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INTRO TO ADME

Slim Shady PHARMACOLOGY A English 75 cards

Cards in this deck (75)

  1. 1Four phases of PK (pharmacokinetics)Absorption, distribution (around the tissues), metabolism (drugs metabolised notably in the liver) and excretion (of the metabolites from kidneys)
    ADME - collectively determines the time course of the drug action.
  2. 2Half-lifethis is the time taken for the drug concentration measured at any time-point to half
  3. 3what can excessive responses arise frominhibited liver metabolism or delayed excretion (renal dysfunction)
  4. 4what causes sub-optimal responsesIncomplete absorption or enhanced first path metabolism
  5. 5drug distributionDrugs distributed through body compartments that are based on lipid-solubility and molecular size.
  6. 6Where does drug metabolism occur, and what is the purposeChiefly in the liver to
    1. deactivate the drug
    2. change chemical nature of drug so that it is sufficiently water-soluble to be excreted via urine/bile.
  7. 7Factors affecting absorption1. Barriers
    intravenous - none
    Oral - gastrointestinal mucousa
    Topical - skin epithelium, subcutaneous tissues
    2. Drug factors themselves affecting rate/extent of absorption:
    so its molecular size, lipid solubility, ionisation at physiological pH, chemical form and pharmaceutical form of the drug.
    3. Patient factors;
    The size of their absorptive surface, blood flow to site of absorption, and for drugs given orally, stomach emptying and intestinal transit.
  8. 8Bioavailabilitythe rate at and the extent to which a nutrient is absorbed and used
    so 100% absorption and 100% bioavailability for drugs entering the body intravenously.
    100% absorption for intramuscular injections and subcutaneous injections but not 100% bioavailability
    (lower for both absorption/bioavailability for topical/oral etc.)
  9. 9Pharmaceutical formationssolid tablets (oral),
    semi-solid - oinments/creams/suppositories/ pessaries
    liquids - syrups, suspensions
    and aerosol (inhalation)
  10. 10easier absorption for drugs in relation to their molecular weight and lipid solubilityDrugs more easily absorbed and passed through body with low molecular weights and sufficient lipid solubility
  11. 11Drugs with molecular weights greater than 5000 daltonse.g. heparin, proteins (e.g. monoclonal antibodies) will have difficulty crossing membranes and wont be absorbed through any other route other than injection.
  12. 12How do most drugs pass into membranespassive diffusion, thus since they are then penetrating the bilayer they need some degree of lipid solubility
  13. 13what are most drugs (in relation to pH)weak acids or weak bases.
    in alkaline conditions - weak acids are ionised (water-soluble) and weak bases are unionised (lipid soluble)
    In acid conditions - weak bases are ionised (water soluble and weak acids are unionised (lipid soluble)
  14. 14pKaused to indicate the strength of an acid. pKa is the negative log of the acid dissociation constant or Ka value. A lower pKa value indicates a stronger acid. That is, the lower value indicates the acid more fully dissociates in water
  15. 15intestinal pHapprox 7-8 (weak base) so largely ionised and water soluble, thus the intestines are hostile to weak acids since it favours the absorption of weak bases.
  16. 16strong acid and strong baseA strong acid will react with a strong base to form a neutral (pH = 7) solution.
  17. 17strong acid and weak baseA strong acid will react with a weak base to form an acidic (pH < 7) solution.
  18. 18strong base and weak acidA weak acid will react with a strong base to form a basic (pH > 7) solution
  19. 19examples of drug that is weak acidaspirin
    (very little absorption occurs across the gastric muscuosa due to its less surface area and reduces blood flow, but small amounts of aspirin can still be absorbed via the small bowel - pH of small bowel ranges from 5.5 to 7.0.)
  20. 20examples of drug that is weak basediazepam
  21. 21Besides lipid solubility, what else is an important factor in terms of drug absorptionRate of drug penetration through a cell membrane - which is determined through surface area of the absorption site - and the thickness and concentration gradients existing between both sides.
    Passive diffusion continuous on both sides until conc's are equal - but this cannot occur at site of drug absorption. so conc on outside of drug will remain higher than that of the tissue into which it is absorbed.
    This is because, the drug molecules having crossed the absorption surface of the small bowel muscosa are not allowed to accumulate locally - instead they instantly enter the capillaries of the portal circulation - so consequently diffusion continues until higher dosage is absorbed.
  22. 22Factors increasing drug penetration ratelipid solubility, surface area, concentration gradient, molecular weight and membrane thickness (obvs the thinner the more easier it is for drug to enter target cells)
  23. 23Mechanism of absorption for most drugsThis is passive diffusion - again, rate at which this occurs depends on size of the drug molecule and its lipid-solubility. So, for small, highly lipid-soluble drugs, the diffusion occurs so rapidly that absorption is limited primarily by the perfusion of the tissue which removes the absorbed drug to maintain the conc gradient.
    But.. for drugs with low lipid solubility, the rate-limiting step for absorption is the rate of membrane penetration.
  24. 24Mechanisms for passing drugs with low lipid solubility across the absorptive surfaceinvolves participation of specific carrier proteins (transporters) which enable passage of drugs through the membrane and doesn't require ATP (energy) - this is known as facilitated diffusion.
  25. 25Pinocytosisprocess by which a cell invaginates to form endosomes which would contain a small amount of extracellular fluid containing a drug - this enables larger molecules such as polypeptides and small proteins to cross the membranes but is not a common mechanism of a drug
  26. 26Factors affecting the RATE of drug absorption1. Surface area of the absorption surface - so for example drug absorption from the intestinal lumen is more effective than from the stomach
    surface area would be reduced from those having sections of small bowel removed (e.g. crohn's disease)
    2. Perfusion of the tissue from which drug absorption is taken place - this will determine how fast drug molecules are removed from the area once absorbing surface has been penetrated - this in turn depends on the vascularity of the surface (this differs of course among tissues.)
    3. Rate of gastric emptying - this is fastest when stomach is empty and so is slowed by presence of food (especially fat)
    this emptying can be increased by dopamine antagonists such as metoclopramide and is reduced by antimuscarinic agents such as propantheline (reductions in gastric emptying may alter rate of drug absorption but wont affect the extent of drug absorption - unless drug is damaged in the stomach that is.)
  27. 27Pharmaceutical formation and drug absorption ratesDrugs that are liquids - so those already dissolved in aqueous solutions will rapidly disperse following administration and thus will be rapidly available for absorption over large SA (surface area) of gastrointestinal mucosa.
    Drugs given via the mouth - so capsules/tablets - needs to disintegrate before dissolving for absorption - these will usually disintergrate when reached the duodenum rather than at the stomach to protect them from destruction there. These are known as being enteric-coated (prevents the drug being released in the acidic conditions of the stomach before reaching the intestine)
    Tablet-modified release - related to drugs that are incorporated into a complex matrix from which they are released from slowly - delaying absorption and pro-longing drugs action - so these are modified-release formations.
  28. 28Route for oral drugsSwallowed by mouth, going down the oesophagus into the stomach, and then into the small bowel, and here they can be absorbed across the large surface area of the (x )small bowel mucosa to then travel to the liver via the portal venous circulation.
    They then travel from liver to the heart via the hepatic vein (so going into the systemic circulation) - due to involvement of small bowel muscosa this is often referred to as the enteral route
  29. 29Oral drugs where they directly enter the systemic circulationBuccal and sublingual
    buccal tablets -Designed to dissolve slowly when placed between the cheek and gums
    sublingual tablets - under tongue dissolve quickly
  30. 30rectal administrationdrugs are inserted through the anus into the rectum - reduces its exposure to venous portal system and liver
  31. 31intravenous injectionthe administration of medication by injection directly into a vein - avoids intestinal absorption - so it is able to directly enter systemic circulation
  32. 32intramuscular injectionsInjection of a medication into a muscle tissue
    usually leads to rapid effect but the rate of absorption into systemic circulation is highly dependent on muscle blood flow
  33. 33transdermal administrationapplication of a drug in patch form, which is then absorbed into the blood through the skin (can directly enter systemic circulation)
  34. 34topical administrationApplication of a drug to skin/particular mucosa membranes, usually for a local action (lotions/creams/ointments)
  35. 35Subcutaneous injectionadministered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis (dermis and epidermis collectively is the cutis) - highly effective in administering insulin, morphine
  36. 36limitations of oral administration(only a proportion of drug is bioavailable for distribution to the body tissues - some molecules may be lost due to destruction by gastric acid binding to food)
    BUT most important limiting factor is something called first-pass metabolism by enzymes in intestinal wall and liver. There are also enzymes responsible for phase-2 conjugation reactions. Mucosal cells also contain transporter proteins which can return drug molecules to the intestinal lumen. The effect of these processes can be so extensive that no active drug actually reaches the systemic circulation.
  37. 37what accounts for most first-pass metabolismPassage of portal blood flow through the liver that accounts for most first-pass metabolism of drugs giving orally due to livers great enzyme content - notably the phase-1 metabolising enzymes of the cytochrome P450 system
  38. 38cytochrome P450 systemRefers to a set of enzymes that metabolise numerous substrates via oxidation (Phase I reaction)
  39. 39How can first-pass metabolism in intestines and liver be avoided through oral absorptionadministering drugs to other absorptive surfaces on GI tract that do not involve drainage into the portal circulation - so these include the buccal and sublingual mucosa and the rectal musoca.
    so sublingual and bucca administration needs to be rapid, avoid first-pass metabolism in liver and intestines, it must be a convenient location and should be able to be removed easily from the site of absorptions - e.g. glycerol trinitrate and fentanyl.
    and rectal administration also needs to be convenient, used for patients who cannot swallow or are vomiting, it needs to also avoid first-pass metabolism e.g. paracetamol, diazepam.
  40. 40Advantages and disadvantages of intravenous injectionsA's - no concerns about absorption, dose is 100% bioavailable, avoids first-pass metabolism, has a rapid, high conc e.g. analgesics, antibiotics, diuretics
    V's - adverse effects may also be rapid in onset and potentially augmented (so drugs with low therapeutic index may not be desirable in high conc's in plasma - intravenous infusions should instead be used here since drug is administered over longer period of time)
    - achieving intravenous access required technical expertise.
  41. 41intravenous infusion vs injectionAn infusion is when fluids, medication, or blood is given through a catheter directly into a vein.
    An injection refers to the administration of medication using a needle and syringe
    Main difference between an infusion and injection is the period of administration. On the one hand, injections are often done within minutes. On the other hand, infusions can take anywhere between 30 minutes to several hours.
  42. 42Intramuscular injection advantagesA's - requires less training/experience in comparison to intravenous injections/rapid absorption/avoiding first-pass metabolism e.g. adrenaline, antibiotics and anti- psychotics.
    V's - painful, the rate of the absorption can be unpredictable, potential for damage to important structures.
  43. 43common muscles for IM injections?the deltoid muscle of the upper arm and the gluteal muscle of the buttock. In infants, the vastus lateralis muscle of the thigh is commonly used.
  44. 44A's and V's of subcutaneous administrationA's - relatively simple to administer, rapid absorption of lipid-soluble drugs, avoids first-pass metabolism, e.g. insulins, diamorphine, heparins
    D's - accommodates small volumes only, injection sites difficult to find and can sometimes cause lipoatrophy in patients with diabetes.
  45. 45A's and V's of topical and transdermal administrationTransdermal - slow unpredictable absorption BUT avoids first-pass metabolism - e.g. nicotine, opioids,
    oestrogen, glycerol trinitrate.
    Topical administration - Again, these drugs are intended to act locally e.g. antibiotics, corticosteroids.
  46. 46Alternative drug administration methodsto the eye and ears(e.g. corticosteroids, antimicrobials), to the nose (decongestants), to the peritoneal cavity (antibiotics), corticosteroids can also be applied to the joints (intra-articular), also vaginal (oestrogen), intrathecal/epidural, intra-arterial (vasodilators), and intra-cavernosal.
  47. 47Drug absorption interactions1. Binding of drugs in a non-absorbable form
    - e.g. colestyramine binding to levothyroxine and warfarin
    2. Reduced rate of gastric emptying - by antimuscarinic drugs (tricylic antidepressants)
    3. Reduced gastric acidity - anti-ulcer drugs can influence ionisation or breakdowns of others
    4. Altered first-pass metabolism and bioavailability (increased by phenobarbital for example) (decreased by cimetidine for example)
  48. 48first pass metabolismthe substance degradation of an orally administered drug caused by enzyme metabolism in the liver/intestines before the drug reaches the systemic circulation
  49. 49movement of drugs through the bodyintracellular fluid and fat and interstitial (extracellular) fluid and the circulation itself (plasma) - drugs are able to move between these compartments - again, by passive diffusion down conc gradient (sometimes actively against conc gradient)
    with short dosages, drugs move from plasma to interstitial fluids, and then to intracellular fluid -- eventually an equilibrium will be reached when the conc's of each compartment means that the rate of entry and exit from each is equal. But without further drug administration this equilibrium will not last since the elimination of drug from the plasma by metabolism or excretion will create a gradient favouring movement of the drug out of the tissues.
  50. 50what is distribution of drug molecules between membrane compartments dependent onTheir molecular size, lipid solubility, ionisation, ability to bind with plasma proteins, rate of blood flow and any existing special barriers (such as the Blood brain barrier).
  51. 51three ways in which drug molecules move around the body1. Bulk flow transfer - movement of larger doses of drug over long distances in bloodstream - so its rate depends on blood flow, its unaffected by the chemical nature of the drug,
    2. Filtration - movement of drug molecules dissolved in a volume of fluid through gaps in the endothelium - so rate depends on conc of drug in fluid and the rate of fluid transfer (relates to the hydrostatic pressure gradient which is driving fluid across the endothelium) filtration depends on hydrostatic and osmotic pressures - so it is limited by blood flow rather than lipid solubility and is not saturable.
    3. Diffusion - movement of drugs, molecule by molecule, over short distances (usually across membranes) and these are greatly influenced by chemical nature (size, lipid solubility etc.) and rate depends on the conc gradient across the membrane.
  52. 52Protein binding of drugsMany drugs bound to proteins in the plasma - e.g. weak acids bind to (algmin) and weak bases to alpha-1-acid glycoprotein, whereas steroids bind to globulins.
    For drugs displaying this property, association and dissociation are rapid and reversible. Binding takes place as soon as drug molecules enters the plasma. Throughout the drugs residence in the body until the last molecule has been eliminated, and the plasma contains no drug, the fraction bound will remain unchanged unless displacement occurs as a result of competition from other drugs/endogenous substances (free fatty-acids).
  53. 53As plasma drug concentration increasesMore and more drug molecules become bound, thus maintaining a constant fraction. This creates a protective depot of drug in the blood
  54. 54Why cannot bound proteins with the sort of created protective depot cannot leave plasmabecause molecules carrying the drugs are too large to enter capillary walls
  55. 55Drugs that are more than 90% bound to plasma proteinsaspirin, warafin, diazepam, quinidine.
  56. 56first stage of distributionfirst stage of distribution is the transfer of drug molecules from the plasma to the interstitial fluid - this involves crossing a layer of vascular endothelial cells
    since normal endothelium is made up of a continuous layer of cells - this means any drugs crossing into the interstitial fluid must cross either the two membranes and cytosol of the endothelial cell or, it must travel through the small gaps separating the cells.
    These gaps are packed with a lose matrix of proteins which act as filters retaining the large molecules and letting the smaller ones through.
  57. 57discontinuous endotheliumfound within organs with specialised functions such as the liver and spleen - this allows the free passage of drugs in water which filters between the cells.
    This filtration is also important in capillaries, which have large pores, allowing nearly all free drugs in plasma to be filtered
  58. 58What must occur for drugs to pass through membranesThey must dissolve in the aqueous solutions surrounding it and not be bound with large molecules such as proteins.
  59. 59benefit of the membrane having a large surface area and non-specific nature of simple diffusionmeans simple diffusion is not saturable (i.e. rate of transfer of drugs across the membrane will increase with conc of drug being increased)
    non-specific aspects advantage means that process wont be inhibited by other drugs/molecules.
  60. 60Factors affecting diffusion rateChemistry of membrane (such as its thickness and chemical composition) lipid solubility of drug/molecule, size and conc gradient.
  61. 61PynocytosisThe intake of small droplets of fluid by a cell by cytoplasmic engulfment. This occurs in mainly white blood cells and certain kidney and liver cells.
    (so its involving invagination of certain part of membrane and trapping of a small vesicle containing extracellular constituents - vesicle contents can then be released within the cell or extruded from its other side through fusion with another part of the membrane - i.e. exocytosis)
    Important for transport of some macromolecules such as insulin which via this process is able to cross the blood brain barrier.
  62. 62Drugs too large to pass through membranesi.e. amino acids and glucose, neurotransmitters
    These are transferred via carrier proteins (transporters)
    this can either be in form of passive transport or active transport and both processes are saturable since bioavailability of the drugs in terms of the levels of their conc in fluids can overwhelm the availability of carrier proteins
    so this is facilitated diffusion (or carrier-mediated diffusion)
  63. 63UniportA membrane transport process that transports a single type of molecules/ion at once.
  64. 64symportA membrane transport process that carries two substances in the same direction across the membrane.
    (co-transport)
  65. 65antiportA membrane transport process that carries one substance in one direction and another in the opposite direction.
    (also co-transport)
  66. 66drug transporter proteinsOAT's - organic anion transporters
    OCT's - organic cation transporters
    P-glycoprotein (P-gp)
    these drugs important in crossing particular drug transporter sites - such as the blood brain barrier, the renal tubules, hepatocytes and the intestinal mucosa
  67. 67what is meant by the term volume of distributionvolume of fluid required to contain the total amount of drug in the body at the same conc at which drug present in the plasma.
    so, volume of distribution (L) = mass of drug (mg)/plasma conc (mg/L)
    Vd = A/Cp
    NB: this can be termed the 'apparent volume' since it is relating the two variables as shown in equation to give an idea of what the volume of distribution will be but wont be true, since it cannot realistically be accurately measured.
  68. 68What does it mean in terms of the apparent volume of distribution for drug molecules highly bound in the tissuesThe resulting low plasma concentration of drug molecules means that the apparent volume of distribution can exceed the volume of the body
  69. 69Calculation - drugs conc's across plasma, interstitial fluid and intracellular fluid for 500mg IV injection (Drug A has Cp of 100mg/L), (Drug B has 31mg/L for its Cp), (Drug A - Cp is 5)Vd = A/Cp = 500/100 = 5L - A
    Vd = A/Cp = 500/31 = 16L - B - so it has been able to transfer through interstitial fluid but not actually enter the cells.
    Vd = 500/5 = 100L - C - so has passed through intracellular and interstitial fluids - since this volume is higher than that of the body - it infers that much drug molecules have become bound within the intracellular space.
  70. 70body volumeso Vd expressed usually as for a 70kg adult or per kg for a 70kg adult - of which will usually have body volume (water) of 42L. (0.6L per kg)
    small Vd - here we are talking about 5-10L - suggests that drug volume largely contained within vascular compartments
    large Vd - means there has been a large uptake of drug molecules by most tissues.
  71. 71half-lifetime taken for drug concentration in the body plasma to fall by half.
    When time/volume of distribution is short - half-life is short - time to reach steady state is short -short time for elimination of drug (opposite for larger Vd's)
    so drugs with small Vd's need to be given repeatedly to maintain the therapeutic concentrations of drug in body/plasma and drugs with high Vd's needs to be given less frequently.
    volume of distribution -volume of the drug that must be cleared before elimination is complete, and this along with the rate of clearance is one of the two determinants of half-life (other is time taken for drug to be distributed)
  72. 72Apparent volume of distributionvolume of fluid required to contain the total amount of drug in the body at the same concentration as that in the plasma - estimated by measuring plasma drug concentration shortly after dosing.
  73. 73One compartment modelLogarithmic concentration- time plot appears as though a single compartment is rapidly filled from which there is an exponential reduction from which the drug is eliminated with a rate constant (K)
  74. 74two compartment modelfull equilibration to steady state may take several hours in reality because although some parts of the body are readily accessible for distribution after administration of drug to body others may require longer for full equilibration to take place.
    This is usually due to sequestration of the drug into specific organs - depends on factors such as blood flow, and protein binding.
    The logarithmic conc time curve may show two curves which represent two distinct kinetic phases. True volume of distribution can only be calculated when second phase is completed and conc at time 0s can be estimated.
  75. 75sequestrationan accumulation and storage of certain compound in the chemical system

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A PHARMACOLOGY Flashcards on INTRO TO ADME, created by Slim Shady on 23/11/2020.
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