Saturday, 16 February 2019

Penicillin and penicillin allergy

February 16, 2019

  • Penicillin
  • Mechanism of action
  • Mechanism of bacterial resistance
  • Spectrum of activity
  • Pharmacokinetics
  • Precaution
  • Therapeutic uses
  • Limitations / drawbacks of PenicillinG
  • Penicillin allergy/ adverse effects
  • Semisynthetic penicillins

You will learn in this article above mentioned topics.

😊 Hello dear visitors...

Your welcome,
You are learning Pharmacology at onlycology.


PENICILLIN 

Penicillin was the first antibiotic to be used clinically in 1941. It is a miracle that the least toxic drug of its kind was the first to be discovered.

It was originally obtained from the fungus Penicillium notatum, but the present source is a high yielding mutant of Penicillium chrysogenum.

The penicillin nucleus consists of fused thiazolidine and beta-lactum rings to which side chains are attached through an amide linkage.

Penicillin G is highly water soluble, it is stable in the dry state but solution deteriorates rapidly at room temperature.

MECHANISM OF ACTION 

Beta-lactum antibiotics produce bactericidal effect by inhibiting cell wall synthesis in susceptible bacteria.

Bacterial cell wall is composed of peptidoglycan, which is highly cross linked structure that makes the cell wall rigid and also gives it stability.

There are three stages involved in the biosynthesis of peptidoglycan.

The third stage is inhibited by beta-lactum antibiotics. The mode of action of Penicillin is given below as flowchart.👇



                




MECHANISM OF BACTERIAL RESISTANCE 

Bacteria develop resistance to beta-lactums mainly through the release of beta-lactumases, which hydrolyse the beta-lactum ring and inactivate them.

The other mechanism of resistance to beta-lactums are due to :
i) altered penicillin binding protein  (PBPs)
ii) decreased penetration of the drug to its site of action.

SPECTRUM OF ACTIVITY 

1. Bactericidal effect on Gram +ve cocci - Streptococci, Pneumococci. etc.

2. Bactericidal effect on Gram -ve Gonococci - Neisseria gonorrhea, Neisseria meningitis.

3. Bactericidal effect on Bacilli - Bacillus anthracis, etc.

4. Bactericidal effect on Trypanoma palladium.

PHARMACOKINETICS

Most of the orally administered penicillin G is destroyed by gastric acid.

Absorption of sod.PnG from i.m. site is rapid and complete. It is distributed mainly extracellulary; reaches most body fluids but penetration is serous cavities and CSF is poor.

About 60% is plasma protien bound.

It is little metabolized because of rapid excretion.

The plasma t 1/2 of PnG in healthy adult is 30 min. 

Tubular secretion of PnG can be blocked by probenecid-higher and longer lasting plasma concentration are achieved.

Probenecid has also been shown to decrease the volume of distribution of Penicillins.


PRECAUTION 

  • Before giving penicillin, history of previous administration and allergic manifestations, if any, must be noted.
  • In patients with history of asthma, allergic rhinitis, hay fever, etc, there is an increased risk of Penicillin allergy, hence penicillin should be avoided in such cases.
  • Sensitivity test should be performed by an Intradermal test. Itching, erythema and wheal formation are watched for a negative skin test does not ensure absolute safety.
    • Inj. Adrenaline and hydrocortisone should be kept ready before injecting penicillin to treat the anaphylactic reaction.

      THERAPEUTIC USES 

      1. Pneumococcal infections : In pneumonia, meningitis or other serious infections, penicillin G can be used as alternative of Cephalosporin if the organism is sensitive, it should be continued for 7 to 10 days.

      2. Streptococcal infection : Pharyngitis, sinusitis, rheumatic fever, otitis media, celulitis, etc. are effectively treated with procaine penicillin G 6 lac units i,m, once daily for 10 days.

      3. Meningococcal meningitis : penicillin G is effective by intravenously, it should be given only for confirmed cases. 

      4. Gonococcal infection : penicillin was the drug of choice for gonococcal infections. Because of the emergence of resistant organisms, penicillin are not preferred at present. 

      5. Syphilis : penicillin G is the drug of choice for syphilis. Treponema pallidum is very sensitive to penicillin and is killed at very low concentration of drug.

      6. Diphtheria : it is acute infection of upper respiratory tract caused by C. diphtheriae. Penicillin G is used for this treatment for 10 days.

      7. Clostridial infection : The main treatment is the neutralisation of toxin by using human tetanus immunoglobin. For gas gangrene, Penicillin G is the drug of choice.

      LIMITATIONS / DRAWBACKS OF PENICILLIN G

      1. Orally not very effective.
      2. Short duration of action.
      3. Narrow spectrum of antibacterial activity.
      4. Destroyed by penicillinase enzyme.
      5. Possibility of anaphylaxis.

      PENICILLIN ALLERGY / ADVERSE EFFECT

      Local irritancy and direct toxicity : 
      • Pain at i.m injection site, nausea on oral ingestion, and thrombophlebitis, of injected vein are dose related expression of irritancy.
      • toxicity to brain can cause mental confusion, muscular twitching, convulsions and coma when very large dose is injected.
      • bleeding has also occured due interference with platelets function.
      • intrathecal injection of Penicillin G is no longer recommended because it has caused arachnoiditis and degenerative changes in spinal cord.
      • accidental i.v. injection of procaine penicillin produces CNS stimulation, hallucination.
      Hypersensitivity :
      • Rash
      • itching
      • urticaria
      • fever
      • wheezing, angioneurotic edema, serum sickness, exfoliative dermatitis are less common.
      • anaphylaxis is rare but may be fatal.
      • Super infection
      • Jarisch-Heixheimer reaction.

        SEMISYNTHETIC PENICILLIN

        Semisynthetic penicillins are produced by chemically combining specific side chains or by incorporating specific precursors in the mould cultures.
        They are :
        • Ampicillin
        • Amoxicillin
        • Dicloxacillin
        • Nafcillin
        • Cloxacillin
        • Bacampicillin
        • Piperacillin
        • Carbenicillin

          Ampicillin

          • It is active against all organisms sensitive to PnG.
          • Due to spread use resistance may develop.
          Pharmacokinetics: Orally absorption is incomplete, excreted in bile, however primary channel of excretion is kidney.

          Amoxicillin 

          It is a close congener of ampicillin, similar to it in all respects except:
          • Oral absorption is better.
          • Incidence of diarrhoea is less.

          Carbenicillin

          • The special feature of this penicillin congener is its activity against pseudomonus aeroginisa and indole positive proteus which are not inhibited by PnG.
          • Klebsiella and gram positive cocci are unaffected by it.
          • It is inactive orally and is excreted rapidly in urine.
          • High dose can cause bleeding, dose is - 1 to 5 gram every 4 to 6 hours.

          Piperacillin

          • This antipseudomonal penicillin is about 8 times more active than carbenicillin.
          • It has good activity against klebsiella and is used mainly in neutropenic / immunocompromized patients having serious gram negative infections.
          • Elimination t1/2 is 1 hr.

           😊 I hope you've got help, if you have any suggestion or any question regarding this article "Penicillin and penicillin allergy,, please comment i will be very happy.

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          Also read :
          Antianxiety drugs, classification, medication, etc..
          Congestive heart failure          ACE inhibitors
          Antihypertensive drugs and classification

          Sunday, 10 February 2019

          Antibiotics resistance

          February 10, 2019
          Definition, types; mutation, gene transfer, prevention of drug resistance.

          Hello dear visitors ðŸ˜Š 

          Your welcome,
          You are learning Pharmacology at onlycology.



          ANTIBIOTICS RESISTANCE 

          Resistance is defined as the unresponsiveness of a microorganism to antibiotic.
          The resistance may be natural or acquired.

          Natural resistance 

          Natural resistance is genetically determined, for example, normally gram negative bacilli are not affected by penicillin G.

          This type of resistance does not pose significant clinical problem.

          Acquired resistance 

          •  It is the development of resistance by an organism (which was sensitive before) due to the use of an AMA over a period of time.
          • This can happen with any microbe and is a major clinical problem.
          • However, resistance development is dependent on the microorganism as well as drug.
          • Gonococci quickly developed resistance to sulfonamide, but only slowly and low grade resistance to penicillin.
          Resistance may be developed by mutation or gene transfer.

          Mutation : It is stable and heritable genetic change that occurs spontaneously and randomly among microorganisms.

          It is not induced by AMA. 

          Mutation and resistance may be :

          i) Single step : A single gene mutation may confer high degree if resistance; emerges rapidly, e.g. enterococci to streptomycin, E.coli and Staphylococci to rifampin.

          ii) Multistep : A number of gene modifications are involved; sensitivity decreases gradually in a stepwise manner.

          Resistance to erythromycin, Tetracyclines and Chloramphenicol is developed by many organisms in this manner.

          Sometimes mutational acquisition of resistance is accompanied by decrease in virulence, e.g. certain rifampin resistant Staphylococci and low grade penicillin resistant gonococci have decreased virulence.

          Gene transfer :

          Infectious resistance from one organism to another can occur by :

          i) Conjugation : It is the transfer of genetic material between bacteria during mating, e.g. enterococcal and Staphylococcus aureus resistance to vancomycin.

          ii) Transduction :  It is the transfer of DNA from one bacteria to another through bacteriophage, e.g. transfer of Antibiotics resistance among the strains of S.aureus.

          iii) Transformation : It is transfer of genetic material through naked DNA, e.g. Penicillin resistance in pneumococci.

          Resistance bacteria 》》 Release naked DNA into the environment 》》 Taken up by sensitive bacteria that develop resistance to AMAs

          ■ Resistant organism can be :

          a) Drug tolerant : Loss of affinity of the target biomolecule of the microorganism for a particular AMA, e.g. resistant Staph. aureus and E. coli develop a RNA polymerase that does not bind rifampin.

          b) Drug destroying : The resistant microbe elaborates an enzyme which inactivates the drug,
          e.g.
           (i) beta-lactamase are produced by Staphylococci, Haemophilus, Gonococci etc which inactivate penicillin G.

           (ii) Chloramphenicol acetyl transferase is acquired by resistant E. coli, H. influenzae.

          c) Cross resistance : Organisms that develop resistance to an AMA may also show resistance to other chemically related AMAs.

           The cross resistance among AMAs could either be one way or two way. The cross resistance among tetracyclines and sulfonamides is usually two way.

           Tetracycline 》《 Doxycycline  ( Tetracycline)
          Sulphadiazine 》《 Sulphadoxine (Sulphonamides)
          Gentamycin 》 Streptomycin

           The one way resistance is seen between gentamycin and Streptomycin. The Gentamycin resistant organisms may be resistant to Streptomycin also.

           But many Streptomycin resistant organisms still respond ti Gentamycin.

          Also read something more about Antibiotics: 👇

          Antibiotics • Classification • Antibiotics selection • Problems arise with use of Antibiotics • Why Combination of Antibiotics • Top 10 Antibiotics

          Prevention of drug resistance 

          • No indiscriminate and inadequate or unduly prolonged use of AMAs should be made.
          • Prefer rapidly acting and selective AMAs whenever possible; broad spectrum drug should be used only when a specific one cannot be determined or is not suitable.
          • Use if combination of AMAs whenever prolonged therapy is undertaken, e.g. tuberculosis, SABE.
          • Infection by organisms notorious for developing resistance, e.g. Staph.aureus, E.coli, M.tuberculosis, Proteus etc. must be treated intensively.


           😊  I hope you've got help, if you have any suggestion or any question regarding this article "Antibiotics resistance,,please comment i will be very happy.
          Thanks

          Friday, 8 February 2019

          Antibiotics

          February 08, 2019
          • Antibiotics
          • Classification
          • Antibiotics selection
          • Problems arise with use of Antibiotics
          • Why Combination of Antibiotics
          • Top 10 Antibiotics

           You will know here something interesting  about Antibiotics in this article.

           Hii dear visitors 😊
          Your welcome, you are learning Pharmacology at onlycology.

          ANTIBIOTICS

          Antibiotics are chemical substances of natural / semisynthetic / synthetic origin, capable of being selectively toxic to pathogen and safe to the parasite, in relatively lower concentrations either by destroying or affecting it's growth/ multiplication.



          CLASSIFICATION

          Can be classified based on :

          A. Chemical structure

          1. Sulfonamides and related drugs : Sulfadiazine, Paraaminosalicyclic acid.
          2. Diaminopyrimidine : Trimethoprim, pyrimethamine.

          3. Quinolones : Norfloxacin, Ciprofloxacin.

          4. beta-lactum antibiotics : Penicillin, Cephalosporin, Monobactums, Carbapenems.

          5. Tetracyclines : Doxycycline, Oxytetracycline.

          6. Nitribenzene derivative :Chloramphenicol.

          7. Aminoglycosides : Streptomycin, Gentamycin, Neomycin.

          8. Macrolide antibiotics : Erythromycin, Azithromycin.

          9. Nitroimidazoles : Metronidazole.

          10. Azole derivative : Miconazole, Clotrimazole, Ketoconazole.

          11. Nicotinic acid :Pyrazinamide, Ethionamide.

          12. Others : Rifampin, Clindamycin, Cycloserine, Viomycin, Thiacetazone.

          B. Mechanism of action

          1. Inhibit cell wall synthesis : Penicillin, Cephalosporin, Cycloserine, Vanomysin.

          2. Cause leakage from cell membrane :Polymixin, Colistin, Amphitericin B, Nystatin, Hamycin.

          3. Inhibit protein synthesis : Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin.

          4. Cause misreading of m-RNA code and affect permeability : Streptomycin, Gentamycin.

          5. Inhibit DNA gyrase : Ciprofloxacin.

          6. Interfere with DNA function : Rifampin, Metronidazole.

          7. Interfere with DNA synthesis : Idoxuridine, Zidovudine.

          8. Interfere with intermediary metabolism : Sulfonamides, Sulfones, Trimethoprim, Pyrimethamine, Ethambutol.

          C. Spectrum of activity 

          1. Narrow spectrum : Penicillin G, Streptomycin, Erythromycin.

          2. Broad spectrum : Tetracyclines, Chloramphenicol.

          D. Type of action

          1. Primarily bacteriostatic : Sulfonamides, Tetracyclines, Erythromycin, Chloramphenicol, Ethambutol.

          2. Primarily bactericidal : Penicillin, aminoglycosides, Cephalosporin, vanomycin, Rifampin, Ciprofloxacin, Cotrimoxazole.

          E. Antibiotics obtained from

          1. Fungi : Penicillin, Cephalosporin, Griseofulvin.

          2. Bacteria : Polymyxin B, Colistin, Bacitracin, Tyrothricin, Aztreonam.

          3. Actinomycetes : Aminoglycosides, Tetracyclines, Chloramphenicol, Macrolides, Polyenes.

          Read important classifications : 
          Classification of drug used in CHF Congestive heart failure
          Antihypertensive classifications


          HOW WILL YOU SELECT ANTIBIOTICS IN CHEMOTHERAPY ?

          1. Identification of infecting organism :
          • It is important for selecting an appropriate antibiotics.
          • Rapidly identified before treatment from body fluids.
          Techniques used for identification - staining technique, biochemicals method, cultivation, testing for microbial antigens, products of immune response.

          2. Empirical therapy :
          • An appropriate antimicrobial agent is used after receiving lab reports of identity and susceptibility except in case of acute illness.
          Sometimes antimicrobial agent is selected based on site of infection, history of patients, kind of infection etc.

          3. Determination of Antimicrobial susceptibility :
          This helps to determine the appropriate antimicrobial therapy.

          4. Effect of site of infection :
          • It is important for an antibiotic to reach appropriate site of action and in appropriate concentration in order to produce effective bactericidal or bacteriostatic effect - i.e. Eradicate the pathogen  from site of infection.
          • BBB offers challenge.
          Nature of drug offers challenge to enter the appropriate site of infection - like - Solubility, molecular weight, protein binding etc.

          5. Patient factors :
          Following needs to be considered before selecting Antibiotics :
          • Host defense / how good is immune response of patient.
          • Renal dysfunction.
          • Hepatic dysfunction.
          • Poor perfusion - i.e. blood supply to site of infection.
          • Age.
          • Pregnancy.
          • Lactation.
          6. Drug factors :
          When any one of the number of drugs could be used to treat infection - then choice is based on specific properties of drug.
          • Spectrum of activity.
          • Type of effect required.
          • Sensitivity of pathogen.
          • Relative toxicity.
          • Pharmacokinetics profile.
          • Route of drug administration.
          • Evidence of clinical efficacy.
          Also read : Routes of drug administration

          PROBLEMS THAT ARISE WITH USE OF ANTIBIOTICS/ ADVERSE EFFECT 

          1. Toxicity : 
          a) local :- oral use - experienced at the site of administration - gastric irritation, pain.
                             Parentral use - abscess formation at the site of i.m injection, thromophelibitis.

          b) systemic :- All antibiotics produce dose related and predictable organ toxocities.
          • Some have high therapeutic index.
          • Some have low therapeutic index.
          e.g. 
          Aminoglycosides : 8th cranial nerve, kidney toxicity.
          Tetracyclines : liver and kidney damage.
          Chloramphenicol : bone marrow depression.
          Polymyxin : neurological and renal toxicity.
          Amphotericin : kidney, bone marrow toxicity.

          2. Hypersensitivity reaction / allergic reaction :
          • All antibiotics are capable of causing hypersensitivity reactions.
          • These are unpredictable and unrelated to dose.
          • Anaphylactic shock can be produced.
          • Penicillin allergy.
          3. Super infection :
          • A fungal infection especially after prolonged use of broad spectrum antibiotics.
          • Difficult to treat due to alterations in the bormal microbial flora of gut, URT.
          4. Development of resistance : 
          • Loss of sensitivity of pathogen to therapeutic effect of an antibiotics - to which it was previously sensitive.
          • Developed by microorganisms when consistently exposed to sub therapeutic concentration of particular antibiotics.
          • Some pathogens are naturally resistant to some antibiotics.

          RESISTANCE DEVELOPMENT

          1. Mutation : when insertion of one or more nucleotides within the genome. The mutated organism replicate with features that can be resist the action of an antibiotic.

          2. Via R factors :  
          • Modification of target sites.
          • Decreased accumulation of Antibiotic.
          • By developing an inactivating enzyme which effectively destroys drug.
          ☆ You must have seen antibiotics given in combination, do you know why ? If not, continue, you will get to know.

          WHY COMBINATION OF ANTIBIOTICS ?

          1. To achieve synergism / additive effect :
          • Synergistic effect sensitizes the organism to the action of the other member of pair.
          • Rapid lethal action - than that of individual member separately.
          • Prolonged post antibiotic effect. ( Aminoglycosides).
          • Two bacteriostatic agents are often additive, sometimes synergistic, i.e. combination of tetracyclines, Chloramphenicol, Erythromycin etc.
          • Two bactericidal drugs are frequently additivd if organism is sensitive ti both.
          • Combination of a bactericidal with bacteriostatic drug may be synergistic or antagonistic depending on the organism.
          2. To reduce severity or incidence of adverse effects :
          • Possible only when combination is synergistic so that dose can be reduced.
          • Especially when the antibiotics are if narrow therapeutic index - which when used alone in effective doses produce unacceptable toxicity.
          • Streptomycin + Penicillin G for SABE.
          3. To prevent emergence of resistance :
          • This principle of using two or more AMAs together is valid primarily for chronic infections neeeding prolonged therapy; has been widely employed in tuberculosis, leprosy.
          • Sulfonamides given with Streptomycin has been found to prevent emergence of resistant H. influenzae.
          4. To broaden the spectrum of Antimicrobial action :
          This is needed in :
          • Treatment of mixed infection.
          • Initial treatment of severe infection.
          • Topically : generally AMAs which poorly absorbed from the local site, needs to given in combination.

          TOP 10 ANTIBIOTICS

          1. Ciprofloxacin
          2. Ofloxacin
          3. Amoxicillin
          4. Streptomycin
          5. Gentamycin
          6. Neomycin
          7. Erythromycin 
          8. Clindamycin
          9. Norfloxacin
          10. Levofloxacin

          Ciprofloxacin : It is the most potent first generation Fluoroquinolone active against a broad range of bacteria.
          • Ciprofloxacin is rapidly absorbed orally, but food delays absorption, and first pass metabolism occurs.
          • High tissue penetrability.
          • Excreted in urine.
          • Adverse effects are - nausea, vomiting, anorexia, dizziness, headache, insomnia, rashes, swelling of lips. Side effects occur only in 10% patients.
          Ofloxacin : It is more potent than Ciprofloxacin for gram positive organisms.
          • Also inhibits M. Tuberculosis; can be used in place of ciprofloxacin.
          • It is lipid soluble, bioavailability is high.
          Amoxicillin :
          • Oral absorption is good; food does not interfere.
          • Higher and more sustained blood levels are produced.
          Streptomycin : Oldest aminoglycoside antibiotic obtained from Streptomyces griseus.
          • Active primarily against aerobic gram negative bacilli.
          • Highly ionized, neither absorbed nor destroyed in g.i.t.
          • Not metabolized - excreted unchanged in urine.
          • Causes nephrotoxocity, hypertension, eosinophilia, rarely Anaphylaxis.
          Gentamycin : obtained from Micromonospora purpurea in 1964 has become most commonly used antibiotic for acute infection.

          Neomycin : obtained from S. fradiae, it is a wide spectrum aminoglycoside, active against most gram negative bacilli and some gram positive cocci.
          • Highly toxic to internal ear and to kidneys.
          • Poorly absorbed from g.i.t.
          Clindamycin : 
          • It inhibits most gram positive cocci.
          • Oral absorption is good, it penetrates to most skeletal and soft tissues, but not brain and CSF.
          • Largely metabolized in urine and bile.
          • Side effects are rashes, abdominal pain, major problem is diarrhoea.
          Hello dear visitors

           😊 I hope you've got help, if you have any suggestion or any question regarding this article"Antibiotics,, please comment i will be very happy.

           Thanks

           Also read : Congestive heart failure
                             ACE inhibitors
                             Antihypertensive drugs and classification
          ,

          Saturday, 2 February 2019

          Pharmacokinetics

          February 02, 2019
          You are going to learn Pharmacokinetics. 
          I have one question:
          What is pharmacokinetics ? If you know comment yes if don't know comment no.

          Hii dear visitors your welcome, you are learning pharmacology at onlycology.
          Let's learn.

          PHARMACOKINETICS

          Pharmacokinetics is the quantitative study of drug movement in, through and out of the body.
          It includes absorption, distribution, binding/localization/storage, biotransformation and excretion of drug.



          All pharmacokinetic processes involve transport of the drug across biological membranes..

          ▪ Drugs are transported across the membrane by : 
          1) Passive diffusion and filtration
          2) Specialized transport 

          Passive diffusion :

          Diffusion of drug across the membrane in the direction of its concentration gradient, 
          You know what here membrane is not playing any role in this process.

          Drugs are foreign substance and specialized mechanism are developed by body for normal metabolites only.

          A more lipid soluble drug attains higher concentration in the membrane and diffuses quickly.

          Filtration :

          Lipid insoluble drug cross biological membranes by filtration if their molecular size is smaller than the diameter of the pores.

          Filtration is the passage of drugs through aqueous pores in the membrane or through paracellular spaces.

          Specialized transport :

          This can be carrier transport or pinocytosis :

          Carrier transport : the drug combines with a carrier present in the membrane and the complex then translocates from one face of membrane to the other.

          Pinocytosis : it is the process of transport across the cell in particulate form by formation of vesicles.

          ABSORPTION

          Absorption is the movement of drug from its site of administration into the circulation. 
          Factors affecting absorption are :
          Aqueous solubility :
          Drugs given in solid form must dissolve in aqueous biophase before they absorb.

          As we know the drug given in watery solution absorb faster than same given in solid form or oily solution.
          Concentration :
          Drug given as concentrated solution is absorbed faster than from dilute solution.

          Area of absorbing surface :
          Larger surface area, faster absorption.

          Vascularity of absorbing surface :
          Increased blood flow hastens drug absorption just as wind hastens drying of clothes.

          Route of administration :
          This affects absorption of drug because each route has its own peculiarities.

          ▪ If you are taking drug orally the presence of food dilutes the drug and retards absorption.
          ▪ Absorption from s.c. site is slower than that from i.m. site, but both are generally faster and more consistent/ predictable than oral absorption.

          ☆ Do you know ?
               Application of heat and muscular exercise accelerate drug absorption by increasing blood flow.

          ▪ Systemic absorption after topical application depends primarily on lipid solubility of drugs.
          ▪ Absorption can be enhanced by rubbing.

          DISTRIBUTION

          Once a drug has gained access to the blood stream, it gets distributed to other tissues that initially had no drug, concentration gradient being in the direction of plasma to tissues.

          The extent of distribution of a drug depends on its lipid solubility, ionization at physiological pH, extent of plasma binding and tissue protiens.

          Redistribution :

          • Highly lipid soluble drugs given i.v. or by inhalation initially get distributed to organs with high blood flow, e.g. brain , heart, kidneys, etc.

          • Later, less vascular but more bulky tissues (muscle, fat) take up the drug-plasma concentration falls and the drug is withdrawn from these sites.

          • If the site of action of the drug was in one of the highly perfused organ, redistribution results.

          • Greater lipid solubility of drug, faster is its redistribution.

          Penetration into brain and CSF :

          Blood brain barrier and blood CSF barrier are lipoidal and limit the entry of non lipid soluble drugs, e.g. streptomycin, neostigmine.

          Passage across placenta :

          Placental membrane also are lipoidal and allow free passage of lipophilic drugs.
          But it is incomplete barrier, because non- lipid soluble drug in higher concentration can access to the foetus.

          Plasma protein binding :

          Most drugs possess physicochemical affinity for plasma protiens.

          Acidic drugs generally bind to plasma albumin.

          Basic drug to alpha 1 acid glycoprotein.

          Extent of binding depends on the individual compounds.

          ☆ Drugs bound to plasma protiens :

          To albumin : Barbiturates, Benzodiazepines, NSAIDs, Penicillin, Sulfonamides, Tetracyclines.

          To alpha 1 acid glycoprotein : Prazosine, Quinidine, Lignocaine, Bupivacaine.

          Tissue storage :

          Drugs may also accumulate in specific organs or get bound to specific tussue constituents, e.g. --

          Skeletal muscle, heart : digoxin.
          Liver : chloroquine, Tetracycline.
          Kidneys : digixin.
          Brain : acetazolamide.
          Retina : chloroquine.
          Iris : ephedrine. Atropine.
          Bone and teeth : tetracycline.
          Adipose tissue : thiopentone, ether, phenoxybenzamine.

          BIOTRANSFORMATION  (METABOLISM)

          Biotransformation means chemical alteration of drug in the body. It is needed to render nonpolar (lipid soluble) polar (lipid insoluble) compound so that they are not reabsorbed in the renal tubules and are excreted.

          The primary site for drug metabolism is liver, others are : kidneys, intestine, lungs and plasma.

          Biotransformation may lead to the following:

          i) Inactivation : most drugs and their active metabolites are rendered inactive or less active, e.g. morphine, propranolol, chloramphenicol.

          ii) Active metabolite from an active drug : many drugs have been found to be partially converted to one or more active metabolite; the effects observed are the sumtotal of that due to the parent drug and its active metabolites.

          iii) Activation of inactive drug : few drugs are inactive as such and need conversion in the body to one or more active metabolites. Such a drug is called a prodrug.
          e.g. Levodopa is prodrug converted to Dopamine in active form.

          Biotransformation reaction can be classified into :

          A) Non synthetic reaction : metabolite may be active or inactive.

          i) Oxidation
          ii) Reduction
          iii) Hydrolysis
          iv) Cyclization 
          v) Decyclization

          B) Synthetic reaction : metabolite mostly inactive.

          i) Glucuronide conjugation
          ii) Acetylation
          iii) Methylation
          iv) Sulfate conjugation
          v) Glycine conjugation
          vi) Glutathione conjugation 
          vii) Ribonucleoside synthesis

          EXCRETION

          Excretion is the passage out of systemically absorbed drug. Drugs and their metabolites are excreted in :


          1. URINE : Through the kidneys. It is the most important channel of excretion for most drugs.

          RENAL EXCRETION 

          The kidney is responsible for excreting all water soluble substances. The amount of drug or its metabolites ultimately present in urine is the sumtotal of glomerular filtration, tubular reabsorption and tubular secretion.

          Glomerular filtration : Glomerular capillaries have pores larger than usual; all nonprotein bound drug presented to the glomerulus is filtered. 

          Glomerular filtration is depends on its plasma protien binding and renal blood flow.

          Tubular absorption : This depends on lipid solubility and ionization of the drug at existing urinary pH.
          Lipid soluble drugs filtered at the glomerular back diffuse in the tubules because 99% of glomerular filtrate is reabsorbed.

          Tubular secretion : Tubular secretion occurs simultaneously during tubular reabsorption of filtrate. 
          This is the active transfer of organic acids and bases by seperate non specific mechanisms whuch operates in the proximal tubules.

          2. FAECES : Apart from the unabsorbed fraction, most of the drugs present in faeces is derived from bile.

          3.EXHALED AIR : Gases and volatile liquids are eliminated by lungs, irrespective of their lipid solubility. 
          e.g. general anesthetics, alcohol.

          4.SALIVA AND SWEAT : These are of minor importance for drug excretion. 
          Lithium, pot.iodide, rifampin, and heavy metals are present in these secretions.

          5.MILK : The excretion of drug in milk is not important for mother, but the suckling infant inadvertently receives the drug.
          Most drugs enters breast milk by passive diffusion.
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