What is pharmacokinetics?
what the body does to the drug
(interpreting data on changing concentrations or amounts of drug and its metabolites in blood, plasma, urine and other body tissues and fluids)
How does a drug reach the systemic circulation?
What is the name of the process by which a drug moves between the systemic circulation and tissues?
What is the name of the process by which a drug it metabolised or excreted from the body?
What are pharmacodynamics?
the effect of drugs and their mechanism of action
(balance between therapeutic effect and toxicity)
Which drugs are the worst absorbed?
strong acids or bases
(they are mostly ionised = cannot cross membranes!)
Why are pharmacokinetics important (4)?
1. important to know if a drug is going to be absorbed if given by a particular route (e.g. orally)
2. need to know the plasma concentration as a function of time (its dynamic)
3. to know where the drug goes once inside the body (distribution) -> determines if histamine is drowsy or non drowsy
4. drug metabolites (are they active or toxic)
Name 3 different enteral (via GI tract) routes of drug administration:
Name 7 different parenteral (not via GI tract) routes of drug administration:
What is bioavailability a measure of?
How well a drug gets into the systemic blood circulation
An oral bioavailability (f) value of 1 means how much of the drug gets into the systemic circulation?
An oral bioavailability (f) value of 0 means how much of the drug gets into the systemic circulation?
Can a drug still be used if it has poor bioavailability?
Why/ why not?
Some will still get into the systemic blood circulation but the rest is lost (excreted)
-> n.b. not very practical to use a drug with v. low bioavailiability
What is an alternative way of measuring bioavailability?
Comparing plasma concentration of drug (Cp) following oral and IV administration, comparing the area under the curves gives a direct experimental measure of bioavailiability
n.b.if area under curves is very similar then the bioavailability is close to 1
n.b. to calculate oral bioavailiability... F = area under curve oral/ area under curve IV
Which 3 factors affect the oral bioabailiability of a drug?
1. poor absorption from gut
2. breakdown of drug in gut
3. first pass effect
What is the first pass effect?
- any drug first absorbed in stomach/ small intestine -> portal circulation -> drug must first pass through liver before it gets into the circulation
- liver = bag of enzymes = metabolise drug to different extents in liver = loss of some of the drug
Where are most drugs absorbed?
The small intestine due to its huge surface area
Through which method do drugs usually cross membranes (e.g. GI mucosa) to be absorbed?
Some drugs are absorbed by alternative routes... give two examples and state how these are absorbed...
L-dopa = transporter in membrane
Iron = transporter
List the 4 different factors that affect drug absorption at a membrane:
1. pKa of drug (lipid solubility)
2. pH at absorbing surface (lipid solubility)
3. GI motility/ food (decreased rate of gastric emptying e.g. opioids = decreased rate of absorption)
4. Drug preparation (e.g. enteric coated aspirin = takes a while to break down = stomach wall not exposed)
Which factor contributes directly to lipid solubility?
pKa of a drug pH at absorbing surface = changes depending on body compartments = ion trapping
What is the pKa of a drug?
the pH at which the drug is 50% ionised
What is the name of the equation relating pH, pKa and ration of ionised to unionised drug?
The henderson hasselbalch equation
What two things does the degree of distribution of a drug (amount in blood or tissues) depend on?
1. Lipid solubility (more likely to get into brain if lipid soluble)
2. plasma protein binding
What does the rate of drug distribution often depend on?
Rate of blood flow to different tissues (particularly for lipid soluble drugs)= especially high to brain!
What is the total body water volume in the average adult?
What is the plasma water volume in the average adult?
What is the blood volume in the average adult?
What is the extracellular water volume in the average adult?
What causes a person to wake up after general anaesthetic is no longer administered via IV?
The brain concentration decreases as the drug redistributes out of the brain back into the blood
What occurs to stop drugs having an effect?
Redistribution into other tissues e.g. brain to fat
How do you measure drug distribution?
Use the apparent volume of distribution
(Vd) = volume of water in which a drug would have to be distributed to give its plasma concentration
Why is this only the apparent volume of distribution?
The value of Vd may exceed total body water if distributes heavily in tissues (exacerbated by binding fate etc)
What is volume of distribution used for (3)?
- gives an approx. indication of where the drug goes in the body
- partly determines the half life of a drug
- can be used on pharmacokinetic calculations (e.g. clearance)
What is plasma drug binding important for?
Because drugs that are bound to plasma proteins cannot leave the blood
- e.g. warafin binds strongly to plasma proteins = why it has such a low tissue distribution (probably only limited clinical significance)
What is excretion?
The movement of drug or its metabolites from the inside to the outside of the body
What is metabolism?
A chemical change in the drugs structure (does not include ionisation)
What is elimination?
removal of the drug from the body (excretion + metabolism)
What is t0.5?
the half life of drug in plasma
(the time it takes for the Cp = plasma concentration, to fall to half of its initial value = when you start measuring... not always t=0)
Is t0.5 high or low when a drug is eliminated quickly?
How long do pharmacological effects last?
- can be much longer than plasma concentration (e.g. metabolite of aspirin = salicylic acid = still has pharmacological properties)!
What is clearance?
It is equal to the amount of plasma which is cleared of its drug content per unit time
What are the units of clearance?
ml/min or L/h
Why is it more useful to measure clearance than rate of elimination?
Clearance stays fairly constant
Rate of elimination of most drugs varies with [plasma] -> more drug = increased rate of elimination
Which 3 factors can alter the values of clearance in a patient?
Effects of other drugs
What happens to clearance in patients with liver disease?
What is the most common order of drug elimination?
(t0.5 is constant)- a container of water with a hole in the bottom -> more water in container = water comes out faster
What is zero order elimination?
When the rate of process is independent of drug concentration (t0.5 can vary)
This happens when there is saturation (e.g. pump... the same amount of water is removed no mater what the level of liquid in the container
n.b. few drugs are eliminated this way
What is pseudo zero order of elimination?
Initially zero order (saturated at high plasma concentration)
Becomes first order (no longer saturated because lower Cp)
e.g. T0.5 increases the more ethanol you drink/ phenytoin you take
What is the y intercept of the graph:lnCt = ln Co -kt?
n.b. t = 0 is the only point we know the exact amount of drug in the body! None has been broken down!!
If Vd increases or Cl decreases what happens to t0.5?
Why are pharmacokinetics often more complex clinically?
- Drugs often do not distribute evenly between tissues
- drugs could distribute to compartments with different kinetics (redistribution)
As rate of absorption of a drug decreases what happens to peak plasma concentration?
As rate of absorption of a drug decreases what happens to the time taken to reach peak plasma concentration?
Why is IV peak concentration reached quickest and is the largest?
There is total absorption before elimination stars to occur but with the others absorption and elimination occur at the same time
What is Css?
Steady state concentration
At Css what is the relationship between rate of infusion and rate of elimination?
They are equal
How many half lives does it take roughly to reach Css?
4-5 (irrespective of infusion rate)
Following any change it takes this many half lives to reach Css
What is loading infusion?
initially give a high rate of infusion then switch to lower maintanance infusion (to avoid toxicity)
= reach Css sooner (if rate of infusion increases, clearance stays the same so Css must also increase!)
through which method are most drugs currently administered?
Multiple oral dosing
What method can you use with multiple oral dosing to reach Css faster?
Loading doses too (first few doses are higher than the rest)
What happens to the rate of fall after a dose of drug is given with more drug?
It is steeper
What would happen to the Css average if you were to give 2 X the dose 1/2 as frequently?
It would be the same
there would be greater around the average (danger of toxicity & no effect)
How do you calculate the rate of infusion for IV infusion?
Rate of infusion = amount of drug/ time
In addition to amount of drug and time what also must be taken into consideration when calculating rate of oral dosing?
How do you calculate rate of oral dosing?
Rate of oral dosing = (D X F) / T
F = oral bioavailiability
D = dose
T= time interval between doses
How do you calculate Css adv?
= (D X F) / (T X Cl)
increase in D = increase in Css adv
decrease in T = increase in Css adv
Are lipid or water soluble drugs and metabolites more likely to be excreted from the kidneys?
What are the 3 processes that determine drug excretion in the kidney?
1. Glomerular filtration (only free drug can filter)
2. Active secretion (into proximal tubule e.g. Penecillin & many drug metabolites)
3. Passive reabsorption (anything lipid soluble will be reabsorbed in the distal tubule)
What is the effect pH of urine can have on reabsorption?
Alters how lipid soluble a drug is (alters degree of ionisation) -> if more ionised = cannot be reabsorbed
What is a forced alkaline diuresis?
Diuretic + sodium bicarbonate
Which drugs does forced alkaline diuresis enhance urinary excretion of?
Weak acids (aspirin & barbituates)
Which drugs have enhanced urinary excretion when urine pH is decreased?
Other than the liver where else are some drugs metabolised?
Intestine (cocaine & digoxin)
Why do we use prodrugs?
The active form of the drug would not reach where it needs to in order to have the desired action
How many phases does hepatic drug metabolism generally have?
Drug ---Phase I---> Derivative ---Phase II---> Conjugate
Lipid soluble ---------------------------> not lipid soluble
(excreted in urine)
What type of reaction (2) is the Phase I reaction of hepatic metabolism?
Hydrolysis/ Reduction= often introduces a new reactive site into the drug molecule
What type of reaction is the Phase II reaction of hepatic metabolism?
Conjugation with Polar molecules = water soluble = easier to excrete in urine
How many pathways of metabolism do most drugs undergo?
Most undergo >1
e.g. Amphetamine (oxidation and deamination)
What is the most important enzyme involved in the metabolism of drugs?
What is the collective name of drug metabolising enzymes in the liver?
Where abouts are microsomal enzymes involved in Phase I reactions located?
In the endoplasmic reticulum of the liver
Which class of enzymes in the liver are the most important in oxidation reactions in the liver?
mixed function oxidases
How does the cycle for phase I reactions work (4)?
1. Oxidised cytochrome p450 combines with a drug substance = binary complex
2. NADPH donates and electron to the flavoprotein reductase (reduces oxidised cytochrome p450 complex)
3. a second electron is introduced from NADPH via flavoprotein reductase = reduces molecular oxygen = activated oxygen-cytochrome P450 substrate complex
4. complex transfers activated oxygen to the drug substrate to form oxidized product
Why do we have different profiles for metabolising drugs?
We have different isoforms of cytochrome p450 = prefer different drug substrates
Where do phase II reactions happen?
In the CYTOSOL OF LIVER CELLS
Why does phase II reactions (creating a polar molecule) increase urinal excretion of a drug?
- polar molecules cannot cross membranes (not readsorbed in distal tubule)
- still actively secreted in proximal tubule
Name a drug that can form more than 1 metabolite:
Aspirin (makes 4)
How do drugs make more than 1 metabolite?
they can be metabolised by a number of pathways
Can a single metabolite be produced by two different pathways?
e.g. aspirin the glucaronide can be added onto two different places
Which 5 factors affect drug metabolism?
1. enzyme induction
2. enzyme inhibition
3. genetic polymorphisms
what can cause increased synthesis of cytochrome p450 over a number of days?
Some drugs and environmental pollutants
List three things that induce the liver to synthesise more cytochrome p450?
Phenobarbitone (epilepsy drug)
When cytochrome p450 is induced what other substrates does it effect?
Other substrates for THE SPECIFIC CYTOCHROME!! (e.g. phenobarbitone = decreased effects or 1/2 life of warafin and decreases its own 1/2 life)
Give 6 examples of drugs that inhabit p450 enzymes:
What can be the problem of inhibiting cytochrome p450?
increased toxic effect and increased half life
(Prolong the effects of other drugs)
What is an example of a drug of which many people cannot metabolise well because of genetic polymorphisms?
Isoniazid (treatment for leprosy and TB)
Which 6 diseases can inhibit hepatic metabolism for drugs whose hepatic clearance is essentially blood-flow limited (rapidly metabolised in liver)?
cardiac disease (decreased blood flow through liver & kidneys)
Why should disease be taken into consideration when prescribing an individual drugs?
They may need a lower dose of the drug
What causes renal function to diminish?
What happens with an overactive thyroid?
increased metabolism (thyroid hormones enhance activity of enzymes)
At which stage(s) in life is the liver's capacity to metabolise drugs lower?
New born babies
What happens in a Paracetamol overdose (or making slightly too much each day) that causes toxicity?
Saturation of phase II mechanism
=Cytochrome p450 produces phase I product (TOXIC = highly reactive and reacts with anything in cell e.g. cell macromolecules)
-> neutralised if reaches with glutathronine = excreted but this is used up quickly
What are the two main types of drug interaction?
What are pharmacodynamics based on?
Mechanism of action
What are the 4 key processes involved in pharmacokinetics?
Distribution/displacement (not really anything clinically important)
What is the effect of milk on tetracycline absorption?
stops it being absorbed (Ca ions chelate tetracycline)
What is it that aspirin reduces the excretion of in the urine?
Methatrexate (cancer and immunosuppressive drug for arthritis) -> build up in body = toxic
Which drug is used to stop alcoholism?
how does metronidizole stop an individual drinking alcohol?
Disulphram reaction = immediate hangover etc. (feel awful)
What is the effect of the antibiotic erythromycin on liver enzymes?
Inhibits many liver enzymes (increase half life of drug and therefore increased adverse effects)
What are the 4 different types of drugs used in dentistry?
- Analgesics (local anaesthetics)
- Sedatives and anxiolytics