory action.

a) It limits the formation of prostaglandin, thromboxane-A2.b) Prostaglandin is responsible for inflammatory action , it acts as an

chemoattracants for leukocytes (inflammatory cells) . And above, already mentioned ,phenomenon of inflammation

c) Thromboxane-A2 is a substrate of platelet aggregation cascade. Hence if thromboxane-A2 is not let to form then , platelet aggregation is also limited . This results in good therapeutic use of NSAIDs as an anti coagulant. Though anti coagulant sometimes is very harmful (pregnancy , peptic ulcer), while sometimes it is useful too. For example thrombotic plaque in blood vessels , which can be dissolved by these drugs.


Therapeutic uses of NSAIDS:

ANALGESIC:I NHIBITS THE TRANSDUCING PROPERTY OF FREE NERVE ENDINGS BY INHIBITING BRADYKININ, TNF alpha, interleukins etc

ANTIPYRESIS (DECREASE TEMPERATURE BUT DOESNOT CAUSE HYPOTHERMIA IN NORMOTHERMIC INDIVIDUALS)

ANTIINFLAMMATORY ANTITHROMBOTIC CLOSURE OF DUCTUS ARTERIOSUS: PGE2 and PGI2 are responsible for

ductus arteriosus in fetus by Unknown mechanism . NSAIDs inhibits prostaglandin , causing closure of this , and don’t let this unknown mechanism to happen with in 24 hours of birth of baby.(Indomethacin)

Post operative cases: after surgical approach the blood vessels are exposed to the clot{thrombus} hence may travel to vessel causing thrombo- embolism. Hence to dissolve these thrombus ASPIRIN is recommended.


NSAIDs and brain:

Alzheimer's DISEASE: it is believed that Alzheimer's is caused due to continuous degradation of nerve cells Alzheimer disease is characterized by the accumulation of A peptides into extracellular amyloid plaques and the formation of intracellular tangles

In addition, neuroinflammation is thought to contribute to the disease process. Although NSAIDs mainly inhibit cyclooxygenases (COX) and may thus inhibit neuroinflammation, some NSAIDs have recently been shown to target –secretase , an enzyme required for the generation of A -peptides, and decrease the production of the more toxic and fibrillogenic A42, as shown in figure in last slide.

So that several COX-2−specific NSAIDs can increase A42 production by inhibiting -secretase activity (red arrow). Aside from these effects, neuroinflammation and disease progression may also be influenced by NSAIDs acting on peripheral cells or immune cells, thereby altering the production of growth factors and cytokines, which can act across the blood-brain barrier (BBB).


Un-towards effect of NSAIDs

It can cause highly bad effect on bleeding as It don’t let bleeding to stop by inhibiting coagulation cascade. So increase bleeding time and clotting time hence very dangerous in pregnancy case and labor as well as some accidental cuts, laceration, wounds etc.

It causes stomach mucosal damage directly due to its highly acidic nature in one hand and in other hand inhibition of protective COX1 leads to mucosal bleeding.

These all effects are dose dependent Note …………………… If a COX-2 inhibitor is taken, one should not use a traditional NSAID

(prescription or over-the-counter) concomitantly. In addition, patients on daily aspirin therapy (as for reducing cardiovascular

risk or colon cancer risk) need to be careful if they also use other NSAIDs, as other NSAIDs may block the cardioprotective effects of aspirin.

Peptic ulcer - Due to high acidic nature of NSAIDs and it`s inhibition to protective COX1 causes peptic ulcer.


Its major function is to inhibit the leukocytic infiltration, by inhibiting prostaglandin synthesis which leads to inhibition of COX1 as well as , hence a selective COX2 is preferable.

Selective COX2 inhibitors

They inhibits only COX2 targets . they are special type of NSAIDs. And these doesn't blocks the cox1.hence selective and Nobel use is delivered.

COX-2 inhibitors are more expensive than traditional NSAIDs. They are often prescribed for long-term conditions such as arthritis because they may be safer for the stomach. However, some studies have not shown any difference between the incidence of gastrointestinal side effects from traditional NSAIDs and COX-2 inhibitors.

Recent studies have indicated that both NSAIDs and COX-2 inhibitors may have a delaying effect on bone healing but the extent of this effect is not yet known. Short-term use of NSAIDs after a fracture or orthopaedic surgery is generally safe.


Contraindications:

NSAIDs are never to be used in individuals with Inflammatory Bowel Disease (IBD- Crohn's Disease and Ulcerative Colitis) due to its ability to cause gastric bleeding and form ulceration in the gastric lining. Drugs such as Advil should be avoided in persons afflicted with IBD. Pain relievers such as Tylenol (containing acetaminophen) or drugs containing Codeine (which slows down bowel activity) are safer methods than Ibuprofen for pain relief in IBD.

NSAIDs are also associated with a relatively high incidence of renal ADRs. The mechanism of these renal ADRs is due to changes in renal haemodynamics (blood flow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. Prostaglandins normally cause vasodilation of the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of renal function. By blocking this prostaglandin-mediated effect, NSAIDs ultimately may cause renal impairment. Horses are particularly prone to these adverse affects compared to other domestic animal species.

Common ADRs associated with altered renal function include: Salt and fluid retention Hypertension (High blood pressure)

These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic - the so-called "triple whammy" effect


Opoid Analgesic


Opoid Analgesic

Medications that relieve pain without causing loss of consciousness

Painkillers

Classification of pain by onset and duration.

Acute pain

Sudden in onset

Usually subsides once treated

Chronic pain

Persistent or recurring

Often difficult to treat

Classification of pain

Neuropathic Phantom Cancer Psychogenic Central Somatic Visceral Superficial Vascular Referred


Classification of pain by source

Vascular pain

Possibly originates from vascular or perivascular tissues.

Neuropathic pain

Results from injury to peripheral nerve fibers or damage to the CNS

Superficial pain

Originates from skin or mucous membranes

Pain transmission by GATE theory.

Most common and well-described

Uses the analogy of a gate to describe how impulses from damaged tissues are sensed in the brain

THEORY :

Tissue injury causes the release of:

Bradykinin Histamine Potassium Prostaglandins Serotonin

These substances stimulate nerve endings, starting the pain process.


There are two types of nerves stimulated:

“A” fibers and

“C” fibers

“A” Fibers “C” Fibers

Myelin sheath No myelin sheath

Large fiber size Small fiber size

Conduct fast Conduct slowly

Inhibit pain Facilitate pain transmission

Sharp and Dull andwell-localized nonlocalized

Types of pain related to proportion of “A” to “C” fibers in the damaged areas

These pain fibers enter the spinal cord and travel up to the brain.

The point of spinal cord entry is the DORSAL HORN.

The DORSAL HORN is the location of the “GATE.”

This gate regulates the flow of sensory impulses to the brain.

Closing the gate stops the impulses.

If no impulses are transmitted to higher centers in the brain, there is NO pain perception.

Activation of large “A” fibers CLOSES gate Inhibits transmission to brain and Limits perception of pain


Activation of small “C” fibers OPENS gate and Allows impulse transmission to brain Pain perception

Gate innervated by nerve fibers from brain, allowing the brain some control over gate.

Allows brain to:

Evaluate, identify, and localize the pain

Control the gate before the gate is open.

Body has endogenous neurotransmitters

Enkephalins

Endorphins

Produced by body to fight pain

Bind to opioid receptors

Inhibit transmission of pain by closing gate

Rubbing a painful area with massage or liniment stimulates large sensory fibers

Result: GATE closed, recognition of pain REDUCED

Same pathway used by opiates


OPOID ANALGESIC

Pain relievers that contain opium, derived from the opium poppy orchemically related to opiumNarcotics: very strong pain relievers

1. codeine sulfate2. meperidine HCl (Demerol)3. methadone HCl (Dolophine)4. morphine sulfate5. propoxyphene HCl

Classification

Three classifications based on their actions:

Agonist Agonist-antagonist Partial agonist

Codiene Sulphate

Therapeutic uses:

As an analgesic : 30-60mg t.i.d

Also used as anti tussive and anti diarrhoeal agent

Methadone HCl

Methadone hcl,5mg tab

Dose :5-10mg

Inj. Methadone hcl 5mg of salt per ml


Dose :5-10mg.IM/SC.

Morphine sulfate

Acute intractable pain :10mg IM/SC 4 hourly

IV dose :2.5-5mg 4 hourly

Orally :in case of severe pain of cancer

10-50mg every 4 hourly

Site of action

Large “A” fibers

Dorsal horn of spinal cord

Mechanism of action

Bind to receptors on inhibitory fibers, stimulating them

Prevent stimulation of the GATE

Prevent pain impulse transmission to the brain

Therapeutic uses.

Main use: to alleviate moderate to severe pain

Opioids are also used for:

Cough center suppression

Treatment of constipation


Side effects

Euphoria

Nausea and vomiting

Respiratory depression

Urinary retention

Diaphoresis and flushing

Pupil constriction (miosis)

Constipation

OPIATE ANTAGONISTS

naloxone (Narcan) naltrexone (Revia)

Opiate antagonists bind to opiate receptors and prevent a response.Used for complete or partial reversal of opioid-induced respiratory depression.

Naloxone

Dosage

Adult: 0.4-2mg IV, IM or SC every 2-3 min.

Post operative: 0.1-0.2mg repeatedly as reqd.

In neonates-respiratory depression due to obstetric analgesia: 10mcg /kg IV, IM or SC.


Opoid TOLERANCE

A common physiologic result of chronic opioid treatment

Result: larger dose of opioids are requiredto maintain the same level of analgesia.

Physiological Dependence

A pattern of compulsive drug-use characterized by a continued craving for an opioid and the need to use the opioid for effects other than pain relief.

Opioid tolerance and physical dependence are expected with long-term opioid treatment and should not be confused with psychological dependence (addiction).

Misunderstanding of these terms leads to ineffective pain management and contributes to the problem of under treatment.

Physical dependence on opioids is seen when the opioid is abruptly discontinued or when an opioid antagonist is administered.

Narcotic withdrawal

Opioid abstinence syndrome

Narcotic Withdrawal Opioid Abstinence Syndrome

Manifested as:

anxiety, irritability, chills and hot flashes, joint pain, lacrimation, rhinorrhea, diaphoresis, nausea, vomiting, abdominal cramps, diarrhea

IMPORTANT POINTS.


Oral forms should be taken with food to minimize gastric upset.

Follow proper administration guidelines for IM injections, including site rotation.

Withhold dose and contact physician if there is a decline in the patient’s condition—especially if respiratory rate is below 12 breaths/minute.

Constipation is a common side effect and may be prevented with adequate fluid and fiber intake.

Patients should be instructed to change positions slowly to prevent possible orthostatic hypotension.


antibiotics, analgesic,anti-inflammatory drugs

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