PharmacoKinetics Flashcards
Pharmacokinetics NMEONIC
ADME
ADME “A”
Absorption, uptake of the drugs into the blood stream.
ADME “D”
Distribution,
movement of drugs from blood stream into extravascular fluids and tissues
ADME “M”
Metabolism,
Biotransformation of drugs (chemical change of the drugs)
ADME “E”
Excretion,
removal of drugs by kidneys (Plus other organs - kidneys are the main site)
Primary organ responsibility for metabolism of drugs
liver mainly. some metabolism in the gut.
Excretion of the drug primary organ & alternative routes
Kidney main , sweating, bile, faeces, breastmilk
“physico/physical” chemical properties of the drug are
Lipid soluble
water soluble
Lipid soluble medications excretion method
needs to undergo metabolism prior to excretion
water soluble medication excretion method
doesn’t need to undergo metabolism, can go straight to the kidneys for excretion
absorption is dependent on the route. capsules are absorbed
in the GI tract/ gut wall
capsules pass through what before getting to the blood stream
hepatic/portal circulation to the liver
liver metabolises what
lipid drugs
what does the liver do when it metabolises
it turns lipid soluble drugs into water soluble drugs
once the drug is in the systemic circulation it gets distributed to
the body tissues
after being in the circulation the drug can do two different things
be excreted or re-cycled through the blood stream
absorption definition
‘process of transfer of the drug from the site of administration into systemic circulation
bioavailability definition
the proportion of a drug or other substance which enters the systemic circulation (it is highest 100% for IV administered drugs)
what affects absorption ?
route, age, diet, other medicines, medical conditions, particle size and formulation, gut content, gastrointestinal motility, splanchnic blood flow
what factors can affect drug distribution
blood flow rate, drug reservoirs, permeability of capillaries for drug molecules, increased total body water as a % of total body weight (babies high water, elderly low water)
Why are lipid soluble drugs highly distributed
the cell membrane contains a fatty acid layer which allows lipid soluble drugs to easily pass through the membrane
water soluble drugs tend to stay where
in the plasma
Metabolism definition
chemically inactivates a drug by converting it into a more water soluble compound, or metabolite which can be excreted from the body
Cytochrome p450 system does what
Umbrella term for a family of enzymes which are responsible largely for drug metabolism, most common cyp3a4
factors affecting drug metabolism
alteration of liver enzyme function, hepatic blood flow, physiological status, genetic factors, other drugs
when would the hepatic blood flow affect drug metabolism
liver disease (as the blood flow through the liver is reduced)
what condition would cause the drug metabolism to be affected ?
liver disease (what happens as we age - unhealthy lifestyle), very young or very old
what genetic factors can affect drug metabolism?
acetylation status, ultra rapid codeine metabolisers
what other drugs can affect drug metabolism
enzyme inducers or enzyme inhibitors
what is the acetylation status
bioavailability is to do with what step in ADME
absorption
enzyme inducing drugs do what
enhance the production of enzymes which break down drugs - faster rate
drugs implicated in enzyme induction include
phenytoin , rifampicin, carbamzepine
enzyme inhibiting drugs do what
inhibit enzymes which break down drugs leading to a decreased rated
drugs implicated in enzyme inhibition include
erythromycin, ciprofloxacin, omeprazole, amiodarone
excretion options for the body
kidneys (urine) , liver (bile ->faeces - duodenum), breast milk, lungs, sweat, tears and saliva
what is the major characteristic of compounds excreted in urine?
they are polarised and water soluble
drugs that are lipid soluble require what before urinary excretion
liver metabolism to increase their water solubility
elimination via the kidney depends on what (4)
blood flow to the kidney, glomerular filtration rate, active secretion of drugs into the kidney tubule, passive reabsorption back into the tubule
aging physiological changes ?
decreased ratio of lean body mass, decreased levels of serum albumin (main plasma protein important in drug distribution) decreased liver and renal function
elderly patient altered drug sensitivities ( common )
increased response to centrally acting drugs i.e. benzodiazepines,
increased response to warfarin
decreased alpha/beta receptor responses
aging and metabolism in the liver issues
physiologic changes in the liver include a reduction in size by 25-35% and a decrease in hepatic blood flow of more than 40%.
decreased blood flow leads to a reduced presystemic drug metabolism (phase 1 metabolism reduced, phase 2 metabolism generally preserved)
decreased liver size leads to reduced hepatic drug metabolism which leads to increased half life of some drugs, especially those with high clearance ratios will not be metabolised as quickly
ageing and excretion issues
at 70, renal function is at best 50%, reduced glomerular filtration rate and tubular secretion lead to an increased possibility of accumulation of all drugs and metabolites eliminated via the kidneys, increased half life of water soluble drugs
What is the half life
the period of time required for the concentration or amount of drug in the body to be reduced by one half
what is plasma clearance
the removal of a drug from the plasma is known as clearance
what is the volume of distribution
the distribution of the drug in various body tissues is known as volume of distribution
what is the symbol what represents the half life
t½
what is a steady state
when plasma concentration is at the correct level to be therapeutic and they are maintained by regular dosing
The removal of a drug from the body
elimination
two drugs with high half lives
warfarin, digoxin
The removal of a drug from plasma
clearance
Physiological factors that reduce the absorption of a drug include
rapid intestinal transit time, reduced splanchic circulation (such as occurs in shock) and the presence of food in the stomach.
first pass metabolism
- that is the extent to which the drug is destroyed on its first passage through the liver. If a drug is rapidly metabolised by the liver, the amount of active drug the reaches the systemic circulation will be reduced.
Bioavailability is defined as
the fraction of an administered dose that reaches the systemic circulation.
oral route advantages
convenient, non sterile, good absorption
oral route disadvantages
first pass destruction for most drugs, gi irritation, potential for interactions, inactivation by acids, variable absorption
sublingual advantages/disadvantages
avoids first pass and gastric acids/few preparations available
rectal advantages/disadvantages
avoids first pass and gastric acid/ aesthetically unacceptable
intravenous advantages/disadvantages
rapid access drug with complete bioavailability, useful for irritant drugs/ inceased levels of drug to the heart, sterility, risk of sepsis and embolism
intramuscular & subcut advantages/disadvantages
rapid absorption, depot for slow release/painful, risk of tissue damage, absorption variable
lungs administration advantages/disadvantages
large surface area, ideal for topical use/requires sound patient technique, can require bulky equipment
What does plasma consist of?
Most of it is water – about 92%, whilst plasma proteins form about 7%. The remaining 1% is other dissolved solutes such as inorganic ions.
Most, but not all, plasma proteins are manufactured in the liver including xxx
Albumins
The most abundant plasma protein ?
albumin
35% of plasma proteins are ?
globulins (contain antibodies, others transport)
the remaining 4% of plasma proteins include things such as
fibrinogen, 1% metabolic enzymes
highly bound drugs elimination may be
delayed
Extensive plasma protein binding will —– the amount of drug that has to be absorbed before effective therapeutic levels of unbound drug are reached
increase
why would someone with low albumin levels require less drug
as the drug is not bound to albumin it takes less to reach the therapeutic effect
most common biochemical process that occurs in metabolism
oxidation
what is oxidation catalysed by
ctyochrome p450 enzymes
the drug is said to be xx after phase 1 reactions
oxidised
phase 2 metabolism involves what
catabolism
Phase 2 metabolism involves conjugation which involves what
that is, the attachment of an ionised group to the drug.
what is a pro drug
it is a drug administered which is classed as inactive until it has completed stage 1 metabolism
Some drug metabolites can be toxic such as those produced from paracetamol. These are usually detoxified by phase 2 conjugation joining with what?
glutathione.
the process of the liver metabolising the drug is called what
hepatic biotransformation
Grapefruit juice and the herb St John’s Wort inhibit what activity
Cytochrome P450 activity.
Other routes of excretion from the body can include
bile, saliva, sweat, tears, faeces, milk and exhaled air.
Most drugs are metabolised first prior to being excreted. However, some drugs, such as
aminoglycoside antibiotics are polar compounds and are excreted by the kidneys without being metabolised first.
The excretion of drugs by the kidney utilises three processes, all which occur in the nephron, the microscopic functional unit of the kidney. These processes are:
Glomerular filtration,
Tubular secretion and
Tubule reabsorption.
What influence does urine pH have on drug excretion?
Urine pH greatly influences whether a drug is excreted quickly or slowly.
How can urine pH be manipulated in clinical situations?
It can be manipulated to control the excretion of certain drugs from the body.
What happens to acidic drugs in alkaline urine?
Acidic drugs are more readily ionised in alkaline urine.
What happens to alkaline drugs in acidic urine?
Alkaline drugs are more readily ionised in acidic urine.
Why is the ionisation of drugs in urine important for excretion?
Ionised (polar) substances are more soluble in water, so they dissolve in body fluids more readily for excretion.
How can aspirin poisoning be treated in terms of urine pH?
By making the urine more alkaline with sodium bicarbonate to increase the ionisation and excretion of salicylic acid (aspirin metabolite).
Drug metabolism in the liver consists of?
pHASE 1 AND 2
