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MEDSCI 204 > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

What is ADME?

A

Absorption, distribution, metabolism, excretion

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2
Q

What is IDE?

A

Input, distribution, elimination

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3
Q

Elimination =?

A

Metabolism, Excretion

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4
Q

Why is ADME important?

A

ADME properties of a drug directly influence the concentration time profile in the body.

Time to peak concentration, peak concentration, time to be eliminated etc

This is important because concentration relates to drug effect

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5
Q

Pharmacokinetic and Pharmacodynamic plots

A

Conc/time = pharmacokinetic

Effect/Conc = pharmacodynamic

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6
Q

Reasons for failure in drug development

A

Clinical safety, efficacy, formulation, PK, commerical, toxicology, cost of goods, other

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7
Q

Drug disposition diagram

A
  • Binding to plasma proteins
  • Reversible flow into other tissues
  • Binding and storage in tissues
  • Metabolism
  • Metabolites
  • Biliary excretion
  • Renal excretion
  • Rest of concentration at site of action -> pharmacological effect
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8
Q

Major organs involved in ADME

A

Gastro-intestinal (GI) tract (absorption)

Liver (metabolism)

Kidney (excretion)

Lungs (absorption and excretion of volatile anaesthetic gases)

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9
Q

Drugs physico-chemical properties

A
  • Multiple physico-chemical properties of the drug can influence ADME processes
    • Solubility
    • Lipophilicity
    • Ionisation (pKa)
  • Chemical structure
    • Susceptibility to metabolism
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10
Q

Membrane transport

A
  • Passive diffusion
  • Facilitated diffusion
  • Active transport
  • Endocytosis
  • Filtration
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11
Q

Passive diffusion

A
  • Most common mechanism for drug absorption
  • Driven by concentration gradient
    • At equilibrium unbound concentrations of drug on either side would be the same
  • Nonselective
  • Lipophilic, uncharged and small molecules pass easily
  • Small charged molecules like Na+ and Ca2+ don’t pass and instead are regulated by the cell
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12
Q

Facilitated diffusion

A
  • Passive diffusion of drugs through transmembrane proteins
    • Driven by concentration gradient
  • Requires recognition by carrier or channel protein
    • e.g SLC transporters
  • Sugars and amino acids usual substrates
    • Less important for drugs
    • e.g tetracycline diffusion into bacteria
  • Rate is usually faster and can saturate
  • Can have competing ligands for the same transmembrane protein
  • Important in the tubules of the kidney, the GI tract etc
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13
Q

Active transport

A
  • Uses cellular energy to transport drugs across membrane
    • Is not driven by concentration-gradient, can oppose concentration gradient
  • Requires recognition by membrane transporters
  • Drug transporters highly expressed in specific organs
    • Liver, kidney, blood brain barrier, gut epithelium
  • Active transport allows cell to:
    • Accumulate compounds essential for growth
    • remove waste products
    • Be protected against toxins
  • ATP binding cassete (ABC transporters)
    • Present in GI, brain and kideny, where they act to efflux from cell
    • Wide range of substrates, eg cyclosporine, digoxin
    • Can be induced and inhibited, e.g St Johns wort will induce transporter (source of DDIs)
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14
Q

Endocytosis

A
  • Drugs is taken up by cell in vesicles (endocytosis)
    • Degraded in lysosomes
    • Released by cell (exocytosis)
  • Energy dependent
  • Mainly for drugs with MW > 1000 Da
    • E.g cytokines, hormones, growth factor, antibodies such as monoclonal antibodies, immunoglobulins, nano-formulations
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15
Q

Filtration

A
  • Most drugs pass through cells to cross biological barriers, except at:
  • Blood capillaries
    • Contain fenestrations that allow rapid interchange between blood and interstitial fluid
  • Glomerular capillaries (kidney)
    • Extremely porous allowing passage of all plasma constituents except macromolecules (MW > 30,000)
  • Some cells in the liver also have fenestrations
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16
Q

Routes of drug administration

A
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17
Q

Drug absorption

A
  • Transfer of drug from administration site ot the systemic circulation
    • Requires passage through biological membranes
  • Drugs administered orally must be absorbed before they can cause their pharmacological effect
    • Several barriers to overcome, so absorption is usually delayed and incomplete
    • Big concentration on delivery side, low concentration inside the cell and in the circulation
  • Relevant for extravascular drug administration
    • ie oral (po), subcutaneous (sc), intramuscular (im), rectal (pr), sublingual (sl)
    • Not relevant for administration directly into system circulation (ie intravenous, i.v)
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18
Q

Absorption: Rate and Extent: 2 Things

A
  1. Rate: How rapidly the drug gets from the site of administration to the systemic circulation, Rate of absorption: IV < Inhalation < Intramuscular < Subcutaneous < Rectal/Sublingual < Oral < Topical < Transdermal
  2. Extent: How much of the administered dose enters the system circulation, bioavailability, F = 1: 100% enters arrives at circulation; F<1, incomplete absoprtion
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19
Q

Example of rate and extent of absorption on concentration profile

A
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20
Q

Most popular routes of drug administration

A
  • Intravenous
    • Rate of absorption is immediate
    • Extent of absorption is 100%
  • Oral
    • Rate of absorption
    • Extent of absorption is incomplete
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21
Q

IV: Advantages & Disadvantages

A
  • Advantages
    • Very rapid
    • Precise control
    • Can be administered as bolus, infusion or both
    • No absorption involved (100% bioavailable)
    • Good for drugs that are too irritating to be taken by mouth or given by tissue injection
  • Disadvantages
    • Required hospitalisation
    • Careful preparation of injected material (sterile, non-particulate)
    • Most hazardous (no recall if you give too much)
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22
Q

Oral (po) administration

A
  • Most common route
    • 80% of all prescriptions
  • Advantages
    • Safest, most convenient & economic
  • Disadvantages
    • Slow (1/2 - 3h for effect)
    • Unpredictable with regard to:
      • Rate
      • Extent
      • Reproducibility
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23
Q

Absorption sites in GI tract

A
  • Oral mucosa
    • Thin epithelium and highly vascularised but limited absorption due to short contact time
  • Oesophagus
    • No absorption due to rapid transit time
  • Stomach
    • Acidic pH, small surface area (0.5 m2) and is lined by a thick mucus layer
    • Absorption site for weak acids and neutral drugs
  • Small intestine
    • Major site of drug absorption
    • Have villi which provide extremely large surface area (200m2) and are very vascular with 1/3 of cardiac output
  • Large intestine
    • Little absorption
    • Colon microbiota and metabolising enzymes can break down drug
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24
Q

Factors affecting GI absorption of oral drugs

A
  • Drug characteristics
    • Dosage form: tablet, capsule, liquid, coating
    • Dissolution rate
    • Water and lipid solubility
    • Ionisation - if ionises, slow absorption as needs transporter
    • Chemical stability
    • Liability for metabolism
  • Patient characteristics
    • Gastric emptying rate
    • Intestinal motility
    • Drug-food interactions in the gut
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25
Q

Gastric empyting rate

A
26
Q

Intestinal motility

A
  • The time taken for drugs to pass through the GI tract affects their absorption
    • Stomach: 2-5h
    • Small intestine: 3-4h
    • Large intestine: 10h - days
  • Disease state can influence intestinal motility
    • E.g diarrhea, gasteroenteritis, irritable bowel syndrome
  • High motility can prevent adequate absorption
    • Particularly for poorly water soluble drugs e.g digoxin
  • Low motility can expose the drug to gut metabolism
  • Gut motility can be impacted by other drugs
27
Q

Drug-food interactions in the gut

A
  • Drugs may interact with food in the GI tract
    • This can affect rate and extent of drug absorption
  • Grapefruit juice can affect the metabolism of co-administered drugs
  • Tetracycline and dairy products or divalent/trivalent metal ions
    • Forms insoluble complex with metal ions, reducing absorption
28
Q

What is drug distribution?

A
  • Transfer of drug from blood circulation to various tissues in the body
    • Distributes into interstitial and intracellular fluids
  • Essential for drug to get to its site of action
29
Q

Capillary permeability

A
  • Most capillaries are relatively porous
    • Thus drugs leave the blood regardless whether they are poorly lipid soluble, charged or polar
  • Exception: brain capillaries have no pores and an additional layer of glial cells - known as blood brain barrier
    • only lipid soluble drugs diffuse across brain capillaries into the brain (unless they undergo active transport)
30
Q

Body fluid compartments and molecular weight of drugs

A
  • Water soluble drugs restricted to extracellular fluid
  • Lipid soluble/non-ionised drug can diffuse into the intracellular fluid
  • High molecular weight drugs confined to plasma
31
Q

Drug distribution & blood flow

A
  • Tissue that recieves more blood recieves more drug
  • Rate of distribution to tissues depends on relative blood flow:
    • Heart, lungs, brain, liver and kideny receive drug very rapidly
    • Slower rate to less well perfused organs, such as muscle, skin and fat
32
Q

Plasma protein binding effect on drugs

A
  • Drugs frequently bind to proteins in the plasma
    • e.g albumin, a1-acid-glycoprotein, steroid hormone binding globulins
  • Bound drug will remain in circulation
    • Is pharmacologically inactive
    • Is protected from metabolism and excretion
    • Binding is usually reversible and rapid
  • Binding to tissue proteins may also influence where drugs collect (e.g digoxin, myocardium and skeletal muscle)
33
Q

Outcomes of drug metabolism

A

Metabolism is the biotransformation of drugs. Enzyme causes a chemical change to the drug molecule; either building molecule up or breaking it down

  • Plays a vital role in drug elimination
    • = metabolism + excretion
    • altering the chemical structure of the molecule often means its ability to move around the body is altered (easier to excrete), or a change in its effects (ability to bind to receptors)
  • Metabolism often terminates drug activity, but can also cause
    • Increased drug activity
      • Activation of prodrug (e.g acetylsalicyclic acid aka aspirin -> salicylate
    • No change in activity
      • Metabolite is also biologically active (e.g diazepam -> nordiazepam
    • Production of toxic or carcingenic metabolites
      • e.g paracetamol -> NAPQI
34
Q

Possible sites of drug metabolism

A
  • Liver
    • Major site of drug metabolism
  • Intestinal wall
    • CYP450 enzymes
  • GI tract
    • Gut bacteria and proteases
  • Plasma
    • Esterases (prodrug activation, metabolism)
  • Lungs
    • Metabolism of aerosol sprays
35
Q

Liver metabolism diagram

A
36
Q

Metabolism reactions (require that the substrate, enzyme and any cofactors are in high supply)

A
  • Oxidation
    • Increase proportion of oxygen on the molecule
  • Reduction
  • Hydrolysis
    • Water molecule is added to compound, usually resulting in bond cleavage (ORH = phase 1 reaction)
  • Conjugation (phase 2 reaction)
    • Addition of endogenous substrate
    • Usually increase molecular mass, polarity, water solubility = easier to excrete as it is not as mobile
    • Glucuronidation, sulphation, acetylation, glutathionylation

Enzymatic metabolism may occur sequentially, may compete, or may not occur at all; opportunistic or parallel

37
Q

Oxidation

A
  • CYP450 family most important oxidative enzymes
    • cytochrome P450 dependent mixed function oxidases
    • located mainly on the smooth endoplasmic reticulum, some around the mitochondria
  • Oxidation can occur by other enzymes
    • Alcohol dehydrogenase
    • Aldehyde dehydrogenase
    • Aromatase
    • Amine oxidases
    • and others
38
Q

CYP450 family

A
  • Superfamily of more than 20 gene families in humans, just 4 isoforms responsible for majority of phase I oxidative reactions (CYP3A4, CYP2D6, CYP2C9 and CYP2C19)
  • Requires O2, NADPH and cytochrome P450 reductase
  • Five features of CYP oxidation
  1. Substrate binding
  2. Oxygen binding
  3. Oxygen splitting
  4. Inserting oxygen into substrate
  5. Release of the metabolite
39
Q

CYP3A4 nomenclature

A

CY = cytochrome

P = p450

3 = Family

A = Subfamily

4 = Isoform

40
Q

Factors influencing drug metabolism

A

Organ function - Liver, Kidney, Heart, Gut

Patient - genetic, constitution

Diseases other drugs

Diet, Cigarettes, Alcohol

Age, Sex, Pregnancy

41
Q

Drug excretion

A
  • The process by which drugs are removed from the body
  • The kidney is the most important organ for drug excretion
    • Expelled in the urine
    • 3 processes
      • Glomerular filtration
      • Tubular secretion
      • Tubular reabsorption
  • Other forms of excretion include:
    • Bililary excretion
      • Larger molecules > 400 daltons and ionised
    • Faecal excretion of non-absorbed drug
    • Excretion through tears, respiration, sweat, milk, saliva
42
Q

Role of Kidneys

A
  • Regulated volume & composition of body fluids
  • Conserve essential compounds and remove waste products
  • Specialised transport systems
    • e.g for electrolytes, glucose and amino acids
  • Removes water soluble drugs and metabolites
    • dependent on physico-chemical properties
  • Lipophilic drugs and metabolits usually retained
    • Same properties that allow them to move around the body often prevent them from being excreted
43
Q

Drug excretion at the kidney, process summary

A
  • Small molecules that can fit through glomerular will pass through easily
    • Larger molecules will not filtered
    • Bound to plasma proteins = cannot pass
  • Active transport in tubules will pump substrates into lumen
    • Creates a high concentration that promotes reabsorption
    • Ionised, large and polar molecules can be pumped in that way
  • Once inside the lumen of the tubules
    • Lipophilic, non-ionised drug that will be reabsorbed into surrounding capillaries using the concentration gradient and escape excretion
    • Hydrophilic & ionised drug will not be able to reabsorbed, these will be excreted in the urine
44
Q

Factors that influence renal drug excretion

A
  • Body size
  • Age
    • Renal function decreases 50% with age (25-75yr)
    • GFR only about 30% in a term neonate
  • Pregnancy
    • Renal function increases 50%
  • Disease
    • Renal disease, heart disease
  • Other medications
45
Q

Summary of ADME diagram

A
46
Q

Concentration-time curve after oral dose: Exposure

A

Exposure = Area under conc-time curve (AUC)

Typical units = mg.h/l

47
Q

Oral vs IV PK diagram

A
48
Q

Oral bioavailability

A
  • Not all drug reaces the systemic circulation after oral dosing
    • Partial absorption
    • First pass metabolism
  • Bioavailabilty reflects the fraction of dose that reaches the systemic circulation
    • Calculated relative to IV PK
  • F = (AUC po / AUC IV) x (dose IV/dose po)
  • Ideally F should be >20% for drug to be given orally
  • Assuming clearance = same
49
Q

How can rate be estimated?

A

Tabs, the absorption half life (units, h-1)

Long Tabs, slow absorption. Fast Tabs, fast absorption

Another way to compare rate is to look at the time of peak concentration (Tmax - a PK variable we can measure from the plot)

50
Q

Drug distribution: Volume of Distribution

A
  • The reversible movement of drug between body compartments once it has entered the system circulation
  • Defined/quantified by the parameter volume of distribution (VD)
    • Proportionality constant between the dose we give and concentration we measure
51
Q

Volume of distribution: Equation and Factors

A

VD= (amount of drug in the body (mg))/ (plasma drug concentration (mg/L))

  • Determined by:
    • Body mass and composition
    • Tissue blood flow
    • Tissue binding - increase in volume of distribution
    • Plasma protein binding - decrease in volume of distribution
    • Physico-chemical properties of the drug
      • e.g lipophilicity
    • Natural barriers (e.g blood brain barrier)
52
Q

Loading dose (LD)

A
  • Initial dose administered to achieve a target concentration rapidly
    • Dependent on Vd
    • Helps to fill bath (Vd) faster to rapidly achieve the target concentration
    • The bigger the Vd the higher the dose required to achieve target concentration
  • Loading dose (mg) = Vd (L) x target concentration (mg/L)
  • If no loading dose is used, the volume takes time to fill up, so the larger the Vd, the longer the time to reach the target conc
  • Usually given as IV bolus so that target conc is reached quickly, then maintained by IV infusion, but oral loading doeses can also be used
53
Q

Clearance (CL)

A
  • A constant that describes the relationship between drug concentration and the rate of elimination
  • Clearance L/h = elimination rate (mg/h) / concentration (mg/L)
  • Can also estimate it from Clearance (L/h) = Dose / AUC
  • Plasma clearance = sum of clearances from individual organs
54
Q

Maintenance dose rate

A
  • Dose rate to achieve and maintain a target concentration
    • Steady state concentration (Css)
  • At steady state, plasma concentrations remain constant. This occurs when the rate of drug elimination is equal to the rate of input
  • Maintenance dose rate = Clearance x target concentration
  • mg/h = L/h x mg/L
  • A rapidly cleared drug will need a large maintenance dose to keep drug concs at target levels
55
Q

Maintenance dose calculation - repeat oral dosing

A
  • Account for F (bioavailability) and DI (dosing interval) at once daily dosing (24 hourly)
  • CL x Css x DI = F x Dose
56
Q

Half life (T1/2)

A
  • Time required for drug concentration to fall by half
  • Depends on VD and CL
  • T1/2 = 0.7 x VD/CL
  • Usually a constant irrespective of drug concentration
  • The amount of drug in the body at any time is related to the number of half-lives from drug administration
  • If the half-life is known, then it is possible to estimate:
    • How much drug is left in the body
    • How long it will take to reach steady state
  • A drug with a long-half life will take a long time to reach steady state
    • cannot be reduced by increasing the dose
57
Q

Accumulation

A
  • With repeated dosing or infusion, drug will accumulate in the body until input rate = elimination rate
  • Steady state occurs when drug accumulation is complete and concentrations have plateaued
  • The time required to reach steady state is related to half-life
    • Accumulation is >90% complete after 4 half-lives
    • Generally agreed that steady state is reached after 4-5 half-lives
    • If wait>5 half-lives before re-administration, drug will not accumulate
58
Q

Accumulation to Css graph

A
59
Q

Accumulation calculation

A
  • Aim to achieve target concentration at steady state with constant rate IV infusion of theophylinne in an asthma patient
  • How long will it take to reach target concentration?
    • After 4 half-lives >90% of the drug’s steady state
    • Therefore time required = 4 x 9 = 36h
  • What if theophylline had a smaller Vd of only 5L?
    • T1/2 = 0.7 x 5/2.8 = 1.3h
    • Time required = 5.2h
    • smaller bathtub, less fill time!
60
Q

Sensible adjustment of dosing rates for changes in CL

A

Elimination may be impacted by body size, immaturity, old age, drug interactions, pathology of the liver, kideny, cardiovascular system.. etc, etc

captured by CL & this allows sensible dose adjustment

MEDSCI 204 (4 decks)

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