PK: Drug Excretion Flashcards
2 ways drugs are eliminated
Metabolism
Excretion
Absorption vs elimination phase during the time post-ingestion
6 routes for drug excretion // elimination
- Renal
- Biliary/gastrointestinal
- Pulmonary
- Skin
- Mammary - drug delivery to baby
- Salivary - drug monitoring
Name 3 renal processes that account for renal drug excretion
Glomerular filtration
Active tubular secretion
Passive reabsorption across tubular epithelium
What passes through glomerular filtration
Molecules less than 20 kDa filtered i.e. enter filtrate
Protein bound drugs or not filtered (plasma albumin 68 kDa)
What is tubular secretion
What compounds does it apply to
MOA
Active carrier mediated elimination
secretory mechanisms for both acidic and basic compounds
can transport against electrochemical gradient and when the drug protein is bound
Describe reabsorption
What drugs does it apply to
Passive diffusion back across the tubular epithelium
Lipid soluble drugs with a high tubular permeability are excreted slowly
- polar water soluble drugs remain in the urine
- pH partitioning is relevant
Generally, what is renal excretion most important for
Low MW polar substances
GLOMERULAR FILTRATION
What drugs does it allow to cross
What is it affected by
What is GFR
- Free drug in plasma (unbound) if use across capillary membrane into filtrate in Bowman’s capsule
- Large drugs > 20,000 Da retarded
- Not affected by pH or lipid solubility
- GFR = 120ml/min (movement into Bowman’s capsule
ACTIVE TUBULAR SECRETION
What % of plasma is unfiltered in glomerulus
How are drugs transported to lumen
Give an example
- 80% plasma is unfiltered in glomerulus
- 2 carrier systems transport drugs to lumen
- 1 carries acid drugs, other carries bases
- Carried against electrochemical gradient
- e.g. penicillin
- Not dependent on PP binding
- Carrier removes free drug and alters equilbrium
Give an example of competition with regard to active tubular secretion
Probenecid inhibits tubular secretion
What is reabsorbed in distal tubule
What is this reabsorption limited by
- Water is greatly reabsorbed
- 99% of filtered drug is reabsorbed passively
- Lipophilic drugs cross passively - easily
- Polar (metabolised) drugs stay in lumen and are excreted
- Reabsorption is limited by pH trapping
Define renal clearance
Volume of plasma, containing amount of substance that is eliminated by the kidney per unit time
Cp = plasma conc
Cu = urinary conc
Vu = rate of urine flow
Variation in renal clearance for different drugs
< 1ml/min to theoretical max of 700 ml/min
How is the theoretical max of renal clearance measured
PAH clearance (nearly 100%)
How to know if a substance will be secreted or reabsorbed
Baseline renal clearance = f*GFR
If actual renal drug clearance is GREATER than f*GFR, the drug must be secreted
If actual renal clearance is LESS than f*GFR, it must be reabsorbed
What significantly limits the time course of action of the drug at its targets
Drug clearance
If hepatic blood flow is 800 ml/min and 10% of the drug is metabolised by hepatic enzymes with each passage through the liver, what will be the rate of clearance of the drug from the blood
80 ml/min of blood cleared of the drug
Define total body clearance
Sum of all the different clearance processes occurring for a given drug
What would a short half-life result from
Rapid metabolism
Rapid excretion
What would a long half-life result from
Extensive plasma protein binding
Slow metabolism
Poor excretion
IV vs oral administration
IV administration on a semilog plot
2 parameters Plasma t1/2 is determined by
Activity of metabolising enzymes or excretion mechanisms - clearance
Distribution of drug between blood into tissues - high Vd (drug mainly located in tissue) results in prolonged t1/2
As a general rule, what happens after 4 half lives
4 half lives after stopping drug, plasma conc will have fallen by 94%
First order vs zero order kinetics of elimination
1ST ORDER - constant proportion of drug is eliminated per unit time (majority of drugs)
0 ORDER - constant amount of drug is eliminated per unit time e.g. ethanol
Importance of t1/2
Helps to determine the time required to reach steady state with chronic dosing
Determines duration of action after a single dose (usually logarithmic)
How many half lives does it take to reach steady state
3-5 half lives
What is the importance of dosing frequency
Avoids large fluctuations in plasma conc during the dosing interval
How can the elimination half life help
WILL NOT help us understand the dose per day to administer but will help us decide how frequently to give the drug
Dosing frequency effects on drug plasma levels
Determination of steady state from plasma half life
4 half lives after starting drug plasma conc, steady state is reached
Why does it take 4-5 half lives to reach steady state
- When a patient is taking a drug on a regular basis, there is an ongoing process of drug absorption and, concurrently, an ongoing process of drug removal with the drug’s metabolism and clearance
- Eventually there comes a point when the amount of drug going in is the same amount of drug getting taken out => steady state
- The average serum level in the 2nd dosing interval is (most likely) higher than that of the 1st dosing interval and this trend will continue
- Around 4 x t1/2 - 5 t1/2 from the 1st dose has disappeared from the serum, there is no substantial difference in the average serum conc from dose N to the next dose => steady state
Infusion characteristics
How to ensure a drug will act almost immediately
Infusion and bolus dosing
What values are equal to each other @ steady state
Infusion rate = elimination rate
Clearance x plasma conc = elimination rate
Clearance x plasma conc = infusion rate
Clearance = infusion rate/plasma conc
ml/min = mg/min//mg/ml
Define therapeutic dosing
Seeks to maintain the peak plasma drug conc below the toxic conc and the trough drug conc above the minimally effective concentration (MEC)
Why is clearance important
Determines the maintenance dose rate to achieve Css (Conc of drug at steady state plateau)
At steady state, what is elimination rate equal to
Maintenance dose rate (DR)
At steady state, what is maintenance dose rate equal to
Elimination rate
Formula for maintenance dose rate (DR)
DR (mg/hr) = CL (L/hour) * Css (mg/L)
How is clearance measured
Formula for clearance
Many drugs are cleared by a combination of drug metabolism and renal excretion
Rate of excretion in urine and the blood conc at the same time
CL = U*V/P (U = urine drug conc, V = urine flow and P = plasma conc)
What is metformin used to treat
Type 2 diabetes
How does frequency affect drug conc
Infliximab treats
Inflammatory bowel disease
Lithium treats
Psychiatric disorders
Aminoglycosides (vancomycin, gentamycin) are used to treat
Antibiotics to fight infection
Describe the structure of the antibiotic gentamicin
How does this affect the way it is administered
Highly polar cation - poorly absorbed in the GI tract
Needs to be administered IV, because given orally the drug would not work
Maintenance dose only VS loading and maintenance dose
How are most drugs eliminated
By a first-order process
Definition of steady state
Equilibrium point where amount of drug administered exatly replaces the amount excreted
Define clearance
Represents the theoretical volume of blood which is totally cleared of drug per unit time
Define t1/2
Time necessary for the concentration of drug in the plasma to decrease by half
Why would a loading dose of drug be given
To achieve therapeutic drug concentration rapidly
How can the inter-individual variability in responses to a drug be classified
Internal factors as sources of variability
Age
Race & ethnicity
Sex
Prengnancy
Disease
Genetic polymorphisms of drug metabolism
External factors as sources of variability
Drug-drug interactions
Diet
Environment influences on drug metabolism
Effect of age on drug elimination
Drug elimination is less efficient newborn babies (and older adults)
- relative lack of conjugating activity in the newborm
drugs commonly produce greater and more prolonged affects at the extremes of life
Metabolism of chloramphenicol (eye infections)
Effect on baby
Metabolised to a toxic metabolite, which is normally conjugated and removed
In newborns to conjugation enzymes are not developed leading to toxic accumulation of the metabolite leading to pallor and cyanosis (grey baby syndrome)
Why is morphine not used in labour
Can pass through the placenta
Therapeutic level for mother is toxic for baby
What happens to our body composition as we age
Fat contributes to a greater proportion of body mass
What effect might increased fat (as part of our body mass) have on drugs
Half life of lipid soluble drugs might increase (e.g. benzodiazepines)
How does our GFR change as we age
What affects free plasma levels of drugs
GFR declines by 50% by 75, and closely correlates with decline in creatinine clearance
Doses may need to be adjusted over time for long-term medicines
General decrease in metabolic capacity, lower levels of albumin can affect free plasma levels of drugs
Variation in drug consumption between older and younger people
Older adults typically consume more drugs than younger adults (polypharmacy), increasing the potential for drug-drug interactions
How does sex impact plasma drug conc
Content of water and lipid varies between genders that will have an impact on plasma drug conc
e.g. ethanol
How does pregnancy affect the drug disposition of the mother
Maternal plasma albumin levels are reduced - influences protein binding
Cardiac output, GFR and renal elimination are increased - potential increase of renal elimination of drugs
CYP2D6 is induced in pregnancy, leading to increased metabolism of certain drugs
How does pregnancy affect the foetus
Most drugs that are uncharged with MW < 600 will traverse the placental barrier
In the foetus, drug metabolising capacity is very limited, and the kidneys are not efficient at eliminating drugs
Effect of renal dysfunction
Impaired renal function can cause toxicity, as the drugs that are metabolised and/or renally eliminated will accumulate
Effect of nephrotic syndrome
Oedema of intestinal mucosa and reduced plasma albumin binding
Liver dysfunction (cirrhosis) and drug metabolism
- Oxidative metabolism is impaired, affecting metabolism of benzodiazepines using this pathway e.g. diazepam
- Drugs metabolised by glucuronidation (e.g. loraxepam, morphine) are NOT affected
- Conversion of prednisone (prodrug) → prednisolone is reduced
Drugs affected by liver cirrhosis and their route of metabolism
Diazepam - N-demethylation
Barbituates - oxidation
Methadone - oxidation
Drugs NOT affected by liver cirrhosis and their routes of metabolism
Lorazepam - glucuronidation
Morphine - glucuronidation
Paracetamol - glucuronidation
What do pharmaceutical companies avoid doing
Avoid development of a drug that is metabolised by a highly polymorphic enzyme
What is a possible risk succynylcholine (muscle relaxant)
impaired enzyme that prolongs action, resulting in resp paralysis
What is Isoniazid used to treat
What is its nickname
Anti-TB drug
Slow acetylator
What is clopidrogel used to treat
What is it metabolised by
Anti-platelet drug - ischaemic heart disease treatment
A pro-drug metabolised by P4502C19 - some patients are deficient in this enzyme
What enzyme is involved in metabolising 20% of drugs
In what populations is it functionally inactive
CYP4502D6
Functionally inactive in 8% of caucasians, 1% of Asians
(also G6PD deficiency)
Where are dietary heterocyclic amines found
How are they activated
What do they cause
In what species are they present
- BBQ, fry, roast
- Activated by CYP1A2
Cause colon tumours - Constitutively present in humans and rats but not monkeys
How is Isoniazid (anti-TB) metabolised
In what populations are slow acetylators present
What proportion of people have fast acetylators
How does this affect the blood levels of ioniazid
Isoniazid is metabolised by N-acetyltransferase
45% of whites and blacks in the US have slow acetylators
> 90% of Asians and Inuits have fast acetylators
Blood levels of ioniazid are 4-6 times higher in slow acetylators than fast acetylators
Isoniazid metabolism
Why is codeine of no benefit to some people
Must be 0-demethylated for activation, by CYP2D6
What enzyme metabolises 25% of all drugs
In what proportion is the inactive polymorphism of this enzyme present
CYP2D6
5-10% in European caucasians
< 2% in Southern Asians
What sort of gene is associated with G6PD
What does it result in
What does it leave the person susceptible to
X-linked gene
G6PD confers partial resistance to malaria
Susceptible to haemolysis in response to oxidative stress, by exposure to dietary factors (broad/fava beans) or drugs (primaquine, nitrofurantoin)
What does Abacavir treat
What side effect did some patients experience
Side affect is associated with…
What measure has now been introduced
- A reverse transcriptase inhibitor effective in treating HIV infection
- Some patients noted getting a severe rash
- Susceptibility to this effect found to be closely related to a particular HLA variant
- Testing for HLAB*5701 now standard of care for all patients before receiving Abacavir
Give an example of hormones (proteins) used as drugs
Recombinant hormones
Therapeutic monoclonal antibodies (adalimumab, infliximab)
What are thiopurine drugs (e.g. azathioprine) used for
Immunodilators in autoimmune diseases
e.g. inflammatory bowel disease, vasculitis
Give an example of a thiopurine drug
Azathioprine
What is azathioprine a prodrug of
What can azathioprine cause
What is the standard of care as a result
Mercaptopurine
Can cause bone marrow suppression if patients have low thiopurine-S-methyltransferase
TPMT testing is now the standard of care before starting treatment with a thiopurine
Differences between conventional drugs and biopharmaceuticals
What does trastuzumab do
A humanised monoclonal antibody that antagonises epidermal growth factor (EGF) by binding to one of its receptors
(Human EGF receptor-2: HER2)
What are all breast cancers now tested for
What patients receive Trastuzumab
All breast cancer patients are now tested for overexpression of HER2
HER2 +ve patients receive Trastuzumab
HER2 -ve patients do not, because they would not benefit
What was theralizumab (TGN1412) supposed to be a potential treatment for
B cell lymphoma
Effect of atropine on the body
Inhibits gastric emptying, Ca2+ supplements and levothyroxine
Name the inducers of microsomal enzymes
What are the consequences
Drugs e.g. barbituates, carbamazepine, ethanol
Environmental pollutants
Industrial chemicals
Food
A drug can increase its own metabolism, or that of a co-administered drug OR can result in the production of toxic levels of reactive drug metabolites
What drugs inhibit tubular secretion
Probenecid and penicillin
What effect do diuretics have
Increase reabsorption of lithium
Difference in control and epileptic subjects when exposed to anticonvulsant medications
What does enzyme inhibition result in
Give an example of an inhibitor of microsomal enzymes
Decreased metabolism of drugs that can allow the drug levels to reach toxic conc and prolong the presence of the active drug in the body
e.g. Ketoconazole (anti-fungal agent)
What is alendronate used to treat
Parkinsons
What is the systematic bioavailability of alendronate sodium
How does it change with the ingestion of food
Recommendation for its administration
0.75%
Absorption is further reduced by 40% when the drug is taken 1-2 hours before ingestion of food and by as much as 90% when taken up to 2 hours after food ingestion
Alendronate must be taken after overnight fast, at least 30 mins before food
How does grapefruit juice affect drug metabolism
Psoralen derivatives and flavonoids inhibit P4503A4, decreasing first-pass metabolism of coadministered drugs e.g. statins
How does cranberry juice affect drug metabolism
Inhibits CYP3A and CYP2C9
How does St Johns Wort affect drug metabolism
Can induce P450 expression and thus increase metabolism of co-administered drugs
How does cigarette smoke affect drug metabolism
Polycylic hydrocarbons can induce P450 enzymes
Gentamicin -
ABSORPTION
Gentamicin is highly polar cation - poorly absorbed in GIT => needs IV
Gentamicin - DISTRIBUTION
Protein binding < 30% => high Vd
High conc in renal cortex - risk of nephrotoxicity
Water soluble - dose based on lean body weight
Gentamicin - EXCRETION
Hydrophilic - readily excretable
Urine - > 70% as unchanged drug
Half life depends on renal function, hence measuring renal function is very important
Ideal pharmacokinetics of a drug in development
- Once daily, small dose required
- well absorbed
- small First pass effect
- high absolute oral bioavailability
- small/moderate protein binding
- known correlation between plasma levels and effects
- metabolites are not active or toxic
- balanced clearance between liver and kidney
