Pharmacokinetics Flashcards
1
Q
What is ADME?
A
Absorption, distribution, metabolism, excretion
2
Q
What is IDE?
A
Input, distribution, elimination
3
Q
Elimination =?
A
Metabolism, Excretion
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
5
Q
Pharmacokinetic and Pharmacodynamic plots
A
Conc/time = pharmacokinetic
Effect/Conc = pharmacodynamic
6
Q
Reasons for failure in drug development
A
Clinical safety, efficacy, formulation, PK, commerical, toxicology, cost of goods, other
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
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)
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
10
Q
Membrane transport
A
- Passive diffusion
- Facilitated diffusion
- Active transport
- Endocytosis
- Filtration
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
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
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)
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
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
16
Q
Routes of drug administration
A
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)
18
Q
Absorption: Rate and Extent: 2 Things
A
- 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
- Extent: How much of the administered dose enters the system circulation, bioavailability, F = 1: 100% enters arrives at circulation; F<1, incomplete absoprtion
19
Q
Example of rate and extent of absorption on concentration profile
A
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
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)
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
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
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
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
- Increased drug activity
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
- Substrate binding
- Oxygen binding
- Oxygen splitting
- Inserting oxygen into substrate
- 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
- Bililary excretion
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
