Lecture 3 - Pharmaocdynamics And Pharmacokinetics Flashcards
What are the 4 main processes in drug administration?
Absorption
Distribution
Metabolism
Excretion
What form of a drug is functional?
When it is the free drug and not bound to transporters
What are the regulatory bodies interested in the Pharmacokinetics of a drug that are responsible for approval and standardisation of dosing?
MHRA
EMA
FDA
What are some key factors that must be considered when assessing pharmacokinetics?
Bio-availability
Half-life
Drug eliminate
Inter patient variability
Drug-drug interactions
What bodily functions should we consider when thinking about pharmacokinetics?
Renal function
Stress
Pyrexia
Liver function
Gi function
CVS function
Immune status
What is bioavailability?
The measure of drug absorption where it can be used
How much of a drug can be measured of a drug in the plasma when its given via IV or oral
What method of drug administration gives 100% bioavailability?
IV (intravenous)
How would you calculate bioavailability of a drug given via oral?
Fraction of what the IV would be
AUC oral/AUC IV x 100
What affects bioavailability?
Absorption ability (formulation, age, food, vomiting, previous surgery)
First Pass metabolism
What is first pass metabolism?
When drugs are metabolised before they reach the systemic circulation (gut lumen, ,gut wall, liver and even lungs)
What drug uis given to help relieve an angina attack via being absorbed by tongue mucosa?
GTN spray
How does GTN spray work?
Smooth muscle vasodilation helping widen blood vessels supplying the heart
Why is metformin a modified released preparation?
Side effect of metformin is GI upset, so by making it so you have to take it less frequently reduces the frequency of GI upset
What is a modified released preparation?
When the drug is modified to be released at a specific rate so that large fluctuations inn plasma concentration dont happen so have to take drug less frequently
Why shouldn’t modified release tablets be crushed before taking?
Negates the affect of the modification that controls the rate of release of the drug
How does metformin work?
Decrease the livers synthesis of glucose helping to treat diabetes Mellitus (Gluconeogenesis)
Also makes body more sensitve to insulin
What are some factors that affect the ability of a drug to be distributed through the body?
Blood flow/capillary structure (how well perfused the tissue is)
Lipophilicity and hypophilicity
Protein binding
What are some common proteins that bind to drugs?
Albumin (acidic drugs)
Globulins (hormones)
Lipoproteins (basic drugs)
Glycoproteins (basic drugs)
What stops the majority of drugs from affecting the brain?
What cells contribute to this?
Blood Brain Barrier
Foot processes of Astrocytes
What is the volume of distribution of a drug?
The volume of distribution (Vd) is a pharmacokinetic parameter representing an individual drug’s propensity to either remain in the plasma or redistribute to other tissue compartments
What is negative about a narrow therapeutic index?
A small change in concentration of the drug can have toxic affects if too high or very little affect if too low
What is important to consider when prescribing multiple drugs?
One may have a higher protein binding affinty that the other. So when the other drug is administered it may displace the first drug from the protiens leading to more free circulating drug than anaticapted leading to toxic affects
What is apparent volume of distribution>
The amount of a drug given whose concentration can be measured in the plasma
What would the apparent voliuiume of distribution of a drug that’s given as a 100mg dose but its measured as a plasma concentration as 20mg/L?
100mg/20mg/? = 5
Vd = 5L
What would the apparent voliuiume of distribution of a drug that’s given as a 100mg dose but its measured as a plasma concentration as 5microg/L?
100/5 = 20L
Vd = 20L
What is the significance of a drug having a larger apparent volume of distribution than another?
Means less of the durg is located in the plasma meaning its being more deeply abosrbeddd Ito other compartments going to other parts of the body
What is indicated by a smaller apparent of Vd?
What is indicated by a larger apparent Vd?
Drug is confined to plasma and extracellular fluid
Drug is distributed tthorugoth the tissues
What is the Total Body water of a 70kg male?
42Ll
What is the main key. Metaboliser of drugs in the body?
Liver
What are the phase 1 reactions a drug undergoes?
What does Phase 2 reactions a drug undergoes do?
Modifies existing functional groups to increase net charge
Oxidation
Reduction
Hydroloysis
Carried out by phase I enzymes (CYPs)
Phase 2 adds large charged molecules to increase net charge
Which CYPs to the majority of Phase I catalysed reactions use?
Cytochromes P450 (CYP450)
Where are CYP450s abundantly located?
Smooth ER of hepatocyets and most other tissues
What type of reaction carried out by CYP450 enzymes to drugs is most common?
Oxidation
What is the main isoenzyme in the CYP450 family improtant in the majority of durg therpatuics?
CYP3A4
What can CYP450 enzymes do to a drug???
Inactivate a drug
Activate a drug
What do CYP450 enzymes convert codeine into?
Morphine
What do CYP450 enzymes convert diazepam to?
Oxazepam
What group of people can have the CYP2D6 enzyme be absent in?
European Caucasians
What group of people is CYP2D6 often over active in?
North and East Africans
What are some substrates for CYP2D6?
B blockers
SSRIs
Opioids
Why is important to consider race when prescribing drugs?
Certain groups of people have different levels of CYp450 enzymes so metabolise certain drugs at different rates
How does CYP4503A4 get affected by grapefruit jucie?
Inihivbts action of CYP450(3A4) which increases the risk of certain drugs exerting toxic affects because the levels of the drug in the body will b e higher
What are the ways that drugs are eliminated by the body?
Kidney
Sweat
Tears
Genital secretions
Saliva
Breast milk
Faeces
Volatile compounds like gas
What size drugs does the kidney typically eliminate from the body?
Those with low molecular weight (small molecules)
What affects the renal elimation of drugs??
GFR and protein binding
Competition for transporters like OATS
Lipid solubility, pH and flow rate
What size drugs are typically removed form the liver?
Those of Hiuigher molecular weight (larger)
What amino acid do drugs being eliminated by the kidney conjugate with?
Glucuronic acid
What liquid produced by the liver is an important route for conjugates?
Bile
How are hepatic elimated drugs removed from the body?
Faeces or reabsorbed
What drugs do we have to worry about when giving a patient Abx?
Warfarin
Morphine
What are the 2 types of elimation kinetics?
Zero order
First order
What is zero order elimation kinetics?
When the rate of drug clearance is constant
What is first order elimation kinetics?
The concentration of the drug is proportional to the rate of its elimination
How does zero order kinetics appear on a [drug] - time graph?
Straight diagonal downwards line (slide 29)
How does first order elimation kinetics appear on a [Drug]-time graph? (slide 29)
Downwards curve
How does the natural log of a first order elimination kiiinetcis appear on a ln[drug] time graph?
Straight diagonal downward line
What is the equation for half-life?
T1/2 = 0.693/K
K = rate
What is clearance of a drug that has 1000ml/min that goes into thee kidneys but only 100ml/min comes out?
10% clearance
What is clearance?
Volume of blood cleared per unit time (mL/min)
The constant proportion of a drug that is removed from the body
E.g the kidneys will clear 10% of a drug
What is the equation for clearance>
Cl = rate of elimination from body / drug conc in plasma
How are clearance and elimination related?
Clearance rate doesn’t change (always clears 10% of the blood from drug) but if your increase the drug concentration the m ore drug in the Same volume is cleared so elimation rate increases
What is the units for elimation rate?
Mg./min
What is the equation relating half life, Vd and CL?
T1/2 = (0.693 x Vd) / CL
What can change the length of half life for a drug?
Vd of the drug
CL of the drug
What needs to be considered when determining dosages for patients?
Volume of Distribution
Clearance which determines the overall rate of elimination
What type of elimination kinetics do most drugs exhibit at therpatueic doses?
First order kinetics
What are some drugs that can exhibit zero order kinetics at very high doses?
Alcohol
Salicylic acid
Phenytoin
What is the danger of giving too much of a drug that has zero order elimination kinetics?
Only a certain amount of the drug can be elimated so subsequent doses can have very large unpredicitve toxic effects
Why do drugs with zero order kinetics need to be carefully monitored?
Have unpredictability in plasma [Drug] which can lead to toxic affects
Addition of a small dose of drug can lead to very large increase in circulating plasma drug conc leading to toxic affects
What do we need to consider with monitoring patients drug responses?
Drug-drug interactions
Toxic side effects
Is the therapeutic effect being achieved?
What is steady state plasma concentration?
Where the plasma concentration of a drug is effectively constant where the rate of drug administration is = to the removal/clearnce of a drug
What is the significance of the steady state plasma concentration of a drug?
Its the ideal concentration/level we want the drug to sit at
Therapeutic benefit optimal at steady state
After how many half lives does the steady state plasma conc of a drug get reached?
4-5 half lives
What is the equation for plasma steady state concentration (Css) which links rate of infusion and clearance?
Css = rate of infusion/Clearancce
When taking multiple doses of drugs, what is the most common route of administration?
Oral administration
Look at slide 40 graph 2, what is slowly happening with each dose of drug?
Slowly closer to achieving a steady state plasma concentration
What is the equation for rate of drug administration?
Rate of administration = (Dose x oral Bioavailability) / dose time interval
How are administration and elimination related when the drug is in steady state?
Administration = elimination
Assuming the drug is in a steady state how can we formulate an equation for steady state plasma concentration?
If in steady state administration rate = elimination rate
Rate of admin = (DxF)/t
Rate of elimination = CL x Css
So. (DxF)/t = CL xCss
Therefore. Css = (D x F) / (t x CL)
How can we calculate/formulate an equation to determine maintanence dose to ensure we keep/mainatin steady state plasma conc of drug?
When in steady state admin rate = elim rate
Css = (D x F)/(t x CL)
D = (Css x (t x CL)) / oral bioavailability
Css = steady state plasma conc (or levels of drug we want mainataining in the plasma)
CL = clearance
F = bioavailability correction
T = dose interval
What is a loading dose?
When a high dose of a drug is given usually at the start of treatment in order to reach therapeutic concentrations
Single dose to achieve desired concentration taking into account apparent Vd (volume of distribution)
Why would we need to use loading doses?
Need a rapid onset
Drug may have a long half life
What are some drugs that we often need a loading dose for since they have a long half life (t1/2)?
Digoxin
Phenytoin
Amiodarone
What type of drug is amiodarone?
Class III antiarrythmetic
What type of kinetics does phenytoin show?
Zero order kinetics
What is the equation for volume of distribution (Vd)?
Vd = Dose/[Drug] in plasma
What is the equation for loading dose?
Loading dose (Dose) = Css x Vd
What is the significance of a drug having a very large apparent Vd?
Gets everywhere (sequesters in to the tissues and not a lot in the plasma)
What is amiodarone often used to treat?
Supra ventricular tachycardia
Why is it important to consider the t1/2 of a drug?
Need to consider when terminating medications
Interactions with other drugs
Need to consider dosing for long term
What is the aim of a dosing schedule?
Maintain dose within therapeutic range
Safe
Achieve adherence (since med might not work unless patient takes it in the intended way
What is selectivity?
The ratio of a drug that achieves a given level of response at one receptor subtype compared to another receptor subtype
What is affinity?
Strength of interaction between a drug and its receptor
What is potency?
The concentration of drug needed to elicit a given response
What is efficacy?
The ability to produce the maximal response
What type of ligand is adrenaline?
Agonist
What is an example of a competitive antagonist?
Naloxone (mu opioid receptor)
What is a functional antagonist?
A drug which reverses the affect of another drug by binding to a receptor and causing an opposite effect in the tissues to that of the other drug
What is a nemonic for remembering CYP inhibitors?
Grapes Are Very Delicious Curing Cardiovascular (disease)
What does the pneumonic for CYP inhibitors stand for?
Grapes Are Very Delicious Curing Cardiovascular (disease)
Grapefruit juice
Amiodarone
Verapamil
Diltiazem
Clopidogrel
Clarithryomycin
What are some substrates of CYP2C19?
Warfarin
Clopidogrel
Phenytoin
Omeprazole
What are some substrates of CYP3A4?
Amlodopine
Atorvastatin
Simvastatin
