7. Kinetics Flashcards
What is Vd?
volume of disttribution
Equation for Vd
conc of drug in body/conc of drug in plasma
Drugs distributed through body water are …
- lipid-soluble
- readily cross cell membranes e.g phenytoin, ethanol
Drugs distributed through body water have low or high Vd?
relatively high
Drugs confined to plasma compartment are …
- too large to cross capillary wall easily
- e.g heparin
Drugs confined to plasma compartment have low/high Vd?
low
Drugs distributed in extracellular compartment are …
- cannot easily enter cells
- due to low lipid solubility
- e.g gentamicin
Drugs distributed in extracellular compartment have high/low Vd?
relatively low
Drugs that accumulate outside plasma compartment are …
- bound to tissues or stored in fat
- e.g chloriquine, tricyclic, antidepressants
Drugs that accumulate outside the plasma compartment have high/low Vd?
high
Compare Vd of
- drugs distributed in body water
- drugs confined to plasma conpartment
- drugs distributed in extracellular compartment
- drugs that accumulate outside plasma compartment
- confined to plasma is low
- drugs in extracellular relatively low but higher
- drugs in body water relatively high
- drugs outside plasma comp is high
Define ‘Vd’
- what volume of your body have to be for a given amount of drug
- to yield a concentration equal to that seen in plasma
Define ‘distribution’
- pharmacological term used to quantify the distribution of medication
- between plasma and rest of body
- after oral or parentaral dose
List the 4 mathematics of processes governing amount of drug in body and how it changes over time
- absorption
- distribution
- metabolism
- excretion
Define ‘absorption’
movement of drug across membranes
Define ‘distribution’
where drug goes within body
Define ‘metabolism’
how drug is broken down
Define ‘excretion’
how drug is removed from body
Define ‘bioavailibility’
the fraction of administered dose which enters systemic circulation
Define ‘first pass metabolism’
- process occurring in intestine and liver before drug reaches systemic circulation
Where does first pass metabolism occur?
- intestine
- liver
Explain enterohepatic recirculation/HER
- drugs that are eliminated in bile can be reabsorbed in the GI tract
- may occur after any route of administration
- secreted into bile which is then stored in gall bladder and reduced into duodenum
- many drugs undergo some degree of this - hard to generalize characteristics
Examples of drugs that undergo enterohepatic recirculation
- morphine
- erythromycin
- oral contraceptives
- lorazepam
Elimination is the sum of what 2 processes?
- metabolism
- excretion
What are the main systems involved with elimination?
- kidneys
- hepato-biliary system
- lungs
Define ‘metabolism’ in relation to drugs
- most drugs are lipophilic
- must be made more water soluble prior to elimination (makes it more polar)
Drug metabolism is … … of the drug, in … phases
enzymatic modification
2
Major site of metabolism for drugs is …
liver
Where does phase 2 of drug metabolism occur?
cytosol
Why is drug metabolism needed?
Give what is formed at each stage
- drug to a derivative in phase one (ensures it’s lipophilic to get into target area)
- phase 2 is derivative to conjugate (makes it polar for excretion)
What chemical reactions are involved with drug to derivative?
- oxidation
- hydroxylation
- dealkylation
- deamination
- hydrolysis
What chemical reaction occurs in derivative to conjugate?
- conjugation
Give the chemicals formed in drug metabolism of aspirin
- aspirin is the drug
- becomes salicylic acid as derivative
- glucoronide as conjugate
Which stage of aspirin metabolism is the active NSAID drug?
- derivative stage
- salicylic acid
Phase 1 reactions usually consist of …, … and …
… are important enzymes but others are involved like …
Often involves introduction of …
- oxidation, reduction, hydrolysis (oxidation most common)
- cytochromes P450
- plasma cholinesterase
- or exposing of a functional group (like hydroxyl) - called functionalisation
Role of phase 1 reactions
- decrease lipid solubility but may increase pharmacological/toxicological activity
- many benzodiazepenes form metabolites which are more pharmacologically active than parent drug
- important for activation of pro-drugs
… speed up phase 1 reactions
cytochromes
Phase 1 reactions are cata/anabolic
catabolic - makes smaller molecule from larger one
Explain the cytochrome P450 enzyme family
- often called CYPs
- large superfamily of heme co-factor-containing enzymes
- metabolise thousands of endogenous and exogenous compounds
- individual members referred to as isozymes
Where are CYPs found? What kind?
- mainly in intestine and liver - in liver hepatocytes (highest amount in body), enterocytes in intestine
- small amounts in kidneys, white blood cells and nasal passages
Where are CYPs found in cells?
always in endoplasmic reticulum
Give basic CYP reaction
RH + O2 + NADPH + H+ -> ROH + H2O + NADP+
What is redox potential?
- reduce, reoxidise and regenerate activity
- as ionic form of haem group
How does a basic CYP reaction occur?
- enzyme is the haem group attached to a polypeptide
- combine and creates a functional drug complex
- driven by enzyme, needs cofactors and byproduct is production of water and functionalised drug
where does ethanol metabolism occur?
almost entirely in liver
Explain ethanol metabolism
- ethanol to acetaldehyde
- by alcohol dehydrogenase 2/3
- and CYP2E1 1/3 (but in chronic administration)
- acetaldehyde to acetic acid by aldehyde dehydrogenase
What inhibits stage 2 of ethanol metabolism?
metronidazole
CYP2E1 is a … and is only used in ethanol metabolism when?
- P450
- lots of ethanol is given/chronic administration
Phase 2 metabolism is mainly … reactions and the functional group serves as …
What happens?
- conjugation
- point of attack for conjugation systems
- large group e.g glucuronyl, sulphate and acetyl is attached
Role of phase 2 metabolism
- further decreases lipid solubility
- almost always results in pharmacologically inactive metabolite
- conjugate is excreted in urine or bile
Explain glucuronidation
Mediated by?
Characteristics?
- commonest conjugation reaction
- important for endogenous compounds like bilirubin and exogenous compounds
- mediated by UDP- glucuronyl transferases, an enzyme system with broad substrate specificity
- due to polar nature, glucuronides are usually pharmacologically inactive and rapidly excreted
Drug in phase 0 has … and …
How does this change after phase 1 and 2?
- activity and toxicity
- after phase 1, some activity and toxicity
- after phase 2, larger water soluble compound has been added so no activity and toxicity
Glucuronide conjugation reaction is … dependent
enzyme - need to drive high energy
How does paracetamol metabolism occur for therapeutic doses?
- mainly by conjugation with sulphate and glucuronic acid
- only a minor proportion metabolised by CYP450 to a toxic metabolite
- toxic metabolite normally detoxified by glutathione (another phase 2 reaction)
- detoxification with glucuronic acid and sulfation and glutathione-5-transferase
- finally becomes mercapturic acid
Does paracetamol metabolism have a phase 1?
- no
- straight to phase 2
- add big molecules to make it water soluble then when oxidised makes NAPQI which is toxic
What happens in an overdose of paracetamol metabolism?
- pathways of conjugation are saturated and co-factors are depleted
- as such, more paracetamol is metabolised via CYP450
- toxic metabolite reacts with liver proteins instead of glutathione (depleted)
- tissue damage occurs leading to hepatic necrosis
Phase 2 is good for … but what’s the drawback?
- removing drugs from system
- rate limited and depends on amount of conjugates we have
For the average person in UK, daily intake of food additives is …
8g
Additives in our lives include …
- cosmetics
- food additives
- smoking
- alcohol
How do we excrete things?
- urine
- bile
- lung
- milk
- sweat
Explain renal excretion
- wide variation in rate at which drugs are excreted by kidneys
- rapidly cleared from blood e.g penicillin
- slowly cleared from blood e.g diazepam
- metabolites cleared faster than parental compound
When drugs come out in urine, they are … or…
- unchanged
- more polar
3 processes of renal excretion
- glomerular filtration
- tubular reabsorption
- tubular secretion
Water soluble drugs/metabolites are excreted …
through the kidneys
How do lipid soluble drugs get to be excreted in urine?
- filtered in glomeruli
- reabsorbed on distal portion of nephron
- metabolism to more polar compounds
- excretion in urine
Even the most lipophilic drugs that undergo metabolism will have …
a small fraction of administered dose appearing unchanged in urine
…% of renal blood flow is filtered through glomerulus
20
Explain glomerular filtration
- drugs of molecular weight less than 20,000 diffuse into glomerular filtrate (most drugs)
- plasma albumin (MR 68,000) almost completely held back
- highly ppb drugs found in lower concs in filtrate than in plasma (like warfarin) 98% ppb conc in filtrate, 2% in plasma
2 factors that don’t affect glomerular filtration
- lipid solubility
- pH
Rate of entry to glomerular filtration depends on 2 things?
- concentration of free drug in plasma
- molecular weight
…% of renal blood flow and therefore what? passes onto peritubular capillaries of proximal tubule
- 80
- 80% of drug
Explain active tubular secretion
- drug molecules transferred to tubular lumen by two carrier systems
- which can transport against an electrochemical gradient
- acidic drugs and endogenous acids e.g penicillins, uric acid
- organic bases e.g morphine
What is the most effective mechanism of drug elimination?
active tubular secretion
ppb is not a barrier to …
Many drugs share same … which can lead to …
- carrier mediated transport
- transporter
- competition
2 systems for tubular secretion
- for acids like penicillin, furosemide, probenecid
- for bases like amiloride, amphetamine, cimetidine, procainamide
Volume of urine is about … of the filtrate
1%
Explain passive diffusion/tubular reabsorption
- drug concentration increases as water is reabsorbed
- highly lipid soluble drugs have high tubular permeability and are slowly excreted
- highly water soluble drugs have low tubular permeability and concentrate in urine (100x that in plasma)
Extent of absorption in tubular reabsorption depends on …
- drug lipid solubility (i.e pKa)
- pH of tubular fluid
If the fluid becomes more alkaline in tubular reabsorption what happens?
- then an acidic drug ionises, becomes less lipid soluble - reabsorption diminishes
- a basic drug becomes un-ionised and reabsorption increases
How does tubular reabsorption apply to patients?
- helps with excretion in emergency situations
- increase/decrease excretion by adding acid or base
For weak bases e.g …, ionisation is greatest at …
For weak acids e.g …, ionsisation is greatest at …
- pethidine, acid pH
- aspirin, alkaline pH
pH partition impacts what of drugs?
- rate at which drugs permeate membranes - and distribution of drug between aqueous compartments
- weak acids accumulate in compartments of relatively high pH whereas weak bases do the reverse
How does pH partition affect urine excretion?
- weak bases more rapidly excreted in acidic urine (drug is largely ionised and thus not reabsorbed)
- weak acid more rapidly excreted in alkaline urine
Urinary acidification does what?
It’s important in what?
accelerates excretion of weak bases and vice versa
- important in overdose - ion trapping
Mechanisms of elimination depend on…
physiochemical properties of the compound
Methods of elimination for different properties
- volatile
- water-soluble
- lipid-soluble
- volatile gases are eliminated by exhalation
- water-soluble compounds are done to some degree unchanged in urine (or excreted in bile)
- lipid-soluble compounds undergo metabolism to more water-soluble metabolites that are excreted in urine/bile
Define and explain ‘saturable elimination’
- elimination mechanisms like enzymes are typically not saturated at therapeutic doses od drugs but some exceptions like phenytoin
- increasing dose disproportionately increasing conc (linear to non-linear kinetics)
- often called Michaelis-Menten kinetics
What are Michaelis-Menten kinetics?
- when dose is increased and disproportionately increases concentration
- linear to non-linear kinetics
Clearance is an … parameter
elimination
Define ‘clearance’
best measure of ability of the eliminating organs to remove a compound from the body
How to work out total body clearance or CL?
- sum of all organ CL processes
- e.g hepatic CL + renal CL + other CL
How can clearance be defined using volume?
- volume of plasma/blood cleared of compound per unit of time (mainly L/hr but can be any)
Equation for CL after IV dosing
IV dose/IV AUC 0-> infinity
Equation for clearance after oral dosing
oral dose x F/oral AUC 0-> infinity
Dose/AUC after oral administration gives what?
- CL/F (often called oral clearance)
- can be calculated with CL = Ke x Vd
Give another elimination parameter that isnt clearance
- elimination rate constant or Ke
- half life
Define ‘half life’
- time taken for conc of a compound to reach 50% of current value
- units are time
Equation for half life
0.693/Ke
Rule of thumb for half life
- takes 5 half lives for a compound to reach a steady state
- rate in = rate out after chronic exposure
Half life is the reciprocal of …
elimination constant
- rate of elimination under same conditions is the same
How does exposure to chemicals and additives affect drugs?
- important factor in perturbation of drug metabolising enzymes
- compounds can induce or inhibit them
Explain induction of drug metabolising enzymes
- increased synthesis of enzymes of phase 1 and 2
- increased metabolism therefore of inducing agent (autoinduction) and other drugs
- inducers include enzymes and isozymes
- over 200 drugs can be inducers like rifampicin, ethanol or carbamazepine
- smoking and ethanol chronic exposure are inducers too
Implications of induction of drug metabolising enzymes
- decreased drug effectiveness on chronic exposure
- need to increase drug dose
- in multiple drug therapy, can be problems when inducer is withdrawn from regimen
- basis of drug-drug interaction like oral contraceptives and rifampicin
Paracetamol metabolism is induced how?
- CYP450 metabolism to a toxic metabolite enhanced by ethanol or isoniazid consumption
Explain inhibition of drug metabolising enzymes
- inhibition of CYP system done by many drugs
- reduced rate of metabolism and increased pharmacological effect
- basis of several drug-drug interactions e.g terfenadine and ketoconazole
- ethanol acts acutely to inhibit drug metabolism
How is grapefruit juice a inhibitor of drug metabolising enzymes?
- a component of the juice inhibits CYP3A4
- as such inhibits the metabolism of CYP3A4 substrates including terfenadine and nifedipine
