SESSION 7 Flashcards
Define pharmacokinetics
The branch of pharmacology concerned with the movement of drugs within the body
What are the four main processes in drug therapy
Absorption
Distribution
Metabolism
Elimination
Define the different types of drug administration
Enteral- delivery into internal environment of the body- GI tract
- oral
- sublingual
- rectal
Parenteral- delivery via all other routes that are not the GI
- intravenous
- subcutaneous
- intramuscular
Describe drug absorption
- oral route is most common
- normally little absorption in the stomach
- drug mixes with chyme and enters the small intestine
- constant GI movement- presenting drug molecules to GI epithelia
Drug absorption in small intestine:
- typical transit time: 3-5 hours
- varying motility time: 1-10hours
- weakly acidic pH: 6-7
Describe drug absorption on a molecular level with reference to passive diffusion
Passive diffusion I
- common mechanism for lipophilic drugs weak acids/ bases
- e.g. Steroids diffuse directly down concentration gradient into GI capillaries
Passive diffusion II
- weak acid/ bases (pKa- 50% ionised) protonated/ deprotonated species can diffuse
- lipophilic species crosses GI epithelia
- over transit time 4-5 hours, and very large GI SA valporate diffuse into GI capillary bed
Describe drug absorption on a molecular level with reference to facilitated diffusion
- molecules with net ionic + or - charge within GI pH rang can be carried across GI epithelia
- passive process based on electrochemical gradient for that solute molecule
SLCs are either OATs and OCTs
- large family- expressed in all body tissue
- pharmacokinetically important for drug absorption and elimination
- highly expressed in GI, hepatic and renal epithelial
Describe drug absorption on a molecular level with reference to secondary active transport
not utilise ATP- transport driven by pre- existing electrochemical gradient across GI epithelial membranes, e.g. Renal OATS and OCTS
Example:
- fluoxetine- SSRI antidepressant co- transported with Na+
- penicillin co- transported with H+ ion
State the factors that affect drug absorption
Physiochemical factors:
- GI length/ SA
- drug lipophilicity/ pKa
- density of SLC (solute carrier) expression in GI
GI physiology
- blood flow- increase post meal- drastically reduce shock
- GI mobility- low post meal- rapid with severe diarrhoea
- food/ pH- low pH destroys some drugs
First pass metabolism by GI and liver
- gut lumen: bacterial enzymes can denature come drugs
- gut wall: metabolism by two major enzyme groups:
- phase I enzymes: P450S
- phase II enzyme: conjugating - larger expression of both enzymes in liver
- first pass metabolism: reduces availability of drug reaching systemic circulation
Define bioavailability
The fraction of an administered dose of unchanged drug that reaches the systemic circulation
When a medication is administered intravenously, its bioavailability is 100%
Most common comparison oral
How do you measure bioavailability ?
Amount reaching systemic circulation/
Total drug given IV
F= between 1 and 0
Informs choice of administration route
What is the first stage of drug distribution?
- bulk flow- large distance via arteries and capillaries
- diffusion- capillaries to interstitial fluid to cell membrane to targets
- barriers to diffusion- interactions/ local permeability non- target binding
Explain the use of differing levels of capillary permeability
Enables variation in entry by charged drugs into tissue interstitial fluid
- continuous
- fenestrated
- sinusoid - intracellular gaps
What major factors affect drug distribution?
Drug molecules lipophilicity:
- if the drug is largely lipophilic it can freely move across membrane barriers
- if largely hydrophilic, journey across membrane is dependent on factors
- capillary permeability
- drug pKa and local pH
Presence of OATS/ OCTS
Degree of drug binding to plasma/ tissue proteins:
- only. Free molecule can bind to target site
- binding in plasma/ tissue decreased free drug available for binding
- plasma/ tissue protein bound drug act as ‘reservoir’
- binding forces not strong- bound/ unbound in equilibrium
- binding can be up to 100%
Define the 3 main body fluid compartments
Plasma water - plasma water - 3 l
Extracellular water - plasma water + interstitial water - 14 l
Total body water- plasma water + interstitial water + intracellular water - 42 l
Define apparent drug distribution
- provides summary measure of drug molecule behaviour in distribution
- referenced to plasma concentration
- summarises movement out of plasma –> interstitial –> intracellular compartments
- smaller Vd values- less penetration of interstitial fluid
- larger Vd allies- greater penetration of interstitial fluid compartment
Vd= total amount of drug in the body/
Drug blood plasma concentration
Vd unit: litres (assume standard 70kg or litres/kg with reference to weight
Define drug elimination
- metabolic and excretory process
- both processes optimise drug removal
- elimination removes both exogenous and endogenous molecular species
- evolutionary advantage in recognising xenobiotics- potential toxins
- protective and homeostatic function
Describe hepatic drug metabolism: phase I and II
Takes place in the liver via phase I and II enzymes
Enzymes expressed throughout body tissues
Very large hepatic reserve
What do phase I and II enzymes do?
Metabolise drugs- increase ionic charge enhance renal elimination
Lipophilic drugs diffuse out renal tubules back into palms
Drugs usually inactivated after metabolism
Describe how phase I metabolism is carried out by cytochrome P450 enzymes
Metabolism.a very wise range of molecules
Metabolism drugs have increased ionic charge
Metabolised drug eliminated directly and go to phase II
Describe how phase I metabolism can activate prodrugs
Pro-drugs activated by phase I metabolism to active species
E.g. Codeine to morphine
0-15% of codeine metabolised by CYP2D6 to morphine
Morphine x200 codeine affinity for opioid u- Receptor
Describe how phase II metabolism is carried out by hepatic enzymes
Mainly cytosolic enzymes
Generalists but exhibit more rapid kinetics than CYP450s
Enhance hydrophilicity by further increasing ionic charge
Enhanced renal elimination
Metabolised drugs increased ionic charge
Define cytochrome P240 enzymes
Cytochrome P450 enzymes include 3 super families:
- three super families CYP 1,2,3
- 6 isozymes metabolise 90% of prescription drugs
- each isozymes optimally metabolise specific drugs
Isoenzyme- each of two or more enzymes with identical function but different structure
What factors affect drug metabolism?
Many factors of direct clinical relevance:
- age
- sex
- gender heath/ dietary/ disease
Describe CYP450S induction
Other drugs can induce specific CYP450S isoenzymes by the mechanisms of:
- transcription
- increased translation
- slower degradation
If another drug in the body is metabolised by induced CYP450S isoenzyme then its rate of elimination will be increased:
- plasma levels of the drug will fall
- this may have serious therapeutic consequences if levels drop significantly
- occurs over a few weeks
Give an example of CYP450 induction
Carbamazepine (CBZ):
- CBZ is an anti- epileptic drug
- primarily metabolised by CYP3A4
- CBZ induces CYP3A4 lowering its ow levels affecting the control of epilepsy
- careful monitoring of the prescription drug
Describe CYP450 inhibition
certain drugs inhibit CYP450 isoenzymes
inhibition mechanism:
- competitive/ non- competitive inhibition
If another drug in the body is metabolised by inhibited CYP450 isoenzyme then its rate of elimination is slowed:
- plasma levels of drug will then increase
- serious side effects if levels rise significantly
- occurs over a few days
Give an example of CYP450 inhibition
Grapefruit juice:
- grapefruit juice inhibits CYP3A4
- CYP3A4 metabolises verapil which is used to treat high blood pressie
- consequence can be much reduced blood pressure and fainting
Give an example of how genetic variation affect cytochrome 450 isoenzymes
Genetic variants of CYP2D6- converts codeine to morphine
Poor- may not convert codeine to morphine so don’t experience pain relief
Ultra- rapid: lead to morphine intoxification
State the routes of drug elimination
- kidney- main route
- bile
- lungs
- breast milk
- sweat
- tears
- saliva
- genital secretions
Describe the route of renal excretion
Glomerular filtration
- glomerulus- 20% renal blood flow
- unbound drug enter via bowmans capsule
Proximal tubular secretion
- 80% blood via peritubular capillaries
- high expression of OATs and OCTs
- carry ionised molecules
- rapidly pull them in and then kick them out (phase I and II metabolism)
- facilitated diffusion/ secondary active transport
Proximal tubular secretion:
- along tubule length water reabsorbed
- in tubule salutes increase in concentration
- If they are lipophilic they pass back into the blood
- if pH is pKa favourable then there is neutralisation of species and they are reabsorbed back into the blood
Distal tubular reabsorption- examples:
OATs: urate (gout), penicillin
OCTs: morphine, histamine
Transport is subject to competition- if the patient is taking more than one drug they may interact with each other affecting each drug half life
Define clearance
Clearance is the rate of elimination of a drug from the body
Total body clearance =
hepatic clearance + renal clearance
- CL is measured in ml/mm
- Vd- apparent volume of distribution
- real blood plasma volume is 3 litres
- real volume of plasma cannot be completely cleared of drug via glomerular filtration/ tubular secretion
What is the relevant of clearance?
Clearance predicts how long a drug will stay in the body
Together CL and Vd proved an estimate of drug half- life
Define drug heals- life
The amount of time over high 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 is dependent on Vd and CL
What is the drug half- life equation?
T1/2 = 0.693 x Vd/CL
If CL (clearance) stays the same and Vd (volume of distribution) increases then t1/2 also increases
If CL increases and Vd stays the same then t1/2 decreases
Why are linear elimination kinetics linear?
The rate of metabolism/ excretion is proportional to concentration of drug
Conditions are:
- plenty of phase I/ II enzyme sites
- plenty of OAT/ OCT transporters
The rate of metabolism will be proportional to the number of molecules occupying a catalytic site per unit of time
What happens when elimination processes become saturated?
When processes are saturated they become rate limited
They cannot go any faster- saturated
When this happens the elimination kinetics are referred to as saturate zero order
What is the clinical importance of zero order kinetics?
Drugs near therapeutic dose with saturation kinetics are more likely to result in adverse drug reaction
Relative small dose changes can:
- produce large increments in plasma
- lead to serious toxicity
Half- life is not calculable so cannot easily predict drug regime
Explain drug monitoring
Relatively few drugs in adults have zero kinetics at therapeutic does
Problem in elderly and infants with decreased/ immature capacity
Problem in seriously ill patrons - liver disease
As there is reduced hepatic renal capacity so easier to saturate
Examples:
- prozac which is anti depressant
- 20 tablets of paracetamol skulls in salutation of both phase I and II metabolism - fatal
