Pharmacokinetics Flashcards
What are the 6 rights of prescribing?
- Right patient
- Right drug
- Right route
- Right dose
- Right time
- Right outcome
What is the first journey of drugs?
What is pharmacokinetics?
‘What the body does to the drug’
What are the uses of pharamcokinetics?
- Facilitates safe and effective use of medicines
- Determines optimal dosage regimen (dose, route, dose interval, duration of treatment)
- Predicts potential drug interactions
What are the 4 stages of pharamcokinetics?
- Absorption
- Distribution
- Metabolism
- Excretion
What is absorption?
Drug transfer from its site of administration to the systemic circulation (blood).
What are the 4 enteral routes of drug administration?
- Oral
- Rectal
- Sublingual
- Buccal
What factors affect enteral absorption?
- Gastrointestinal (GI) motility
- Absorptive area
- GI blood flow
- Drug particle size and formulation
- Drug physicochemical properties
- Drug binding
What factors affect Drug physicochemical properties of solubility?
- Lipid Soluble = Non-ionized molecules (NaCl)
- Hydrophilic (Polar) = Ionized molecules (Na+; K+)
So:
The more lipid soluble a drug the ________ the absorption
The more water soluble a drug the _______ the absorption
So:
The more lipid soluble a drug the greater the absorption
The more water soluble a drug the less the absorption
What factors affect Drug physicochemical properties of pH?
- Acidic Drugs are better absorbed in acidic media
- Basic Drugs are better absorbed in basic media
- Acidic (Aspirin) better absorbed in the stomach
- Basic (Diazepam) better absorbed in intestines
- Acidic drugs are better excreted in ____ media
- Basic drug better excreted in _____ media
- Acidic drugs are better excreted in basic media
- Basic drug better excreted in acidic media
Can be important in poisoning!!
What are the 4 routes of parenteral drug administration?
Name 4 other routes of drug administration
- Topical
- Transdermal
- Inhalational
- Intrathecal (straight into CSF)
Label the lines
Name the key pharmacokinetics concepts
- Absorption
- First-pass (pre-systemic metabolism)
- Bioavailability
- Bioequivalence
- Volume of distribution
- Cytochrome P450 enzyme system
- Half-life
- Steady state
- Clearance
What is bioavailability?
Fraction of the administered (oral) dose of a drug that reaches the systemic circulation.
What is the equation for bioavailability?
Label each line
If a drug has an oral bioavailability of 20%, the oral dose needed for therapeutic effectiveness will need to be approximately ___ times higher than the corresponding IV dose
5
What is first pass (pre-systemic) metabolism?
This refers to metabolism of the drug prior to reaching systemic circulation.
What is the effect of first pass metabolism on bioavailability?
What is bioequivalence?
Bioequivalence = Two drugs are considered bioequivalent when there is no significant difference in the rate or extent of bioavailability at the same molar dose and under the same conditions
What is the relevance of bioequivalence?
Relevance:
Different formulations from different companies
Different batches of drugs from the same company
Where do most drugs end up after absorption?
Systemic circulation
What is drug distribution?
- Process by which the drug is transferred reversibly from the systemic circulation into the tissues as concentrations in the blood increase, and from the tissues into blood when the blood concentrations decrease during elimination.
- Distribution of the drug into vascular, interstitial and intracellular compartments.
How does drug distribution occur?
- Most drugs transfer by passive diffusion
- Across capillary walls down a concentration gradient
- Into interstitial fluid until concentration of free drug molecules in interstitium is equal to that in plasma
Which drugs undergo which type of transport across membranes?
What is plasma protein binding?
•Drugs bind non-specifically to albumin in plasma
What are the effects of plasma protein binding on drugs?
- Reversible and Saturable
- Unbound or free fraction distributes
- Unbound portion is responsible for the clinical effect
What can free unbound drug do that plasma protein bound drug cannot do?
List the highly protein bound drugs
- Warfarin
- Phenytoin
- Aspirin
- Thyroxine
- Ibuprofen
- Heparin
Furosemide
What factors influence drug distribution?
•Drug physicochemical properties
- Lipid solubility
- Water solubility
- Drug particle size
- Drug protein binding
- The environment – blood flow; pH
What is the Apparent volume of distribution (Vd)?
- A concept that seeks to predict how extensively a drug is distributed throughout the body
- Volume into which a drug appears to be distributed with a concentration equal to that of plasma.
How is Apparent volume of distribution (Vd) calculated?
Vd=Dose (mg)/Concentration (mg/L)
Calculate the volume of distribution and interpret its significance
- Plasma volume in humans is about 2.5 - 3L
- Low volume of distribution
- Drug remains largely in the plasma
What is the significance of a volume of distribution of 50L?
- Large volume of distribution
- Drug has largely left the plasma as plasma volume in humans is about 2.5 - 3L
What is the clinical significance of drugs with a large volume of distribution?
•Drugs that have a large Vd will need to be administered in larger doses to achieve a target concentration in the plasma.
•What do we mean if a drug has a low Vd?
Vd<10L (e.g. warfarin)
–Highly protein bound drug so retained in plasma
Volume of distribution In the middle? Vd10-30L
E.g. gentamicin
–Water soluble drugs, low lipid solubility,
–Distributes into interstitial fluid but not cells
–Dose on Ideal Body Weight to avoid toxicity
•What do we mean if a drug has a high Vd?
Vd>100L (e.g. amiodarone)
–Fat soluble drug distributes into tissues
Which reactions occur in phase 1 of drug metabolism?
Oxidation (P450 cytochrome), Reduction, Hydrolysis (esterases)
What 3 things can a drug be broken down into during phase 1 of metabolism?
What happens in phase 2 of drug metabolism?
Drug solubilisation by conjugation:
Glucuronidation
Acetylation
Sulfation
Methylation
Elimination in urine or bile
What is a prodrug and name 3 examples
- A Prodrug is a drug or compound that is metabolised into a pharmacologically active drug.
- Egs.
- Enalapril to Enalaprilat
- Codeine into Morphine
- Levodopa to Dopamine
List the cytochrome p450 inhibitors
Amiodarone
Ciprofloxacin
Erythromycin/Clarithromycin
Metronidazole
Fluconazole
Isoniazid
Alcohol (acute)
Grapefruit juice
List the cytochrome p450 inducers
- Carbamazepine
- Phenytoin
- Rifampicin
- Alcohol (Chronic)
Which cytochrome p450 process is rapid?
Cytochrome p450 Inhibitor
What is the theraputic index?
Therapeutic Index = Ratio of concentration associated with toxicity (MTC) vs concentration associated with efficacy (MEC).
What can cause potential for an adverse drug reaction?
What are genetic polymorphisms?
- Genetic Polymorphisms are multiple genetic variants (allele combinations) which result in different phenotypes.
- Polymorphisms of drug metabolising enzymes can affect drug handling.
What are the 4 types of metabolisers?
- Extensive metaboliser = Two active ‘normal’ alleles
- Intermediate metaboliser = One normal and one abnormal allele
- Poor metaboliser = Two abnormal alleles
- Ultrarapid metabolisers = Duplication of normal alleles
What is the effect of an ultrarapid metaboliser and a poor metaboliser taking codeine?
- CYP2D6 polymorphism with ultrarapid metaboliser effect causes opiate toxicity in some individuals even at low dose. This causes an exaggerated response to codeine.
- CYP2D6 polymorphism with poor metaboliser effect causes inadequate pain relief by codeine in some individuals.
Label the equation
How is Activity of N-acetyltransferase is genetically determined?
Fast acetylators at increased risk of isoniazid hepatotoxicity
Slow acetylators at increased risk of isoniazid neuropathy
Slow acetylators at increased risk of drug-induced lupus with hydralazine
What is Non saturable metabolism (first order kinetics)?
Rate of drug metabolism is proportional to drug concentration
What type of metabolism does this graph show?
Non saturable metabolism (first order kinetics)
Rate of drug metabolism is proportional to drug concentration
What is Saturable metabolism (zero-order kinetics) and name some examples
Rate of drug metabolism is independent of drug concentration
Phenytoin Alcohol
Aspirin
Methotrexate
Fluoxetine
Verapamil
What type of metabolism does this show?
Saturable metabolism (zero-order kinetics)
Rate of drug metabolism is independent of drug concentration
What is drug clearance?
- The sum of all the drug-eliminating processes, principally determined by hepatic metabolism and renal excretion.
- It can also be defined as the theoretical volume of fluid from which a drug is completely removed in a given period of time.
What are the 2 methods of drug clearance?
•Kidneys are the main drug excreting organ → Urine
- Excretion unchanged
- Metabolised then excreted
What are the components of renal excretion?
- Glomerular filtration - Glomerulus
- Secretion – Proximal Convoluted tubule
- Reabsorption - Distal Convoluted tubule
Name the other excretory methods
- Bile (faeces)
- Sweat
- Exhaled air
- Saliva
- Breast milk
What are the causes of low drug clearance?
- Normal variation
- Renal impairment
- Liver impairment
- Enzyme inhibition
- Genetic poor metabolizer
- Neonate
- Old age
What are the causes of high drug clearance?
- Normal variation
- Increased renal blood flow
- Genetic hypermetabolism
- Enzyme induction
A 59-year-old man presented to the ED with a 2 day history of palpitations, nausea, vomiting and visual disturbances. He had been on digoxin for atrial fibrillation for the past 12 years. He had a recent episode of acute gastroenteritis.
Blood results show acute kidney injury:
Cr 245 (reference range 79-118)
Ur 18 (reference range 2.5-6.7)
eGFR 22 (reference >60)
Explain the most likely cause of his presentation
Digoxin toxicity
Dehydration causes pre-renal acute kidney injury
Digoxin is a water-soluble drug - completely excreted by kidneys
What is half-life?
‘Time for the concentration of drug in plasma to halve’
What does half-life provide information on?
- Time course of drug elimination
- Time course of drug accumulation
- Choice of dose interval
Label the graph on the stages of half-life
What does this graph show?
Steady state
Reached at 5 half lives
What does this show?
Loading dose ORAL
What determines the loading dose?
Determined by the volume of distribution
What does this show?
Loading dose IV
What is the equation for half life?
Loading dose is determined by …
Maintenance dose is determined by …
Dose interval is determined by …
Loading dose is determined by the volume of distribution
Maintenance dose is determined by the clearance
Dose interval is determined by the half life
