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Pharmacokinetics class 2

  1. Pharmacokinetics Absorption & Distribution
  2. Absorption • Absorption is movement of the drug from its site of administration into the circulation. • Both fraction of drug absorbed and rate of absorption is important.
  3. Absorption Factors affecting Absorption of drug: – Aqueous solubility: drug given as watery solution is absorbed faster than when the same is given in solid form or as oily solution. – Concentration: drug given as concentrated solution is absorbed faster than from dilute solution.
  4. • Area of absorbing surface: Larger the surface area faster is the absorption • Vascularity of absorbing surface: increased blood flow hastens drug absorption • Route of administration:
  5. Absorption • Oral: – The effective barrier to orally administered drugs is the epithelial lining of GIT, which is lipoidal. – Lipid soluble are readily absorbed than lipid insoluble drugs – Acidic drugs are unionized in the gastric juice and are absorbed from the stomach – Basic drugs are largely ionized and are absorbed only on reaching the duodenum
  6. Absorption • Surface area of absorption is larger in small intestine, thus faster gastric emptying accelerates drug absorption. • Presence of food delays gastric emptying, thus slower rate of absorption • Certain drugs form poorly absorbed complexes with food constituents (tetracycline with calcium present in milk)
  7. Absorption • Thus, most drugs are absorbed better if taken in empty stomach. • Certain drugs are degraded in the GIT, – Penicillin G by acid, insulin by peptidase and are ineffective orally • Affected by other concurrently ingested drugs due to formation of insoluble complexes – Tetracycline with iron preparations and antacids
  8. Absorption Subcutaneous (SC) and Intramuscular (IM): • Absorption from SC site is slower than that from IM site, but both are generally faster and more consistent than oral absorption
  9. Absorption Bioavailability: • refers to rate and extent of absorption of a drug from a dosage form. • It is a measure of the fraction of administered dose of a drug that reaches systemic circulation in the unchanged form.
  10. Absorption • Bioavailability of drug injected I.V. is 100%, but is frequently lower after oral ingestion because, – The drug may be incompletely absorbed – The absorbed drug may undergo first pass metabolism
  11. Distribution • Once a drug has gained access to the blood stream, it gets distributed to the other tissues that initially had no drug, concentration gradient being in the direction of plasma to tissues.
  12. Distribution • The extent of distribution of a drug depends on its, – Lipid solubility – Ionization at physiological Ph – Extent of binding to plasma and tissue proteins – Presence of tissue specific transporters and differences in regional blood flow.
  13. Distribution • Movement of drug proceeds until an equilibrium is established between unbound drug in plasma and tissue fluids. • Subsequently, there is a parallel decline in both due to elimination.
  14. Distribution • Factors that affect distribution • There are many factors that affect a drug’s distribution throughout an organism, • the most important ones are, – an organism’s physical volume, – the removal rate and the degree to which a drug binds with plasma proteins and / or tissues.
  15. Distribution • Volume of distribution (Vd): • The volume of distribution (VD) of a drug is a property that quantifies the extent of its distribution. • It can be defined as the theoretical volume that a drug would have to occupy, to provide the same concentration as it currently is in blood plasma.
  16. Distribution • It can be determined from the following formula: – Vd = Ab/Cp – Ab, is amount of drug in the body – Cp, is the drug’s plasma concentration
  17. Distribution • formula shows us that there is an inversely proportional relationship between Vd and amount of the drug to be administered. • Increase in plasma concentration, there will be decrease in volume of distribution of a drug.
  18. Distribution • If this formula is applied to the concepts relating to bioavailability, we can calculate the amount of drug to administer in order to obtain a required concentration of the drug in the organism
  19. Distribution • Apparent volume of distribution (V): – The volume that would accommodate all the drug in the body, if the concentration throughout was the same as in the plasma. • Lipid insoluble drugs do not enter cells, hence will have lesser V. – Streptomycin, gentamycin 0.25L/kg. • Drugs extensively bound to plasma proteins are largely restricted to vascular compartment and have low values. – Diclofenac, and warfarin 0.15 L/kg
  20. Distribution • Drugs sequestrated in other tissues may have, higher V. – Digoxin 6L/kg, propranolol 4 L/kg. • Because most of the drug is present in other tissues, and plasma concentration is low. • Pathological states, CHF, cirrhosis of liver, etc, can alter the V of many drugs by altering distribution of body water, permeability of membranes, binding proteins.
  21. Distribution • Removal rate of drug: – A drug's removal rate will be determined by the proportion of the drug that is removed from circulation by each organ once the drug has been delivered to the organ by the circulating blood supply – This new concept depends on a number of distinct factors,
  22. Distribution • The drugs characteristics, including its pKa • Redistribution through an organism’s tissues: – Some drugs are distributed rapidly in some tissues until they reach equilibrium with the plasma concentration. – However, other tissues with a slower rate of distribution will continue to absorb the drug from the plasma over a longer period
  23. Distribution – This will mean that the drug concentration in the first tissue will be greater than the plasma concentration and the drug will move from the tissue back into the plasma. – This phenomenon will continue until the drug has reached equilibrium over the whole organism
  24. Distribution • Presence of natural barriers. These are obstacles to a drug's diffusion similar to those encountered during its absorption. The most interesting are: – Capillary bed permeability, which varies between tissues.
  25. Distribution – Blood-brain barrier: this is located between the blood plasma in the cerebral blood vessels and the brain’s extracellular space. The presence of this barrier makes it hard for a drug to reach the brain. – Placental barrier: this prevents high concentrations of a potentially toxic drug from reaching the foetus
  26. Distribution • Plasma Protein Binding:(PPB) – Most drugs possess physicochemical affinity for plasma proteins – Extent of binding depends on the individual compunds
  27. Distribution • The clinically significant implications of PPB are, – Highly plasma protein bound drugs tend to have smaller volumes of distribution – Leads to temporary storage of drug as bound fraction is not available for action – High degree of protein binding generally makes the drug long acting, as bound fraction is not available for metabolism or excretion
  28. Distribution • One drug can bind to many sites on the albumin molecule • Conversely, more than one drug can bind to the same site, this can give rise to displacement interactions among drugs bound to the same site, – The drug bound with higher affinity will displace that bound with lower affinity.
  29. Distribution • Some clinically important displacement interactions are, – Salicylates displace sulfonylureas – Indomethacin, phenytoin displace warfarin • In hypoalbuminemia, binding may be reduced and high conentrations of free drug may be attained, e.g. phenytoin and furosemide.
  30. Biotransformation of Drugs • Alterations of a drug in a living organism is known as biotransformation. • By this process, a drug may either be inactivated or converted into a more active compound.
  31. Biotransformation of Drugs • Methods of biotransformation: – The reactions which bring about biotransformation of drugs can be classified as, • Phase I reactions (non synthetic reactions): These reactions lead either to activation or inactivation of a drug, • These reactions are further classified as,
  32. Biotransformation of Drugs • Oxidation: it occurs mainly in the liver. – A typical example is oxidation of ethyl alcohol, – Ethyl alcohol Acetaldehyde – Acetaldehyde Acetyl CoA • Reduction: it is less common process. Drugs like chloramphenicol, halothane and warfarin are metabolized by reduction
  33. Biotransformation of Drugs • Hydrolysis: This is brought about by enzymes called esterases which produce cleavage of the ester linkage – e.g: acetylcholine is hydrolised by cholinesterase and converted into choline and acetic acid
  34. Biotransformation of Drugs • Phase II reactions (synthetic reactions): – Synthetic reactions are also called as conjugation reactions lead only to inactivation of a drug 1. Glucuronide formation e.g. Morphine 2. Sulfate formation e.g. Phenols 3. Acetylation e.g. Sulfanilamide
  35. Biotransformation of Drugs • Biotransformation of drugs occurs primarily in the liver, • Other minor sites of biotransformation are kidney, plasma, placenta and testis. • In the liver, drug metabolizing enzymes are present in microsomes and are called as hepatic microsomal drug metabolising enzymes
  36. Biotransformation of Drugs • Factors modifying biotransformation, Inhibitors: drug metabolizing enzymes can be inhibited by certain drugs. Such drugs decrease the metabolism of other drugs. This in turn increases their duration of action. e.g. omeprazole, ciprofloxacin
  37. Biotransformation of Drugs Stimulators: they increase the metabolism of certain drugs by increasing the activity of drug metabolising enzymes • e.g. phenoborbitone and rifampicin Age: Metabolism of drugs is poor in young children because of poor development of drug metabolizing enzymes e.g. lack of glucuronyl transferase for the inactivation of chloramphenicol in new born
  38. Biotransformation of Drugs • Sex: females have less ability to metabolise drugs. • Species: rabbits metabolize atropine due to the presence of atropinase. – Humans lack this enzyme, so atropine is toxic to humans but non toxic to rabbits.
  39. Biotransformation of Drugs • Genetic: Deficiencies in drug metabolizing enzymes can be inherited. – Primaquine produces hemolysis in genetic deficiency of the enzyme glucose – 6-phosphate dehydrogenase. • Body Temperature: increase in body temperature increases drug metabolism, whereas decrease in body temperature has the opposite effect.
  40. Excretion of drugs Excretion of drugs: Various routes of drug excretion are, • Kidney: drugs may be eliminated through the kidney by, – passive glomerular filtration – most of the drugs are eliminated by this mechanism – Active tubular secretion – Passive tubular reabsorption
  41. Excretion of drugs • Lungs: drugs like volatile general anesthetics, alcohol are excreted through lungs • Skin: heavy metal like arsenic and mercury are excreted through skin • Bile: some drugs are excreted into small intestine through bile. These drugs may be absorbed again, carried to the liver and again excreted into small intestine through bile. (This process is called as enterohepatic circulation)
  42. Excretion of drugs • Milk: Milk is more acidic than plasma and hence basic drugs like pethidine are eliminated through it • Saliva: drugs like iodides and metallic salts are excreted through saliva.
  43. Mechanism of drug action • A drug may produce its effect by a number of mechanisms like combining with enzymes, cell membrane or other component of a cell. • Receptor: It is the hypothetical component of the cell with which a drug interacts. The receptor may be on the cell membrane or inside the cell. It may be a protein or enzyme.
  44. Mechanism of drug action • Agonist: is a drug which combines with the receptor and initiates pharmacological action. • Antagonist: is a drug which combines with the receptor and blocks it without producing a pharmacological action.
  45. Mechanism of drug action • Sites of drug action: 1. Drugs may produce localized effects on certain cells, tissues, organs etc., or generalized effects on most cells of the body 2. Drugs may act, 1. Extracellularly 2. On the cell surface 3. intracellularly
  46. Mechanism of drug action • Extracelluar effects: – Action through physical properties, 1. Physical mass: Agar agar produces a purgative effect because of swelling in presence of water 2. Adsorption: magnesium trisilicate acts as an antacid by adsorbing hydrochloric acid in the stomach 3. Radio-activity: radioactive isotopes used for the treatment of cancer produce their effect by emitting ionizing radiations.
  47. Mechanism of drug action – Action through chemical properties 1. Acidity and alkalinity: HCL is effective in the treatment of hypochlorhydria. Sodium bicorbonate acts as an antacid by neutralizing HCL of the stomach 2. Chelation: chelating agents like dimercarprol combine with metals like arsenic and form water soluble complexes. This helps in easy elimination of the metal through urine.
  48. Mechanism of drug action • Action on cell surface: penicillin acts by inhibiting cell wall synthesis of micro-organism • Action inside the cell: some drugs produce their effect by acting on intracellular structures. Anticancer drugs produce their effect by inhibiting nucleic acid synthesis inside the cell
  49. Mechanism of drug action • Action through enzymes: drugs can produce their effect by modifying enzyme activities. – Anticholinesterases like neostigmine act by inhibiting the enzyme acetyl cholinesterase. This prevents the inactivation of acetylcholine and increases its duration of action
  50. Factors affecting drug action • Response to a drug varies from one individual to the other, • Factors responsible for variation in drug effects are, 1. Age: Children are hyper reactive to certain drugs due to poor development of enzymes needed for inactivation or immaturity of renal functions. So lesser dose must be given for children than for adults.
  51. Factors affecting drug action • Formula to calculate child dose: Young’s formula: Age × Adult dose Age +12 Dilling’s formula: Age × Adult dose 20
  52. Factors affecting drug action • Body weight: Dose of a drug must be suitably adjusted in case of lean or obese individuals as body weight as influence on the concentration of the drug. • Sex: women are more susceptible to the effects of certain drugs – e.g: morphine produces more excitation in women than in men.
  53. Factors affecting drug action • Route of administration: the rate of absorption of a drug differs with the route of administration. The dose also varies with the ROA. – IV dose of a drug is less than SC dose. • Time of administration: This factor has definite effect on drug absorption – e.g: Drugs which produces nausea and vomiting should be taken after food. But anthelmintics should be taken in empty stomach
  54. Factors affecting drug action • Physiological factors: body temperature and acid-base status are some factors which modify drug effects. – E.g: salicylates lower body temperature only in fever but not in normal individuals. • Psychological factors: the effect of a drug may be modified by psychogenic response of the patient.
  55. Factors affecting drug action – Sometimes it is necessary to please the patient by psychological means. Placebo which is dummy medication is used for this purpose. • Pathological state: the effect of a drug may be modified in pathological conditions. – E.g; hyperthyroid individuals require large dose of morphine • Genetic factors: the effect of drug may vary due to genetic factors like inherited enzyme deficiencies
  56. Factors affecting drug action • Tolerance: it is the unusual resistance to normal therapeutic dose of a drug. So large dose is required to produce the effect. • Drug interaction: The effect of a drug may be modified by the prior or simultaneous administration of another drug. – The effects produced by drug combinations can be classified as,
  57. Factors affecting drug action 1. Additive effect: the total pharmacological response produced by two drugs is equal to the sum of the individual effects. 2. Synergism: the total effect produced by two drugs is greater than the sum of individual effects 3. Antagonism: two drug act on the same physiological system and produce opposite effects
  58. Drug Toxicty • Drugs can produce toxic effects in addition to pharmacological actions. • Therapeutic index: TI= LD50 ED50 LD50: dose that kills half the population of the animal tested ED50: dose that produces the desired response in half the population of the animal tested TI Provides idea about the safety of the drug. Higher the TI safer is the drug.
  59. Drug Toxicty • Following are the various toxicity produced by the drugs: 1. Intolerance 2. Hepatotoxicity 3. Nephrotoxicity 4. Behavioural toxicity 5. Drug induced diseases
  60. Drug Toxicty • Endocrine disturbances • Electrolyte disturbances • Skin reactions • Carcinogenesis • Teratogenic effects • addiction
  61. Rational use of drugs • Rational use of drugs may be defined as, • Patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and the lowest cost to them and their community.
  62. Rational use of drugs • Rational drug therapy means the use of drugs, which are efficient, safe, low-cost and easy to administer. It requires that health practitioners have adequate medical knowledge and appropriate skill for correct diagnosis and treatment
  63. Indian Pharmacopoeia • Pharmacopoeia: an official book containing a list of medicinal drugs with their effects and directions for their use.
  64. Chemotherapy • It is defined as the treatment of specific infections with chemical agents. • A chemotherapeutic agent may be, – Bacteriostatic : agent which inhibits growth of bacteria – Bactericidal: agent which kills the bacteria
  65. Chemotherapy • Antibiotics: are chemical substances synthesized by various species of microorganisms (MO)which causes suppression of growth and destruction of other MO. – Narrow spectrum: effective against either gram- positive or gram-negative bacteria – Broad Spectrum: effective against both gram- positive and gram-negative bacteria
  66. Chemotherapy • Classification of antibiotics: – Broad spectrum antibiotics • Tetracyclines, chlorampenicol – Narrow spectrum antibiotics a. Effective against gram positive bacteria – Penicilins, erythromycin, vancomycin b. Effective against gram negative bacteria – Streptomycin, kanamycin – Antiprotozoal antibiotics • Paramomycin, fumagillin
  67. Chemotherapy – Antifungal antibiotics • Amphotericin B, Griseofulvin – Antimalignant antibiotics • Actinomycin D
  68. Chemotherapy Mechanism of action of antibiotics: • They act, 1. By inhibiting cell wall synthesis – penicilins, cephalosporins, cycloserine 2. By inhibiting the function of cell membrane – polymixin, nystatin 3. By inhibiting protein synthesis – chlorampheniciol, tetracyclines 4. By inhibiting nucleic acid synthesis –actinomycin D, mitomycin C.
  69. Chemotherapy Sulfonamides and other synthetic antimicrobial agents: • Sulfonamides are derivatives of the parent compound, para aminobenzene sulfonamide. • Classification of sulfonamides, 1. Short acting – sulfadiazine 2. Intermediate acting – sulfamethoxazole 3. Long acting – sulfodoxine
  70. Chemotherapy • Sulfonamides are mainly Bacteriostatic. But at very high concentration, they may have bactericidal effect. • Mechanism of Action (MOA): – Sulfonamides have a structural similarity to para amino benzoic acid (PABA). Because of this they compete with PABA for incorporation into folic acid. They inhibit folic acid synthetase. So folic acid is not synthesised
  71. Chemotherapy • Absorption, fate and excretion – Sulfonamides used for systemic infection are rapidly absorbed, while for local effect on intestine are poorly absorbed, they bound to plasma proteins to the extent of 50%, they are distributed in all tissue fluids except CSF, metabolized by acetylation. Free and acetylated sulfonamides are excreted in urine
  72. Chemotherapy • Adverse reactions: allergic reactions like fever and skin rashes, crystalluria, thrombocytopenia. • Therapeutic uses: lcerative colitis, UTIs, acute bacillary dysentry, meningococcal meningitis
  73. Chemotherapy • Sulfasalazine: it is used in rheumatoid arthritis and ulcerative colitis. • Silver sulfadiazine: it is applied locally as 1% cream. It is effective against large number of bacteria and fungi. It slowly releases silver which produces antimicrobial action. It is used in burns to prevent infections.
  74. Chemotherapy • Trimethoprim and sulfamethoxazole: (cotrimoxazole) • Trimethoprim has antimicrobial and antimalarial properties. It is only bacteriostatic. • MOA: it inhibits the enzyme dihydrate folate reductase. So the conversion of dihydro folic acid to tetrahydrofolic acid is inibited
  75. Chemotherapy • Sulfonamides act by inhibiting the conversion of PABA to dihydrofolic acid, so combination of sulfonamides and trimethoprim prevents synthesis of nucleotides. • Adverse reactions: cotrimoxazole can produce, – Nausea, vomiting and skin rashes – Anemia, leucopenia and thrombocytopenia – crystalluria
  76. Chemotherapy • Therapeutic uses: cotrimoxazole can be used for, – Urinary infection due to E.coli and proteus. – Respiratory infections, gonorrhea and typhoid fever
  77. Chemotherapy Quinolones Nalidixic acid: it is a quinolone derivative, It is effective against gram negative bacteria, especially E.coli. MOA: It acts by inhibiting DNA replication. It is bactericidal. Adverse reactions: nausea, vomiting, diarrhoea allergic reactions like pruritis and urticaria
  78. Chemotherapy Fluoroquinolones They are quinolones containing fluorine in their structure. They act by inhibiting the enzyme DNA gyraze. Classification: – First generation fluoroquinolones • Ciprofloxacin, norfloxacin, ofloxacin – Second generation fluoroquinolones • Levofloxacin, sparfloxacin
  79. Chemotherapy • Ciprofloxacin: – It is more active against aerobic gram negative bacilli (E. coli and Neisseria). It is rapidly absorbed orally. Oral bioavailability is 60 to 80%. About 30% is bound to plasma proteins. Partly metabolized and excreted in urine. – Adverse effects: GI disturbances, dizziness, headache, restlessness and skin hypersensitivity – Uses: UTIs, gonorrhea, typhoid, conjunctivitis
  80. Chemotherapy • Norfloxacin: It is less potent than ciprofloxacin. It attains lower concentration in tissues. Primarily used for urinary and genital infections. It is highly effective in bacterial diarrhoea. • Ofloxacin: it is active against Chlamydia and mycoplasma. Also effective against M.tuberculosis and M. leprae infections, chronic bronchitis, respiratory and ENT infections.
  81. Chemotherapy • Sparfloxacin: it has enhanced activity against gram positive bacteria. Useful in pneumonia, chronic bronchitis, sinusitis and ENT infection. • Gatifloxacin: It has high activity against Strep.penumoniae and many respiratory pathogens. • Moxifloxacin: it is a long acting second generation fluoroquinolone. It is most effective in M.tuberculosis.
  82. Chemotherapy • Penicillins: Penicillins, the most important of the antibiotics, are obtained from penicillium notatum and penicillium chrysogenum.
  83. Chemotherapy • The commonly used penicillin is benzyl penicillin or penicillin G. • Antimicrobial activity: penicillin is a narrow spectrum antibiotic, very effective against gram positive organisms. The sensitivity of various organisms to penicillin is as follows: – High sensitive: gonococci, pneumococci, meningococci – Moderately sensitive: bacillus anthracis, clostridium welchii
  84. Chemotherapy • MOA: penicillin is a bactericidal drug. It acts by inhibiting the synthesis of bacterial cell wall. This action is produced by inhibiting the synthesis and cross linkage of peptidoglycans. • Absorption, fate and excretion: – On oral administration, benzyl penicillin is inactivated by gastric acid. Also food interferes with its absorption. It is rapidly absorbed after SC or IM injection
  85. Chemotherapy – About 60% is bound to plasma proteins – It is distributed to kidneys, liver, plasma and intestine. – Normally it is not taken up by CSF. But high concentrations are present in CSF during meningeal inflamation. It is eliminated through urine by tubular secretion.
  86. Chemotherapy • Repository preparations: Benzyl penicillin is rapidly eliminated through urine. So it has to be administered frequently at an interval of 4 to 6 hrs. This disadvantage is overcome by repository preparations of penicillin.
  87. Chemotherapy • These preparations are relatively insoluble. So they act by slowly releasing penicillin and thus prolonging its effect. The repository preparations of penicillin are: – Procaine benzyl penicilin – Fortified benzyl penicillin (a mixture of procaine benzyl penicillin and benzyl penicillin) – Benzathine penicillin (a dibenzylethylendiamine salt of benzyl penicillin)
  88. Chemotherapy • Penicillin with probencid (probencid competes with penicillin for tubular secretion. This decreases renal elimination of penicilin) • Adverse reactions: 1. Intolerance which includes allergic and anaphylactic reactions. Allergy which is the major problem with penicillin may occur in the form of skin rashes, renal disturbances and hemolytic anemia.
  89. Chemotherapy ………the manifestation of anaphylaxis are cardiovascular collapse, bronchospasm and angioedema. 1. Super infection with klebsiella, aerobacter and candida 2. Miscellaneous like nausea and vomiting on oral administration.
  90. Chemotherapy • Therapeutic uses: – Streptococcal, pneumococcal and meningococcal infections. – Veneral diseases like gonorrhea and syphilis – diphtheria, tetanus and gangrene – Actinomycosis and anthrax. – In the prophylaxis of rheumatic fever and streptococcal infections.
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