Pharmacokinetics 1 and absorption Flashcards
what are the 4 stages pharmacokinetics?
- Absorption from the site of administration
- Distribution within the body
- Metabolism (breakdown and/or conjugation)
- Excretion
Pharmacodynamics
what a drug does to the body
pharmacokinetics
what happens to the drug in the body
Pharmacodynamics specificity
Specific to drug or drug class
pharmacokinetics specificity
Non-specific, general processes
Pharmacodynamics specificity relies on
-Interaction with cellular components
-Effects at the site of action
Concentration-effect relationship
-Modification of disease progression
-Unwanted effects
-Drug interaction
-Inter- and intra-individual differences
pharmacokinetics in the body relies on
- Absorption from the site of administration
- Delivery to site of action
- Elimination from the body
- Time to onset of effect
- Duration of effects
- Drug interaction
- Inter- and intra-individual differences
ethanol metabolism
draw it out
why is pharmacokinetics important?
Critical to new medicines research and development
Understanding pharmacokinetics is important to prescribing safely
Understanding what can go wrong with drug dosing and drug-interactions
what are Fentanyl Transdermal Patches?
opious drug which is 100 times more potent than morphine
what enzyme metabolises Fentanyl?
cytochrome P450 3A4 isozyme
what affects release and how much is released and onset?
12-18 hour onset to reach peak pain relief (slow onset so people think they need more)
temp affects release
40% still in the patch after 72hours
levels fall to 50% after removing the patch 17 hours prior
what are the major routes of administration of drugs into the body?
Sub lingual IV Oral Sub cutaneous Up the bum – suppository – rectal Inhalation Nasal Intramuscular Intravitreal (in the eye) Trans dermal – patch on the skin Pessary spinal canal - into csf
why is intramuscular quicker to get into the blood stream that intradermally?
there are larger and more blood vessels in the blood
Oral administration - Advantages
- Easy
- Slow release
- drugs can be formulated to protect against digestive enzymes and acid
- cheap and safe
Oral administration - Disadvantages
- unsuitable for patients strictly mil by mouth
- mostly absorbed slowly
- unpredictable absorption
Rectal administration - Advantages
good absorption, avoids the first pass metabolism - haemorrhoids vein drains directly into the inferior vena cava
Inhalation administration - Advantages
large SA, bronchodilators steroids targeted to lungs with low levels of absorption
Inhalation administration - Disadvantages
bioavailability depends on the patients inhaler technique and the size of the particles generated
Where are most drugs that are taken orally absorbed?
in the small intestine - large SA
some absorption can take place in the stomach
which factors affect absorption?
ionisation of a drug molecular size gut content (fasted/fed) GI motility particle size and formulation
at what molecular weight does passive absorption become worse/
> 500nm
how long does it take 75% of drugs to be absorbed after being taken orally?
1-3 hours
how are drugs that are taken orally absorbed?
Passive difusion, carria media transporters, pinocytosis/endocytosis
all drugs have to bass at least one cell barrier in order to get into the effector tissue - one method excluded - which is this?
Intra venous
which kind of cell linings are often present barriers to drugs moving from one ‘compartment’ to another
epithelial and endothelial
which barriers are the most difficult to permeate/
BBB and placental
what do aqueous pores do
allow transport of materials
where would you mind fenestrated capillaries
GI tract, renal glomeruli, endocrine glands, choroid plexus
which organs would you fined pores in the capilaries
liver, spleen and bone marrow
drugs freely pass and so detox and excrete
where would you find tight junctions in capillaries?
BBB, muscle and heart
what ways can drugs cross membranes?
Passive diffusion, though aq pore, and carrier protein (requires ATP), pinocytosis take up into vesicle (requires ATP)
what will diffuse across across a lipid membrane?
only unionised (non charged form of the drug)
what do drugs ionise according to?
their pKa
Weak acids will be ionised at
higher pH
Weak bases will be ionised at
lower pH
The pKa is the pH at which ionised and non-ionised forms are..
equilibrium
Alkali drugs
high pKA – ionised in acidic condions
why does aspirin get trapped in the urine?
has a low pKa due to being a weak acid- the urine has a high pKa
why is neurotoxin safe to eat in meat?
neurotoxin is basic - so has a high pKa the gut has a low pKa so safe to eat
alkalising urine can be used to treat overdoses of what drugs
weak acids
where are strong bases ionised?
in the intestines
- poor absorption
with a weak acidic drug such as aspirin where will it be most ionised? pH?
in alkaline pH - such as in the urine
what is the pKa of aspirin?
3.5
pethidine is a weak base drug with a pKa of 8.6, where will ionisation the base be greatest?
low pH, such as in the stomach
carriers in cell membranes mediate the transport of what?
sugars, amino acids, neurotransmitters and metal ions
what do solute carrier transporters (SCLs) do?
passively transport substrates down its concentration gradient
active transport -
transferring against the concentration gradient - requires ATP
how many genes are thought to code for transporters
300
to traverse cellular barriers (Mucose, BB, placenta) drugs must cross
lipid membranes
drugs cross lipid membranes by
passive diffusion transfer or carrier - mediated transfer
what is the main factor that determines rate of diffusional transfer across membranes?
drugs lipid solubility
what is a less important factor in determining rate of diffusional transfer?
molecular weight
henderson- hasselbalch equation states
ionisation of weak acids and weak bases varies with pH
with weak acids and weak bases only……. can diffuse across lipid membranes - pH partition
uncharged species
- protonated form of weak acid
- unprotonated form of weak base
what does pH partition mean?
that weak acids tend to accumulate in compartments of relatively high pH (weak bases do the reverse)
carried mediated transport in the renal tube,BB and GI epithelium is important for some drugs that are
chemically related to endogenous species
Bioavailability (F)
extend and rate at which the active moiety of the drug or metabolite enters the circulation, thereby accessing the site of action.
what bioavailability does IV immediately give?
100%
how would you work out bioavailability?
blood plasma conc. curve
Area under the curve oral route / area under the curve IV
= absolute bioavailability
insulin bioavailability
0% - broken down by enzymes
what is the first pass effect?
where when a drug is taken - absorbed into the GI tract - passes through the portal vein into the liver - the liver breaks down and greatly reduces the bioavailability of the drug
which would have a longer half life? IV or oral?
Oral
oral would take longer to onset, have a more blunter peak plasma concentration and longer duration of action
what affect does slower absorption of drug have on peak conc.
lower peak
Intra venous administration allows
rapid onset and full absorption of drug
what is an IV loading dose called?
bolus
what 2 methods of IV are combined to maintain blood concentration?
iv bolus (loading dose) and then Iv infusion
IV infusion avoids
first pass
sublingual absorption
under the tongue - mucous membrane with lots of capillaries, straight into the blood so avoids first pass
would rectal or oral have higher bioavailability?
rectal
Nasal sprays
nasal cavity is well vascularised, quick into circulation, small molecules with a local effect
intravitreal uses
-used for diabetes retanopothy
(eye drops)
saline based
- antihistamines or antibiotics
what is intrathecal
straight into the spinal canal - into the CSF - crosses the BBB
what are prodrugs?
drugs which are administered but the need to be metabolised by the body to become the active form
example of prodrug?
codine - created into morphine
AZT - doesn’t have direct effect on HIZ, effects reverse transcriptase
which enzyme converts coding to morphine
CYP2D6
the specialist formulation of the contraceptive implant - how does it work?
releases hormones slowly, made of copper which also has a natural effect on our hormone levels
how are antibody-drug conjugates used?
mainly used against cancer, drug which has a selective antibody and a cytotoxic agent - antibody sticks to marker on cancer cell and binding causes the reaction to kill the cells
which form of dosing is most common?
oral
most absorption of oral is in
the small intestine
bioavailibilty requires
absorption and surviving early metabolism (GI wall and first pass)
