Pharmacokinetics Flashcards
What does ADME stand for
Absorption, Distribution, Metabolism, Excretion
What is absorption
The process by which a drug enters the blood stream from site of administration
What is distribution
The process by which a drug leaves the circulation and enters the tissues perfused by blood. Blood independent distribution can occur in tissues by diffusion
What is metabolism
The process by which tissue enzymes catalyse the chemical conversion of a drug to a more polar form that is more easily excreted
What is excretion
The processes that remove the drug from the body
Where does metabolism usually happen
Liver - Hepatic metabolism
Where does excretion usually happen
Kidneys - Renal Excretion
What are the physiochemical factors controlling drug absorption
Solubility
Chemical stability
Lipid to water partition coefficient
Degree of ionisation
How does drug solubility affect absorption
The drug must be dissolved to be absorbed
How does the chemical stability of a drug affect absorption
Some drugs can be destroyed by acid in the stomach or enzymes in the GI tract. Must be stable to avoid this
How do drugs get from the stomach/intestines to the liver
Through portal circulation
What is the lipid to water partition coefficient
~LogP
What effect does the lipid to water partition coefficient on drug absorption
Greater lipid solubility (LogP) = higher rate of diffusion across a membrane
Which ionisation form does a drug need to be to cross the lipid bilayer
Unionised.
What is the pKa
The pH at which 50% of the drug is ionised, and 50% is unionised
How can the proportions of [un]ionised drug be calculated
Henderson-Hasselbalch equation: pKa - pH = log (HA/A-) or log(BH+/B)
How does the degree of drug ionisation affect drug absorption
Must be in unionised state to cross membrane. Acid drug = less ionised in acid environment. Basic drug = less ionised in basic environment.
Where is a slightly acidic drug likely to be absorbed
Stomach (and small intestine because >surface area)
Where is a slightly basic drug likely to be absorbed
Small intestine
Which factors affect GI absorption
Motility (rate of movement) pH at absorption site Blood flow to GI tract Drug formulation Physicochemical interaction
Define oral availability
The fraction of drug that reaches the systemic circulation after oral ingestion
(amount in circulation / amount administered)
Define systemic availability
The fraction of drug that reaches the systemic circulation after absorption.
(amount in circulation / amount absorbed)
What is the enteral route of administration
Drug administration that involves the intestines / GI tract
What is the parenteral route of administration
Drug administration that does NOT involve the intestines / GI tract
What are the advantages of oral administration
Convenient
Non-sterile route
Generally good absorption
What are the disadvantages of oral administration
Some drugs inactivated by acid/enzymes
Variable absorption
Must deal with 1st pass metabolism
Can cause GI irritation
What are the advantages of sublingual administration
Bypasses portal system
Avoids 1st pass metabolism
Avoids gastric acid
What are the disadvantages of sublingual administration
Infrequent route
Few preparations available
What are the advantages of rectal administration
Bypasses portal system, 1st pass metabolism and gastric acid
Used for nocturnal administration of some drugs
What are the disadvantages of rectal administration
Infrequent route
Variable absorption
Aesthetically unacceptable (in UK… french love it!)
Name some enteral routes of drug administration
Oral, sublingual, rectal
Name some parenteral routes of drug administration
Intravenous, Intramuscular, subcutaneous, inhalation, topical, nasal, vaginal, ocular, intrathecal, intracerebral
What are the advantages of intravenous administration
Rapid onset
Continuous infusion
Complete availability
Allows administration of drugs that might have caused tissue damage
What are the disadvantages of intravenous administration
Sterile prep required
Risk of sepsis/embolism
High drug levels at heart
What are the advantages of intramuscular/subcutaneous administration
Rapid onset of lipid soluble drugs
depot injection for slow release possible
What are the disadvantages of intramuscular/subcutaneous administration
Painful
Tissue damage can be caused
Variable absorption
What are the advantages of inhalational administration
Lungs = high surface area
Good for volatile agents
Good for local effect
What are the advantages of topical administration
Ideal for local effect
What are the disadvantages of inhalational/topical administration
There are ‘few’
Name the fluid compartments found in the body
Plasma water
Interstitial water
Intracellular water
Transcellular water
Where can ionised drugs move in the body
Between the plasma and interstitial water
Where can unionised drugs move in the body
Fat/cells Interstitial water (start point) Intracellular water transcellular water
What is the volume of distribution (Vd)
The volume into which a drug ‘appears’ to be distributed with a concentration equal to that of plasma.
What is the Vd for an i/v administered drug
Vd = dose / plasma concentration
What does a Vd <5L show
Drug retained in vasular compartment (v. protein bound or too big to cross wall)
What does a Vd <15 L show
Drug restricted to extracellular water (like perma charged compounds)
What does a Vd >15 L show
Drug is distributed throughout total body water (or ^ conc in specific tissues)
What does MEC stand for
Minimum Effective Concentration
What does MTC stand for
Maximum tolerated dose
What is the therapeutic ratio (/index)
TR = MTC / MEC
What is the desired therapeutic ratio
Higher = safer drugs; lower = unsafe drugs
Define pharmacokinetics
The mathematical analysis of all drug disposition factors (ADME)
What is first order kinetics (in drug context)
When the rate of elimination is directly proportional to drug concentration
What type of graph is given by a drug that shows 1st order kinetics
Exponential. 50% decrease per standard half life.
Define half life (t1/2)
The time taken for concentration of drug in plasma to halve. Inversely related to Kel.
What is the equation for working out a half-life
T1/2 = 0.69 / Kel (rate of elimination)
How does the dose-response curve change for a 1st order drug when the dose conc administered changes
Cp (plasma concentration) changed in direct proportion. Kel and T1/2 are unchanged.
Define Clearance (Cl)
The volume of plasma cleared of drug in unit time.
A constant relating the rate of elimination to plasma concentration
Which type of drug does Clearance (Cl) apply to
First order drugs ONLY
How is Clearance (Cl) determined
Rate of elimination = Cl (clearance) x Cp (plasma concentration)
Why is Clearance (Cl) important?
Determines the maintenance dose rate needed to maintain a given plasma concentration (need to match rate of administration to rate of removal)
What is the rate of elimination/administration at steady state
Cl (clearance) x Cp[ss] (plasma concentration at steady state)
Approx how many half lives does it take for a drug to reach Css (steady-state conc)
5
Approx how many half lives does it take for a drug to be eliminated from the body
5
Define oral bioavailability
The fraction of the drug administered that enters the systemic circulation
What does volume of distribution (Vd) relate
Plasma concentration (Cp) and amount of drug in the body (Ab): Ab = Vd x Cp
Define loading dose
An initial higher dose of a drug given at the beginning of a course of treatment before stepping down to a lower maintenance dose.
How is a loading dose calculated for i/v administration
LD = Vd x target Cp
How is a loading dose calculated for oral administration
LD = (Vd x target Cp) / F (oral bioavailability)
What can half-life determine
The time course of drug accumulation and drug elimination. The choice of dose interval.
What is the dose response curve for zero order drugs
Linear. Drug eliminated at a constant rate
Give an example of how a drug can be zero order
Plasma concentration of drug is greater than Km of an enzyme that metabolises it
How are drugs usually removed by the body
In urine and occasionally the bile.
Rarely by sweat, milk etc
What form is a drug usually in when removed from the body
Commonly a more polar compound, occasionally unchanged (if highly charged)
Which organs are involved in drug metabolism
Mainly liver. Also GI tract, lungs and plasma
What does drug metabolism do
Convert parent drugs to more polar metabolites that are not easily absorbed by the kidney
Usually convert drugs to less pharmacologically active metabolites
What occurs in phase 1 metabolism
Oxidation, reduction, hydrolysis.
Makes a drug more polar and adds stuff that can allow conjugation
What occurs in phase 2 metabolism
Conjugation.
Adds a compound to add polarity. Often glucuronyl, also: sulphate, methyl, acetyl, glycyl, glutathione
How is aspirin metabolised
Aspirin –[1]-> Salicylic acid –[2]-> Glucuronide
Which enzymes are mainly involved in phase 1 metabolism
Cytochrome P450 monooxygenases.
What are CYP450 enzymes involved in
Phase 1 metabolism
Which is the most common type of CYP450 enzyme
CYP3A4
Which are the most common CYP450 gene families in the human liver
CYP1, CYP2, CYP3
Describe the monooxygenase P450 cycle
Drug enters as drug substrate ‘RH’
O2 provides two oxygen atoms
One oxygen atom is added, drug becomes ROH , which leaves the cycle.
Second oxygen combines with protons to form water.
Where does phase 2 metabolism mainly occur
Liver
What happens in a Glucuronidation reaction
Glucuronic acid is transferred to electron-rich atoms of the substrate (N/O/S).
Which enzyme mainly catalyses a Glucuronidation reaction
UDP-glucuronyl transferase
Which three process are involved in renal excretion of drugs
Glomerular filtration
Active tubular secretion
Passive reabsorption by diffusion across the tubular epithelium
When can/cannot a drug be filtered by the glomerular
Large plasma proteins are not filtered. If a drug is unbound, it can be filtered. If it is bound to a protein, it cannot.
Charge has no importance.
How can Clearance by filtration (CLfil) be calculated
CLfil = GFR x fraction of drug unbound in plasma (fup) GFR = Glomerular filtration rate; usually 120 ml/min
How can Clearance by filtration (CLfil) be calculated
CLfil = GFR x fraction of drug unbound in plasma (fup) GFR = Glomerular filtration rate; usually 120 ml/min
How much of the renal flow is filtered through the glomerulus
Up to 20%
How much of the renal flow is delivered to the peritubular capillaries of the proximal tubule
Around 80%
Which two transporters are involved in active secretion of drugs into the lumen of the nephron
Organic anion transporter (OAT)
Organic cation transporter (OCT)
What is the specific role of the Organic anion transporter (OAT)
Transports acidic drugs.
Also endogenous acids (e.g. uric acid) and the marker for renal plasma flow (para-aminohippuric acid PAH)
What is the specific role of the Organic cation transporter (OCT)
Transports basic drugs
Give examples of acidic drugs
Penicillins, probenecid, thiazides
Give examples of basic drugs
Morphine, neostigmine, amiloride, triamterene
How does tubular secretion differ from glomerular filtration
Tubular secretion is able to secrete drugs that are highly protein-bound (filtration cannot)
How much water filtered at the glomerulus is reabsorbed by the tubules
~99%
List factors influencing reabsorption rate
Lipid solubility (Higher LogP = v. reabsorbed and slowly excreted) Polarity (v. polar = excretion, no reabsorption) Urinary flow rate (diuresis decreases reabsorption) Urinary pH (alkaline = acids excreted more. Acidic = bases excreted more)
What does a quantal dose response relationship curve show
The fraction of the population that responds to a given dose of drug VS drug dose
What is the purpose of a quantal dose response curve
Generalises effect of a drug to a population, as opposed to an individual. Can work out ED50, LD50 etc for the population
Describe two types of Drug-drug interactions
Pharmacodynamic - modifies pharmacological effect, not change in tissue concentration
Pharmacokinetic - modifies the concentration that reaches the site of action
Describe pharmacokinetic DDIs that can affect absorption
Metoclopramide - increases rate of stomach emptying
Atropine - decreases rate of stomach emptying
Antibiotics can reduce effectiveness of gut bacteria, which can decrease reabsorption rate (e.g. of oral contraceptives)
Describe pharmacokinetic DDIs that can affect distribution
Plasma protein bound drugs might be displaces by a second drug. Free concentration increased. Only important when drug is highly protein bound or have a low TR (therapeutic ratio)
Describe pharmacokinetic DDIs that can affect metabolism
Some drugs can inhibit or induct specific CYP450 enzymes, which reduce or increase activity.
Phenytoin (induction of CYP3A4), decrease warfarin effect
Cimetidie (inhibition of CYP2C9), increase warfarin effect
Describe pharmacokinetic DDIs that can affect excretion
Drug can share a transporter (e.g. in proximal tubule of nephron).
Probenecid competitively reduces penicillin excretion
List population variation factors that can cause an increased plasma concentration of a drug
Saturable metabolism Genetic enzyme deficiency Renal/liver failure Old/v.young age Enzyme inhibition
List population variation factors that can cause a decreased plasma concentration of a drug
Poor absorption High 1st pass metabolism Genetic hypermetabolism Enzyme induction Non-compiance
What is the result of competitive enzyme inhibition
Higher Km, same Vmax
What is the result of non-competitive enzyme inhibition
Same Km, lower Vmax
What is the result of enzyme induction
Same Km, higher Vmax
How does prescribing change in patients with hepatic impairment
Most important in drugs that are extensively metabolised with a low TR.
Dose adjusted for:
High Cl drugs (affected by blood flow and enzyme capacity)
Low CI drugs (affected by enzyme capacity only)
Describe specific altered drug responses in liver disease
Reduced synthesis of plasma proteins (causes toxicity of PPB drug with low TR)
Reduced synthesis of clotting factors (enhanced sensitivity to oral anti-coagulants)
Impaired excretion of drugs eliminated by the bile (occurs in chloestasis)
Pharmacodynamics:
Hepatic encephalophathy (deterioration of brain function, made worse by many drug classes)
Ascities (fluid build up in peritoneal cavity ass. with liver disease)
How is renal impairment measured
Creatinine clearance (CrCl)
How is drug dosage adjusted in renal imparirment
Drug dosage determined by:
Rate of CrCL (Creatinine clearance)
The fraction of drug that is excreted by the kidney in unchanged form (fu)
If fu = 1 ; adjust dose in direct proportion to degree of CrCl impairment
If fu = 0.5 ; adjust dose for fraction cleared by the kidney
If fu = 0 ; no adjustment needed
What do different CrCl (creatinine clearance) values mean in terms of renal impairment
20-50 ml/min = mild
10-20 ml/min = moderate
< 10 ml/min = severe
How does dosing for children differ to dosing for adults
Often dose by body weight or surface area.
Pharmacokinetics/dynamics are altered in neonates (<30 days old) - poor renal filtration, enzyme deficiencies, poor detoxifying systems, delayed excretion
Many medicines unlicensed for children
How does dosing for the elderly differ to dosing for adults
Often poor rate of excretion.
Clearance is important consideration.
Metabolised or renally eliminated drugs usually have impaired clearance.
How does dosing in pregnancy differ to dosing for adults
Main issue is teratogenicity.
If drug is orally absorbed, assume it can cross the placenta.
Most drugs not recommended, but may not be known to be dangerous.
Benefits need to outweigh risks.
