ESA1 PK Flashcards
Pharmacokinetics can be summarised as:
- Absorption
- Distribution
- Metabolism
- Elimination
How can drugs be administered?
1) Enterally
- Delivery into internal environment of the body- GI tract
- Sublingual
- Oral
- Rectal
2) Parenteral
- Delivery via all other routes that are not the GI
- Intravenous
- Subcutaneous
- Intramuscular
Drug administration mnemonic
Oral
Intravenous
!
Intramuscular
Transdermal
-
Intranasal
Subcutaneous
-
Sublingual
Inhalation
Rectal!
majority of drugs given by which route
oral route
describe the absorption of drugs via the oral route
- drugs move through GI system
- Drugs mixes with chyme and enters the intestine
- Intestine 6-7m in length and 2.5cm in diameter
- Total SA for absorption= 30-35m2
- GI peristalsis ensures mixing of the drug–> meaning drug is presented to GI epithelia
-
Drug absorption in the small intestine (typical trait time -time it takes to pass from stomach to the end of the s.intestine- 3-5h
- Drug has a long time to be absorbed at some point in the s.intestine
- drug absorbed into the heptoportal system
- into the venous system
- to the right ventricle
- to the lungs
- to the left venrtricle
- arterial circulation
drug absorption via
- Passive diffusion
- Facilitated diffusion
- Primary/secondary active transport
- Pinocytosis
Passive diffusion of drugs during absorption
- Common mechanism for lipophilic drugs and weak acid/bases
Lipophilic drugs e.g. steroids diffuse directly down concentration gradient into GI capillaries
Weak acids (protonated- uncharged) /bases (deprotonated)
drugs pass more readily though the membrane if
uncharged
- Protonated species can therefore pass through the membrane
- Deprotonated species are charged and cannot pass through the membrane
pKa relationship with pH
- If the pH of the solution is less than the pKa value then the group will be protonated
- If the pH of the solution is more than the pKa then the group will be deprotonated
example of pKa relationship with pH
i.e. if the drug has a pkA of 5 (valproate- antiepileptic drug) in the s.intestine (pH 6), then most of the drug will be deprotonated.
- Only 10% of the valproate is protonated
- Protonated (uncharged)= lipophilic = can cross GI epithelia
faciliated diffusion
Molecules (or solutes) with net ionic + or – charge (charged molecules) within GI pH range can be carried across epithelia via solute carrier (SLC) transport
–> Passive process based on electrochemical gradient for molecule
SLCs are either Organic Anion Transporters (OATs) or Organic Cation Transporters (OCTs)
- Large family expressed in all body tissue
- Pharmacokinetically important for drug absorption and elimination
- Highly expressed in GI, hepatic and renal epithelia
Secondary active transport (SLC transport)
SLC can also enable drug transport in GI by secondary active transport
- Doesn’t utilise ATP
- Transport driven by existing (ATP created) electrochemical gradient across GI epithelial membrane e.g. Renal OATs and OCTs
e.g.
- Fluoxetine/Prozac* - SSRI antidepressant co-transported with Na+ ion
- Penicillins* - co-transported with H+ ion
Factors affecting drug absorption: Physiochemical factors
- GI length and surface area
- Drug lipophilic/ pKa (how protonated (uncharged) the drug is at GI pH)
- Density of SLC expression in GI
what sort of molecules are most easily absorbed (by passive diffusion)
lipophillic drugs
Protonated drugs (i.e. when the pH is higher than the pKa)
Factors affecting drug absorption: GI Physiology
- Blood flow
- Increase absorption post meal- drastically reducing shock anxiety and exercise (get cramp because blood in intestines and not muscle)
- GI motility
- Slow absorption post meal
- Food/ pH
- Food can reduce/increase uptake of drug
- Low pH destroys some drugs reducing uptake
other factor which affects drug absorption into the blood stream
firts pass metabolism by the GI and liver
First pass metabolism by GI and Liver
Reduces availability of drug reaching systemic circulation- therefore affects therapeutic potential
-
Gut lumen
- Gut/ bacterial enzymes can denature some drugs
-
Gut walls/ liver
- Some drugs metabolised by two major enzyme groups (much larger expression in the liver)
- Cytochrome P450s- Phase I enzyme
- Conjugating- Phase II enzymes
- Some drugs metabolised by two major enzyme groups (much larger expression in the liver)
Bioavailability
Fraction of a defined dose which reaches its way into a specific body compartment - systemic circulation (blood) is the most common reference compartment
- informs choice of admin routes
Bioavailability equation
total drug given IV reaching systemic circulation will be 100%, therefore other routes are compared to this
how to calculate bioavailability
proportion of the amount given orally that reaches systmic ciruclation
what is drug distribution
How drugs journey through the body
- To reach and interact with therapeutic and non-therapeutic target
- Interaction with other molecules- affect on pharmacodynamics
first stage of drug distribution
1) Bulk flow- large distance via arteries to capillaries
2) Diffusion- capillaries to interstitial fluid to cell membrane to targets
3) Barriers to diffusion- interactions/ local permeability/ non-target binding
Drug diffusion across capillaries
- Differing levels of capillary permeability
- Variation in entry by charged drugs into tissue interstitial fluid/target site
- Capillary membranes also express endogenous transporter and OAT/OCTs
Major factors affecting drug distribution
1) Drug molecule lipophilicity/ hydrophilicity
- If drug is largely lipophilic can feely move across membrane barriers
- If drug is largely hydrophillic (mostly protonated at Gi pH) journey across membrane barriers dependent on factors described for absorption
- Capillary permeability
- Drug pKa and local pH
- Presence of OATs/ OCTs
2) Degree of drug binding to plasma and tissue protein
- In circulation many drugs bind to proteins e.g.
- Albumin (globulins)
- Lipoproteins (acid glucoproteins)
Degree of drug binding to plasma and or tissue proteins Albumin as an example
- Only free drug molecules can bind to target site
- Binding to plasma/ tissue proteins (albumin) decreases free drug available for binding
- Plasma/ tissue protein bound drugs act as a dynamic reservoir
- Binding forces not strong (bound/unbound in equilibrium)
- Binding for a given drug can be up to 100% e.g. aspirin (50%)
- Varying number of binding site for given drug
- Competition for binding site affects free plasma conc and pharmacodynamics
body fluid compartments
3 main compartments
- Plasma
- Interstitial
- Intracellular
Increasing penetration by drug into interstitial and intracellular fluid compartments leads to:
- Decreasing plasma drug concentration
- Increasing Vd
Apparent volume of distribution (Vd)
is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma
volume of distribution equation
smaller Vd values
less penetration of interstitial/intracellular fluid compartments
- more drug stays in the plasma
Larger Vd values
- greater penetration of interstitial/ intracellular fluid compartment
- less drug stays in the plasma
What can affect apparent volume of distribution
- Changes in regional blood flow
- Hypoalbuminemia (affecting protein binding)
- Marked increase or decrease in body weight
- Drug interactions
- Renal failure
- Drugs narrow therapeutic ration
- Pregnancy
- Paediatrics
- Geriatric
- Cancer patients
- Anaesthetics
Elimination
- Term used to cover both metabolic and excretory processes
- Elimination removes both exogenous and endogenous molecular species
- Evolutionary advantage in recognising xenobiotics- potential toxins
- Protective and homeostatic function
Drug metabolism largely takes place
in the liver via Phase 1 and II enzymes
- Increases ionic charge enhancing renal elimination
Main route of drug elimination is the
kidney
- Glomerular filtration
- Active tubular secretion
- Passive tubular reabsorption
hepatic metabolism is split into
phase I and II
Phase I and II enzymes
- Metabolise drugs
- By increasing ionic charge- enhance renal elimination
- Lipophilic drugs diffuse out renal tubules back into plasma- not what we want
- Once metabolised- drugs usually inactivated
phase I enzymes
Cytochrome P450 enzyme
Cytochrome P450 enzyme
- Located on external face of ER
- Catalyse:
- Redox
- Dealkylation
- Hydroxylation reactions
- Increase ionic charge
- Metabolised drugs eliminated or go onto phase II
- Some pro drugs activated by Phase I metabolism to active species
Activation of prodrugs example
e.g. Codeine to morphine
Around 0-15% of codeine metabolised by CYP2D6 (exhibits genetic polymorphism) to morphine.
- Morphine has x 200 affinity for Opioid u-receptors as codeine
each isoenzyme of cytochrome P450 enzymes
has a drug that is metabolises optimally
- 6 isozymes metabolise 90% of drugs
Phase II (hepatic enzymes)
- Mainly cytosolic enzymes
- More rapid kinetics than CYP450s
- Enhance hydrophilicity by further increasing ionic charge
- Enhancing renal elimination
- Catalyse:
- Sulphation
- Glucorinadation
- Glutathione conjugation
- Methylation
- N-acetylation
sumamry of phase I and II metabolism
main aim of phase I and II metabolism is to increase ionic charge to make the drug more hydrophilic/lipophillic - so it can be excreted by the kidneys
- some drugs can be excreted after phase I motabolism
- others need both phases
Factors affecting drug metabolism
- Age
-
Sex
- e.g. alcohol metabolism slower in women
-
General health/ dietary/ diseases
-
HRH: Heart, renal, hepatic
- Decreased functional reserve of Phase I and II enzymes
-
HRH: Heart, renal, hepatic
-
CYP450s
- Induction (by other drugs)
- Inhibition (by other drugs)
- Genetic factors
- Genetic variation/ Polymorphisms/ non-expression affect CYP450s
CYP450 induction
If a patient is taking more than one drug at the same time, certain drugs can induce specific CYP450 isozymes
Induction mechanism:
- Increased transcription
- Increase translation
- Slower degradation
consequence of induction
- If another drug in body metabolised by induced CYP450 isozyme then rate of elimination will be increased
- Plasma levels of drug will then fall
- Can have serious therapeutic consequences if level of plasma drug drops significantly
- Induction takes between 1-2 weeks
induction example
Example of CYP450 induction- Carbamesepine (CBZ)
- Anti-epileptic metabolised by CYP3A4
- CBZ induces CYP3A4
- Lowering its own levels affecting control of epilepsy
- CBZ needs careful monitoring
CYP450 inhibition
If a patient is taking more than one drug at the same time, certain drugs can inhibit specific CYP450 isozymes.
Inhibition mechanism:
- Competitive
- Non-competitive inhibition
consequence of CYP450 inhibition
- If another drug in body metabolised by inhibited CYP450 isozyme then its rate of elimination will be slowed
- Plasma levels of drug will then increase
- Serious side effect
- Occurs within a few days
Example of CYP450 inhibition
Grapefruit juice
- Grapefruit juice inhibits CYP 3A4
- CYP 3A4 metabolised verapamil used to treat hypertension
- Consequence can be much reduced BP and fainting
Genetic factors associated with drug metabolism
Genetic variation/ Polymorphisms/ non-expression affect CYP450s
genetic variation of CYP450
-
CYP2C9 not expressed in: 1% Caucasians, 1% Africans
-
Metabolises:
- NSAIDS
- Tolbutamide
- Phenytoin
-
Metabolises:
-
CYP2CI9 not expressed in 5% Caucasians and 30% Asians
-
Metabolises:
- Omeprazole
- Valium
- Phenytoin
-
Metabolises:
Need to consider safety/ efficacy if not metabolised/ rapidly metabolised
genetic polymorphisma nd CYP450
-
Codeine and CYP2D6
- CYP2D6 not expressed in 7% Caucasians
- Prodrugs activated by phase I metabolism to active species
- CYP2D6 is highly polymorphic
- Categorised into
- Poor- may not experience pain relief (codeine has a lower affinity to u-opioids receptors than morphine)
- Normal
- High
- Ultrarapid metabolisers (hyperactive in 30% east africans)
- Categorised into
- CYP2D6 is highly polymorphic
Main route of drug elimination is the kidney.
- Other routes inc:
- Bile
- Lungs (vapour breathed out)
- Genital secretions
- Saliva
- Breast milk
Renal excretion
Involves three processes
- Glomerular filtration
- Active tubular secretion
- Passive tubular reabsorption
Renal capillaries
- Fenestrated
- Increased permeability to enable optimised exchange of ions/molecules
Glomerular filtration
- Afferent arteriole form ball of glomerular capillaries in the bowman’s capsule (20% renal blood flow)
- Small molecules such as ions, water, solutes and unbound drugs can pass through into the nephron to be excreted as urine
Active tubular secretion
Proximal tubule
- Remaining 80% of blood filtered via peritubular capillaries (capillaries that run alongside the nephron)
- High expression of OATs and OCTs to allow unbound drugs to be secreted/ pass from the circulation and into the nephron to be excreted as urine
OATs and OCTs Facilitated diffusion/ secondary AT- carry ionised molecule’s out of the blood (reverse of process in s.intestine)
e.g. OAT:
urate, penicillin’s, NSAIDs and antiviral
e.g. OCT:
morphine, histamine, chloropromazines
Passive tubular reabsorption
Distal tubular reabsorption
- Along total tubule length water is resorbed
- Along tubular length [solute] increases
- Passive reabsorption of lipid-soluble, unionised drug, which has been concentrated so that the intra-luminal conc is greater than that in the perivascular space
passive tubular reabsorption and weak acid/bases
Same as s. intestine but reversed.
Remember drugs must be neutrally charge to be passively reabsorbed.
Drugs reabsorption in the DCT that are Weak acids
- Low pH (acidic urine in DCT): increases absorption of weak acids
- Protonate them, meaning they become neutral and can be reabsorbed
Drugs reabsorption in the DCT that are Weak bases
- High pH (basic): increase absorption
- Lose proton, becomes naturally chargedà reabsorption
What is clearance?
The volume of plasma cleared of drug per unit time
- Measured in ml/min
- Total drug clearance- consists of that from all routes
Vd and clearance predicts
how long the drug will stay in the body i.e. half life of a drug
- Designing dosing schedule
- Therapeutic regime levels
- Minimising adverse reaction
Drug half life t12
‘The amount of time over which the concentration of a drug in plasma decreases to one half of that concentration value it had when it was first measured’
Drug half life t12 equation
T12 is dependent on
Vd and CL
- If clearance stays same and Vd increases then T12 also increases
- If CL increases and Vd stays the same then T12 decreases
example of drug half life
Thus, after two half-lifes, 25% of the drug is left; after three, 12.5%; and after 4 half-lives, 6.25%.
The half-life determines the length of the drug’s effect.
First order kinetics (linear kinetics)
- Elimination of a constant percentage (or fraction) of the drug per unit time. (if a large functional reserve of enzymes)
- That is - if there is Large Functional Reserve and Plenty of Phase I/II Enzyme sites
- Plenty of OAT/OCT Transporters
- For most drugs, the elimination occurs at a rate directly proportional to the concentration of the drug—i.e., the higher the drug concentration, the higher its elimination rate (e.g., 50% per unit time, as shown in the figure).
- Rate of metabolism /transport will be proportional to the number of molecules occupying a catalytic/ carrier site per unit time
What happens when Elimination Processes become Saturated?
When processes are saturated they become rate limited- they cannot go any faster - ALL enzymes or carriers working flat out –> zero order kinetics
Zero-order kinetics (Nonlinear kinetics)
- Elimination of a constant quantity of the drug per unit time independent of the concentration of the drugs
- With a few drugs, such as aspirin, ethanol, and phenytoin, the doses are very large.
- Therefore, the plasma drug concentration is much greater than the Michaelis constant Km, and drug metabolism is constant and independent of the dose
Clinical importance of zero order kinetics
- Drugs at or near therapeutic dose with saturation kinetics
- More likely to result in ADRs/Toxicity
- Relatively small dose changes can produce large increments in plasma [drug] - Lead to serious toxicity
- Half life not easy to calculate
- Greater risk of drug-drug interactions due to taking up sites
Few zero order kinetics drugs used in elderly/ infants
- Decreased/ immature capacity
- Polypharmacy
Few zero order kinetics drugs used in seriously ill (cancer, liver disease and alcoholicss)
Signif reduced hepatic/renal capacity easier to saturate
