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  1. 1. ANTIBIOTICS, ANALGESICS AND ANTIMICROBIALS IN CHILDREN Children because of skill developing immunity are more prone to infections. Oral cavity is one such area where a variety of bacterial, viral, fungal etc. infections are commonly encountered in children. Those conditions in majority of cases makes the use of antimicrobials mandatory. Hence a thorough knowledge of various drugs used in different conditions and their side effects is necessary. Drugs must be used only when definitely indicated and after balancing the possible benefit and risk ratio. It is always beneficial for the dentist / physician to use only those drugs with which he/she is familiar. Administration of drugs does not mean a way to produce good oral health. Infact an injudicious use of any drug for that matter is potentially harmful. It is easy to administer drugs but at the same time it is difficult to control their side effects by removing them from the body. Some of the general guidelines for use of drugs is given below: 1
  2. 2. Guidelines for Drug Therapy: 1. There should be a genuine indication for the use of a drug in the patient. 2. Drugs prescribed should be: - Minimum. - Appropriate and familiar. - Inexpensive. - Of good quality. 3. Preferably generic name should be used for prescription. 4. Optimum dosage is used to achieve desired clinical effects with minimum adverse effects. 5. A short gun therapy is to be avoided. 6. As far as possible oral route is preferred over other route in children. 7. Adverse drug reactions should be anticipated, monitored and appropriately managed. Combinations of drugs may be necessary in certain conditions when the causative agent is not known. A multituding therapy is also used as a measure to minimize 2
  3. 3. drug adverse reactions and to prevent development of drug resistance. Some of the antibiotics commonly used in pedodontics and pediatrics and antimicrobials in general are discussed below. Calculation of Dose: The dose in children is similar to that of adults with respect to body weight. The only difference is in infant that is because of: - Decreased gastric acid. - Decreased plasma protein binding. - Decreased flow to muscles. - Immature kidney and liver functioning. - Increased extracellular fluid compared to adults. The dose is determined by using body surface areas and weight. Some of the formulae used for the calculation of dosage for children are: 1. Clarks rule: Child dose  Childs weight in Ibs / 150 x adult dose 2. Young rule: Child dose  (Age of child / Age + 12) x adult dose 3
  4. 4. Antimicrobial Agents: Some of the antimicrobial agents used in various orofacial and general infections of the body include the following: 1. B-lactamase inhibitors: - Penicillins. - Cephalosporins. - Bacitracins. 2. Aminoglycosides: - Streptomycin. - GEntamycin. - Amikacin etc. 3. Macrolides: - Erythromycin. - Clindamycin. - Roxithromycin. - Arithromycin etc. 4. Sulfonamides: - Trimethoprim - Sulfamethoxazole – co trimaxazole 5. Tetracyclines: 6. Antifungal agents: - Nystatin. - Amphotericin B 4
  5. 5. - Ketakenazole. - Oncanozole etc. 7. Antiviral agents: - Acycloutr - Zidovudine etc. These given agents are of prime correction in oral and facial infections. Some of other antimicrobial agents used in general infections include: 1. Anti tubercular agents. 2. Anti leprocy agents. 3. Anti helmintics. 4. Anti malarials. 5. anti protozoals. B. Lactamase Inhibitors: - Penicillins. - Cephalosporins. - Bacitracins. Penicillins: Even after introduction of a number of antibiotics penicillines enjoy the first place in initial preference against infections in orofacial as well as general parts. Based on its pure form as benzyl penicillin and its modification penicillins are classified as follows: 5
  6. 6. 1. Penicillinase Sensitive: Benzyl penicillin G (sodium or potassium): - 100,000 units per oral 6h - 50-60,000 units/kg/day Im 6h - Benzathane penicillin 1.2 mega units / 3-4 weeks. - Procain penicillin 300,000 units / 12.24hrs Im. 2. Acid resistant penicillins: - Phenoxy methyl penicillins or penicillin V. - Dose 10mg /kg/day. 3. Penicillinase resistant penicillins: Mithicillin 100mg/kg/day Im/Iu of 6hr Oxacillin 50-100mg/kg/day PO/IV of 6 hr. Cloxacillin 50-100mg/kg/day PO/IV of 6 hr. 4. Extended spectrum penicillins: Ampicillin 50-100mg/kg/D PO or IU 6 hr. Amoxycillin 25-50mg/kg/day PO 6 hourly. Carbenicillin 50-500mg/kg/day Im/ IU 6 hourly. Ticarcillin 50-300mg/kg/day IU in vision 4-6 hours. Pipercacillin 100-300mg/kd/day IU in vision 4-8 hourly. 6
  7. 7. Penicillins have bactericidal properly by interfering with synthesis of cell membrane of growing bacterias. Thus creating a defective all membrane. This defect in cell membrane makes it more prone for phagocytosis. Natural penicillins with procain groups are poorly absorbed from stomach because of their inactivation by acid. It is therefore preferable to administer them by parentally. Majority of oral preparations are less than complete dose through GIT and reach to peak plasma concentration at 30-60 minutes. They bind reversibly with free alumin in plasma and exerted in active forms in urine. The half life of pencillin G is 30 minutes whereas extended spectrum penicillins like amoxycyllin it is 50-60 minutes. Therapeutic Uses: Penicillins are used against a wide variety of infections of the body including infections in the oral cavity. Some of the applications include: 1. Streptococcal infections: - St. pharyngitis. - St. abscesses. - Infective endocarditis. - Otitis media and sinusitis. 7
  8. 8. - Pneumonia meningitis. 2. Staphylococcal infections: Vast majority of staphyloccal infections are produced by penicillinase producing species. In case of staphylaccal abscess penicillin G is ineffective and thus penicillinase resistant penicillins like mithecillin and oxacillin are used. Anfections with Anaerobes: Penicillins possess very little action on anaerobes. Most of the infections of dental origin are of mixed variety and penicillins can be effectively administered in treating these infections. 3. Miningococcal infections – Penicillin G. 4. Gonococcal infections – Amoxycyllin and Ampicillin. 5. Syphilis – Congenital syphilis in infants should be treated with procaine penicillin G for 10 days with 50,000 units/kg/day. Primary, secondary and tertiary syphilis of less than 1 year duration. Procaine penicillin G. 2.4 million units / day Im. 8
  9. 9. Plus Probenecid 1gm /day orally for 10 days. 6. Actinomycosis: Although rare in children any form of actinomycosis should be treated with 12- 20 million units of Pencillin G IU / day for 6 weeks. 7. Diphtheria: Procaine Penicillin G 2.3 million units/day 10-12 days in divided doses. Adverse Reactions: 1. Allergy: Although rare penicillins in sensitive patients produce severe anaphylaxis. The prevalence of such reactions is very rare accounting 1 in 1000 individuals. The reaction may be life threatening. 2. Suprainfections: Prolonged usage may had to decreased immunity by acting on normal flora suppressing the growth of only sensitive organisms. Thus the resistant organisms are free to grow producing infections. Ex: candidiasis. 3. Bitter taste of milk in lactating mother from ampicillin. 9
  10. 10. 4. Pseudomembraneous colitis leading to diarrhea. Cephalosporins: Cephalosporins are the next group of antibiotics considered. Based on the period of their introduction from old to recent products they are divided into three generations as first, second and third generation. Some of these drugs according to generations and their doses in children include: 1. First generation cephalosporins: - Cephalexin 25-50mg/kg/D P.O. 6 hr. - Cephazoline 25-50mg/kg/D Im. IU 8-12 hr. - Cefadroxil 30mg/kg/D P.O. 12 hrly. 2. Second generation cephalosporins: - Caphaclor 20-40mg/kg/D P.O. 6-8hr. - Cephamandole 50-150mg/kg/D Im, IU 8-12 hr. - Ceauroxime 30-100mg/kg/D Im/IU 8-12hr. 10
  11. 11. 3. Third generation cephalosporins: - Cefotaxime 100-150mg/Kg/D Im/IU 8-12hr. - Cefoperzone 50-200mg/kg/D Im 8-12 hr. - Moxalactum 50-200mg/kg/D Im /IU 6-8 hrly. - Ceftazidime 50-100mg/Kg/D IV 12 hrly. - Ceftizoxime 30-60mg/kg/D IU 8-12 hrly. The first generation cephalosporins have got same spectrum of activity as that of penicillins. These agents may even be active against B-lactamase producing staphylococcus. Some strains may not be active. As the generation changes from I to II and III the spectrum of activity is increased. The second generation cephalosporins are more active against gram-ve bacilli in addition to the activity of first generation products. The second generation cephalosporins are active against: - Lt. influenza. - Enterobacter. - E-coli. - Klebsiella species etc. The half life of majority of cephalosporins is 30-50 minutes and are excreted mainly through kidnies. 11
  12. 12. The third generation cephalosporins like cefatoxime are highly resistant to beta-lactamase and are very much effective against gm+ve and gm-ve organisms. These drugs have got good activity against pseudomonas species. The half life of these drugs is more than that of I and II generation cephalosporins i.e. 1-2 hours. These drugs in severe infections have to be administered 4-8 hourly. Therapeutic Uses: 1. Dental infections – abscess. 2. As prophylaxis for bacterial endocarditis. 3. Infections from gm-ve organisms. 4. Gonorrhea. 5. Miningitis. 6. Klebsialla, streptococcus pneumonas etc. Side Effects: 1. Anaphylaxis. 2. Nausea vomiting. 3. Suprainfections on indiscriminate usage. 12
  13. 13. 4. Some of the third generation cephalosporins produce blood dyscriasis by reducing platicle functions. 5. Diarrhea etc. Aminoglycosides: The antibiotics belonging to this group are not widely used in dental infections. But in some conditions they are very effective. They are composed of various aminosugars linked by glycoside linkage and are prepared by fermentation of various species of streptomyces. These antibiotics are not given by oral route and Im and IU route is most commonly preferred route for administration. Most of these drugs are highly polar , cations and hence very poorly absorbed from GIT. Less than 1% is absorbed from GIT. These are excreted mainly through urine. The major drawback of these drugs is the severe toxicity produced by these drugs. Aminoglycosides cause – ototoxicity which involve both auditory and vestibular functions of 8th cranial nerve. The next toxicity is nephrotoxicity by impaired renal functions. 13
  14. 14. Hypersensitivity is the next adverse effect seen. Some of the aminoglycosides and their doses are: 1. Streptomycin 40mg/kg/D Im 12 hr. 2. Gentamycin 4-8mg/kg/D Im/IU 8-12 hrly. 3. Amikacin 15-20mg/kg/D Im/IU 8-12 hrly. 4. Tobramycin 6-7.5mg/kg/D Im/IU 6-8 hrly. 5. Sisomycin 3mg/kg/D Im/IU 8 hrly. Dosage should be reduced and intervals between doses should be increased in case of renal damage. Indications: In cases of infections caused by aerobic gm-ve microorganisms. Mechanism of action: They act by interfering with ribosomal function and thus protein synthesis. They are bactericidal in action. Macrolides: The first drugs of preference in patients allergic to penicillins for treatment of infections are macrolides. The drugs belonging to macrolides include: 14
  15. 15. 1. Erythromycin 50mg/kg/D PO. 6-8 hr. 2. Cleandomycin 50mg/kg/D PO. 12 hrs. 3. Roxithromyin 30-50mg/kg/D PO 12 hrs. 4. Vancomycin 30-40 IU 6-8 hrs. 5. Azithromycin 10 PO once daily. 6. Clarithromycin 15 PO 12 hrly. 7. Clindamycin 10-40 IU 6 hrly. 8. Linkomycin 30-60 PO 6 hrly. 9. Polymyzin B 20000IU/Kg/D PO. 8 hrly. Macrolides are the compounds with complex structures with unusual nitrogen containing sugars and a larger molecule weight (>700). Most of the macrolides are given by oral route and are better absorbed from small intestine. The mechanism of action includes inhibition of protein synthesis between 305 and 505 fractions of ribosomes the pharmacological activity makes the bacteriostatic at lower doses and at higher doses these drugs act as bactericidal drugs. 15
  16. 16. Therapeutic uses: Erythromycin among the macrolides is most commonly used drug. The uses in dentistry include: 1. Dental infections with gm+ve and –ve aerobic organisms including: - Apical abscess. - Periodontal abscess. - Pulpitis etc. 2. Infections caused by staph aureus, streptococcus, mycoplasma, pneumoniae, Chlamydia, C. diaphtheria, Tetanus bacilli, B. pertusis etc. Erythromycin is generally safe and preferred in patients allergic to penicillin and cephalosporins. It is available in 5 salts namely: 1. Erythromycin base. 2. Erythromycin stearate. 3. Erythromycin Estolate. 4. Erythromycin ethyl succinate. 5. Erythromycin lactobionate. 16
  17. 17. The main side effects with erythromycin include IT problems and a cholastatic hepatitis like condition where the mucosmembrane and sclera of chilb become yellow with yellowish discoloration of urine. The condition disappears as the drug is withdrawn. Azithramycin has got increased activity against gm-ve organisms along with the spectrum of erythromycin and is better tolerated as compared to erythromycin. Vancomycin acts as cidal drug against staphylococci. Clindamycin or lincomycin may give rise to pseudomembraneous colitis. Quinalones: Quinalones cover a wider area of gm+ve and –ve aerobic organisms. They are mostly used by oral route and are better absorbed in GIT. The mechanisms of action of quinalones is they act by inhibiting the enzyme. DNA gyrase thus interfering with DNA synthesis. The activity thus is cidal in nature. Some of the quinalones include: 17
  18. 18. 1. Nilidixic acid 50-60mg/kg PO 8 hrly. 2. Ciprofloxacin 15-20mg/kg PO 12 hrly. 7-10mg/kg IU 12 hrly. 3. Norfloxacin 10mg/kg PO 12 hrly. 4. Ofloxacin 200mg (adults) 12 hrly. Therapeutic uses: 1. Dental infections caused by gm+ve and –ve aerobic bacterias. 2. Tonsilitis, pharyngitis. 3. URTI. 4. Urinary tract infiltration. 5. Any systemic infections ex: typhoid. The use of quinalones in children is not indicated. It is because, all the species of quinalones produce arthropathy in immature children when used in pregnant female or children. The metabolism of theophyllin is inhibited by liprofloxacin and when two drugs are used concurrently toxicity may occurs. 18
  19. 19. Broad Spectrum Antbiotics: Tetracyclines: Tetracyclines are classified under broad spectrum antibiotics because of their additional spectrum of activity involving pseudomonas. Rickettsia mycoplasma and Chlamydia. Some atypical bacteria and amebae. Some of the tetracycline products are: - Chlor tetracycline. - Oxytetracycline. - Demeclocycline. - Methacycline. - Doxycycline. - Minocycline. Majority of tetracyclines are given orally and few products like oxytetracycline can be given by Im route. The mechanism of actions of these tetracyclines is by interfering with protein synthesis. The site of action is 305 fraction of ribosomes. These drugs a pharmacologically bacteriostatic in nature. 19
  20. 20. On oral administration tetracyclines are absorbed incompletely but adequately form GIT distributed throughout the body and excreted unchanged in urine. The absorbtion of tetracyclines is better in empty stomach and is disturbed by the presence of antacids, calcium magnesium and iron salts. Aluminium hydroxide gels and bismuth subsalicylate. The main mechanism involved is chelation of divalent and trivalent cations. Effects on Calcified Tissues: This makes the main reason for avoiding Ttcln in children. Use of these drugs by children for a short term therapy or long term therapy may develop brown inversible discolorations of involved teeth. The larger the dose relative to body weight more marked will be the discoloration. The risk of this problems on teeth are more when the child is given this drug during the period of 2 months and 90 years when majority of teeth are getting calcified. The total dose of drug rather than duration of treatment is the main factor of consideration. 20
  21. 21. The main mechanism of this discoloration is because of the chelating property and the formation of tetracycline – calcium or the phosphate complex. As the time progresses the yellow fluorescence is replaced by brown discoloration which is indicative of oxidation product of antibiotic. This discoloration is permanent and its formation is hastened by light treatment of infections with Ricket sialchlamydae, mycoplasma pneumonia, amaebiosis. Adverse Reactions: 1. GIT – These drugs produce severe GI problems of varying degrees. They include: - Epigastric burning and distress. - Abdominal and vomiting. - Diarrhea in some cases. The problem increases with increases in dose of the drug. 2. Phototoxicity: Demeclocycline and dozeycyclines producee toxic reactions of skin to sunlight in treated patients. 21
  22. 22. 3. Hepatic toxicity: The jaundice followed by diffuse infiltration of fat in liver is a complication with prolonged tetracycline therapy. Pregnant women are particularly susceptible for hepatic damage. 4. Renal toxicity: By inhibiting protein synthesis treatment in pregnancy causes pigmentation of primary teeth. The period of greatest risk is from mid pregnancy to 4-6 months postnatally. In addition to teeth tetracyclines may also get deposited in skeleton during gestation and throughout childhood. A 40% of depression in bone growth has been demonstrated. This can be reversible in case of a short doe for a lesser period. Dosage: 1. Tetracycline 25-50mg/kg/D P.O. 6 hourly. 15-25mg/kg/D Im 8-12 hrly 2. Doxycyclin 1.5-2mg/kg/D P.O. 12-24 hrly. 22
  23. 23. Chloramphenicol Another drug under broad spectrum antibiotics is chloromphenicol because of its intended activity on H. Influenza species. The drug can be administered by oral Im or Iv route and excreted mainly through kidnies. The drug acts by protein synthesis inhibition and is bacteriostatic. Therapeutic uses: 1. Not indicated in children. 2. In treatment of H. influenza infection. 3. In treatment of Enteric fever. Adverse reactions: 1. Most common adverse reaction of child is bone marrow depression after prolonged usage and it is dose related. A more severe bone marrow aplasia may occurs due to single larger dose or prolonged usage. This shows aplastic anemia. It is totally unpredictable and terminates fatally in many cases. 23
  24. 24. 2. Hypersensitivity: 3. In infants and children if the drug is used indiscriminately it may lead to Grey-Baby syndrome resulting in: - Abdominal distension. - Vomitting. - Refusal to suck and - Dyspnea. The baby develops gray colour due to cyanosis and peripheral circulatory collapse with death in around half of the cases. Dosage: - Chloramphenicol – 50-100mg/kg/D P.O. Im, Iv 6 hrly. - Eye drops – 0.5-1% Sulfonamides: Sulfonamides are the most economic group of antibiotics. The common sulfonamide is a mixture of Trimethoprim and Sulphamethoxazole and is Co- 24
  25. 25. trimaxadazole. They are the first group of antibiotics introduced and were widely used. Antimicrobial Spectrum: Gm positive and gram negative organisms like st. pyogens, st. pneumonia, H. influenza, Nocardia, Actinomycos camphylobacter grganulomatosis etc. The utility of these drugs is reduced because of increased resistance in organisms and increased reports of allergic reactions. Mechanisms: Sulfonamides are competitive antagonists for paraaminobemoic acid and interferes with synthesis of folic acid in the bacterial cells. The pH action is “Bacteriostatic”. Dosage: The co-trimaxazole available contains trimethoprim and sulphamethaxozole in a ratio of 1:5. Each tablet contains 80mg of Trimethoprim and 400mg of sulfamethaxazole. Dosage – Trimethoprim 6mg/kg/D P.O. 12 hourly. 25
  26. 26. Antiprotozoal Agents: Although a number of antiprotozoal drugs are available the drug of choice in dentistry for trating severe infections caused specially by anaerobic organisms is metronidazole. Tinidazole is the recent introduction in treating anaerobes. Metranidazole: Metranidazole has got a wider antiprotozoal and wide antimicrobial properties. The drug is given usually by oral route but can some times be given by IV infusion in the treatment of severe protozoal infections. On oral administration the drug is absorbed promptly and completely and attains peak plasma levels after 1 hour of its administration. The plasma half life of the drug is about 8 hours and excreted mainly through urin. Antimicrobial spectrum: Metranidazole is a cidal drug and is effective against: 1. Trichomonas, amaebae and histiolytica. 26
  27. 27. 2. From dental point of view the drug is effective against anaerobic organisms including bacteriods, fusobacterium, clostridia, B. fragylis, Chlamydia. Clinical Applications: 1. In the management of – Trichomoniasis; Amaebiasis and other protozoal infections. 2. In treating infections caused by anaerobic microorganisms like dental abscess, periodontal abscess etc. Adverse Effects: 1. Mutagenesis, carcinogenesis: Indiscriminate use of metranidazole for a prolonged period of time may cause change in mutation pattern of normal cells. This condition may be reversal in initial periods. 2. One of the side effects that makes it to avoid in children is the metallic taste in saliva, which is not well tolerated by children. 3. Nausea and vomiting. 4. In some patients it may cause blood dysiasis. 27
  28. 28. Dosage: In infections and amebiasia 20mg/kg/D 8 hourly P.O. Tinidazole – 50mg/kg/D P.O. once daily. Hypersensitivity: Body immune mechanisms as provided exhibited by inflammatory reactions is a well known process. In certain conditions these body immune mechanisms may be seen as an exaggerated or excessive manner leading to tissue damage and thus proving harmful to the body. These processes are called as “Hypersensitivity Reactions”. “The term hypersensitivity refers to the injurious consequences in the sensitized host following contact with specific antigens”. Normally in the process of immunity the focus of attention is antigen and its fate i.e. whether bacterial death is the result or neutralization of bacterial toxins. But in cases of hypersensitivity reactions the focus of attention is not the antigen as such but at the same time is concerned with what happens to the host as a result of immune reactions. 28
  29. 29. For the induction of hypersensitivity reactions the host is required to get exposed to the antigen atleast once before the reactions. This initial exposure sensitizes host to the concerned antigen and is called as sensitizing dose or priming dose. Classification: Coombs and Gell: Based on the mechanism of pathogenesis involved in the Coomb and Gell in 1963 classified H.S. reactions in to four groups, namely: 1. Type I – Immediate hypersensitivity – Anaphylactic. 2. Type II – Cytotoxic or cell stimulation 3. Type III – Immune complex or toxic complex disease. 4. Type IV – Delayed hypersensitivity. Type I reaction Reagenic The mechanism here is antibodies are fixed on the surface of tissue cells (mast cells and basophils) in sensitized individuals. The antigen combines with all fixed antibody leading to release of a variety of (vasoactive 29
  30. 30. amines) pharmacologically active substances which produces clinical reaction. Anaphylaxis - It is a classical immediate type of reaction. - The term anaphylaxis was coined by Ricket in 1902. - Theobald Smith observed a triangular phenomenon in Guinea pigs in 1902 following injection of toxin antitoxin mixtures. Ehrlich named this as Theobald Smith phenomenon and showed that this kind of reactions are produces not only by toxin initiation mixtures but also even by injection of normal serum. - Sensitization is most effective when injected parentally may occur by any route including ingestion and even inhalation. - In sensitive individuals a minute quality of antigen is sufficient to cause a severe reaction. - Antigens as well as heptens can induce anaphylaxis. - A minimal interval of 2-3 weeks is needed between sensitizing dose and shocking dose. 30
  31. 31. - Shocking dose is more effective when injected IV and less when intraperitonially and subcutaneously and least when intradermally. Clinical Features: - Due to smooth muscular contraction and increased vascular permeability. - Tissues or organs affected by anaphylactic reaction are known as “target tissues” or “shock organs”. In man fatal anaphylaxis is very rare, immediately after administration of antigen the symptoms begin as: - Itching of scalp and tongue. - Flushing of skin over whole body. - Difficulty in breathing due to bronchial spasm. - There may be nausea, vomiting, abdominal pain, diarrhea, some times blood in stool etc. - Acute hypotension, loss of consciousness followed by death as last consequence. 31
  32. 32. Mechanism of Anaphylaxis: Anaphylaxis can be passively transferred from a sensitive donor to normal recipient by injection of serum. The circulating antibodies are responsible for this passive transfusion. Hemocytotrophic Ig and antibody is the major antibody responsible for anaphylactic reactions. Other Ig have ony a small role. Ig and molecules are bound to a mast cells in tssues and basophils in circulation on exposure to an antigen the Ig and combines with antigen bridging the gap between two cells. This crosslinking increases the permeability of these cells to calcium ions causing dedgranulation of cells including biologically active substances within the granules. These biologically active substances has their pharmacological action are responsible for various reactions. The substances are mediators of reaction and of two types: 1. Primary – Histamin, serotonin, heparin – Eainophil chemotact factor of anaphylaxis; neutrophil; various proteolytic enzymes. 32
  33. 33. 2. Secondary – slow releasing substance of anaphylaxis, prostaglandins, platelet activating factor. Mediators of Anaphylaxis: Primary Mediators of Anaphylaxis: a) Histamin: It is the most important vasoactive amine in anaphylaxis. It is the most important vasoactive amine in anaphylaxis. It is formed by De caboxylation of histidine found in mast cells basophils and pts. On secretion into skin it stimulation sensory nerve endings causing: - Itching, burning sensation. - Vasodilatation and hyperemia by axon reflexes. - Edema by causing increased vascular permeability. - It produces severe smooth muscle contraction including vasculative intesting and especially of bronchioles. - It stimulates secretions. 33
  34. 34. b) Seratonis (S.H.T.) - It is a base derived from dedcarboxylation of tryptophan in mast cells, basophils in small intestine. - It causes vaso constriction, smooth muscle contraction and increased permeability. - Its role in humans is minimum. 34