Clinical Pharmacology Flashcards
What is pharmacokinetics?
What the body does to the drug following administration and refers to the movement of a drug into, through and out of the body
What are the 4 aspects of pharmacokinetics?
Absorption, distribution, metabolism, excretion (ADME)
What is absorption?
The process by which drugs enter the body and move from site of administration in to the blood plasma. The ability of drugs to pass through barriers is determined by their chemical properties, formulation and route of administration
What is distribution?
How the drug is moved around the body and it’s ability to accumulate in certain tissues and organs. It is determined by blood perfusion, tissue binding, regional pH and permeability of cell membranes
What is metabolism?
How the body breaks down the drug. the principle site of drug metabolism is in the liver and occurs in two phases
What is excretion?
The rate and process which the compound exits the body
What state must drugs be in order to be absorbed?
In solution
When would an alternative route to orally be considered ?
A drug is digested/absorbed poorly so only a small amount reaches the blood circulation
A rapid onset of action is required
A drug irritates the stomach lining
What is subcutaneous?
Injection/infusion beneath the skin
What is percutaneous?
Injection/ topical medicine that passes through the skin
Intrathecal?
Injection into the space around the spinal cord
What is the mechanism of beta lactam Antibiotics?
Cell wall synthesis inhibition
What is bulk flow transfer?
In the bloodstream, lymphatic system and CSF or GI tract
how can drug molecules move around the body?
-bulk flow transfer
-diffusion
-transfer across barriers
what is diffusion?
drugs move in bodily fluid s such as the cytoplasm and interstitial fluid
what barriers can drugs transfer across?
epithelial, endothelial and cytoplasmic membranes
what does the chemical nature of a drug impact?
-its ability to diffuse across barriers such as a cell membrane
how can drugs move across cells?
-passive diffusion
-facilitated diffusion
-active transport
-pinocytosis
what is passive transport?
drug passes directly through the lipid bilayer (small lipophilic drugs such as alcohol)
what is facilitated diffusion?
drugs move via solute carrier/membrane transporter proteins (eg large hydrophilic drugs such as certain steriods and chemotherapy agents)
what is active transport?
drug is transported against a conc gradient (low to high) and requires energy expenditure (eg large hydrophilic drugs such as levopoda)
what is pinocytosis?
drug binds to a receptor on a cell membrane and is engulfed by cell into a vessel and is then exocytosed into the blood stream (eg insulin)
what factors affect the rate and extent of drug absorption?
-molecular size
-lipid solubility
-pKa and pH
how does molecular size effect drug absorption?
dependent mainly on this
small molecules diffuse more rapidly and absorption decreases as size increases
how does lipid solubility affect absorption?
non polar/unchargedmolecules dissolve freely in membrane lipids and disuse readily across the cell membrane in contrast to polar/charged molecules.
therefor drug absorption increases as lipid solubility increases and many pharmacokinetic properties of a drug can be predicted from its lipid solubility
how does pKa and pH affect absorption?
-majority of drugs are weak acids or bases therefor exist on an ionised or unionised form
-the ratio of ionised and unionised dorms its dependent on the acid dissociation constant of a drug and will vary with pH
what is the Henderson-hasselbach equation?
the pKa of a drug is equal to the pH of the solution at which 50% of the drug will be ionised and 50% will be unionised
what happens when we increase acidity?
the reaction shifts in favour of the unionised form rather than the ionised form.
this is important as only the unionised form if the drug is lipid soluble
weak acidic drugs are more favourably absorbed in highly acidic environments such as the stomach
what happens when we decrease the acidity?
shifts the reaction in favour of the unionised rather than the ionised form.
weak basic drugs are more readily absorbed in highly alkaline environments like the intestine
what 3 organs must a drug pass when it is administered orally?
stomach intestine and liver
what is the first pass metabolism?
the drug must avoid inactivation and degradation by the stomach acid and digestive enzyme in order to reach the systemic circulation and have therapeutic effect
what is bioavailability?
the amount of drug that reaches the systemic circulation
which types of drug administration surpass the liver stomach and intestines?
intravenous, intramuscular, subcutaneous, sublingual
why is insulin not administered orally?
poor absorption and digestion by enzymes in the GI tract. has a bioavailability of less than 1%
what is drug distribution?
drug distributed to the tissues where it will reach its site of action
it will leave the bloodstream (intravascular) and enter the extracellular fluid (extravascular) and there enter the cells
what factors affect drug distribution?
-increased blood flow
-protein binding
-lipid solubility
how does blood floe affect drug distribution?
drugs will quickly distribute to tissues with high blood flow (eg kidneys liver brain) rather than those with poor blood floe (fat , tendons, cartilage)
how does protein binding effect drug distribution?
drugs can bind to large serum proteins, such as albumin, that can not pass easily across cell membranes. the reduces the amount of unbound active drug
how does lipid solubility effect drug distribution?
lipophilic/non-polar drugs diffuse easily across the cell membrane and can easily distribute into the target tissue
once the drug reaches the blood circulation, what will cause the conc of the drug to continue to fall?
distribution to other tissues
elimination by metabolism and excretion
how much water is in the body?
42L
what is the 4 main compartments of the body water distribution?
-plasma water (3L) water in circulation
-interstitial water (11L) water in space between blood vessels & cells
-intracellular water (28L) sum of water content inside all cells
-transcellular water : water in epithelial lined spaces (eg synovial peritoneal and pericardial and CSF)
what is the volume of distribution?
an estimation of drug distribution and can be defined as the volume of plasma that would be necessary to account for the total amount of drug in a patients body.
how is volume of distribution calculated (Vd)?
from the dose administered (Q) relative to the concentration of that drug in the blood plasma (Cp)
why is Vd used clinically?
estimation used to determine the Loading dose necessary for a desired blood concentration of drug
Vd is further divided by the patients body weight and expressed in terms of litres/kg
how many compartments would a low Vd expect to occupy?
one (plasma)
how many compartments would a medium Vd expect to occupy?
two (plasma and interstitial fluid)
how many compartments would a high Vd expect to occupy?
all compartments (plasma, interstitial, intracellular and transcellular fluid)
what happens when a Vd exceeds the body weight?
also distributed within the tissue
what happens when a drug has a high Vd?
has prosperity to enter the extravascular compartments of the body meaning that a higher dose of a drug is required to achieve a given plasma conc
what happens when a drug has a low Vd?
has a prosperity to remain in the plasma meaning a lower dose of a drug is required to achieve a given plasma conc
what are some Vd concentration examples?
low Vd- 3L
medium Vd- 14L
high Vd- 42L
how do we calculate Vd in L?
dose administered (mg)/plasma conc (mg/L)
what type of receptor is an adrenoreceptor?
G protein coupled receptors
what is the mechanism of action of the antibiotic gentamicin?
inhibition of mRNA translation
what are the two processes of drug elimination?
metabolism and excretion
where does drug metabolism predominantly take place?
liver
what is the goal of drug metabolism?
make the drug the less lipid soluble so that it is easier to excrete and will not be reabsorbed
what are the main excretory routed for drugs?
kidneys, heaptobiliary systems, and the lungs. most drugs leave in the urine
can also be removed in the faeces and exhaled air or in secretions such as milk or sweat
some drugs are secreted in the bile by the liver and can be reabsorbed in the intestine
what are the 3 main roles of the liver in drug metabolism?
detoxify - toxins and carcinogens by converting them into a nontoxic metabolite
activate prodrugs - converting the inactive precursor to an active form
inactivate a drug - converting the active drug into an inactive form
what are phase 1 reactions (non synthetic/catabolic)?
-involves creating a functional reactive group by oxidation, reduction or hydrolysis (known as functionalisation)
Require drug metabolising enzymes, such as the Cytochrome P-450 system, which are embedded in the smooth ER and mitochondria. To reach these enzymes a drug must cross the plasma membrane. This means that:
Non-polar drugs easily cross and are metabolised
Polar molecules either require a specific transport mechanism to be metabolised or they are excreted unchanged in the urine.
what are phase 2 reactions (synthetic/anabolic)?
Involve conjugation (i.e. attachment) of a glucuonyl, sulphate, methyl or acetyl group that usually results in an inactive product.
These two phases will yield drug metabolites that have reduced lipophilicity relative to the parent drug. This will prevent drug metabolites diffusing across the cell membrane and being reabsorbed and instead will increase their excretion
what is patient polymorphism?
Many CYP enzymes show genetic polymorphisms, meaning that there is the presence of two or more variant forms of the gene that can occur among different individuals or populations. Consequently, this can lead to variable enzyme activity between individuals.
what does increases in patient metabolism result in?
will increase the amount of inactive drug so you might not be able to reach the therapeutic dose required.
what does decreases in patient metabolism result in?
reduce the amount of inactive drug therefore high concentrations of active drug will accumulate, which may led to toxic side effects (e.g. babies/elderly).
what are CYP450 inducers/inhibitors?
Patients can be taking multiple drugs at any one time (polypharmacy), which can interfere with the metabolism of the drug of interest. These fall in to two classes: inducers and inhibitors
what are CYP450 inducers?
Upregulate CYP450 enzyme activity, increasing drug metabolism and shortening drug half-life (e.g. ethanol, carbamazepine).
what are CYP450 inhibitors?
Downregulate CYP450 enzymes, decreasing drug metabolism and lengthening drug half-life. (e.g. erythromycin, ritonavir, omeprazole).
what happens during liver disease?
dramatically impacts the CYP450 system, reducing enzyme activity, reducing drug metabolism leading to drug accumulation and toxicity.
how are drugs excreted from the kidneys?
hydrophilic drugs Filtration of the blood begins at the glomerulus where all drugs, except protein bound drugs, diffuse into Bowman’s capsule. The filtrate then passes to the proximal convoluted tubule, which has secretory pumps that can actively transport drugs from the blood into the tubule. However, as the filtrate passes the loop of Henle non-ionised drugs can be reabsorbed back in to the bloodstream.
what are factors that affect drug excretion?
filtration
secretion
reabsorption
how does filtration affect drug excretion?
Filtration in to the Bowman’s capsule by passive transport is dependent on the glomerulus filtration rate (GFR) and drug protein binding. Small drug molecules that are not protein bound are rapidly excreted into the urine. However, high levels of drug will remain in the blood plasma if there is a reduction in drug filtration due to:
Reduction in GFR
Increased protein bound drug
how does secretion affect drug excretion?
Secretion in to the tubular lumen from the blood via active transport is dependent on lipid solubility and concentration gradient of the drug as well as the transporters required to move them. Drug secretion into the lumen will be impaired by:
Drugs that inhibit the transporters
High levels of drug in the plasma that saturate the transporter.
how does resorption affect drug excretion?
Reabsorption in the Loop of Henle by passive diffusion into the blood is dependent on lipid solubility, pH and urine volume. The following parameters will reduce drug reabsorption into the blood and increase drug excretion in to the urine:
Large lipophobic/hydrophilic drugs
Ionised acidic or basic drugs
High urine volume
what is first order enzymatic kinetics?
The majority of drugs function under first-order enzymatic kinetics. This means as the plasma concentration of the drug increases so does the rate of drug metabolism because the number of enzymes actively involved in processing the drug increases proportionally. This linear relationship will continue as long as there is enzyme availability, however once all enzymes are occupied the drug will start to follow zero order kinetics (see below). In addition, the rate of elimination also increases as the kidneys clear the drug metabolites via the urine. This means that the time required to eliminate half of the drug remains constant.
what is zero order enzymatic kinetics?
If a drug functions under zero order enzymatic kinetics then all available enzymes are actively processing the drug and they are saturated. Therefore as the drug concentration increases there are no additional enzymes to process the drug to its inactive metabolite. Consequently, the rate of drug metabolism is now constant as it is no longer increasing with drug concentration. This leads to the accumulation of a drug within the blood plasma, which can cause toxic side effects. In turn, the kidneys are eliminating a constant amount of the drug per unit of time.
what happens during first order metabolism?
↑ Drug concentration ↑ Rate of metabolism
Rate of metabolism is dependent on drug concentration & is proportional
Half-life is constant
what happens during zero order metabolism?
↑ Drug Concentration no longer ↑ Rate of metabolism
Rate of metabolism becomes independent of drug concentration & is constant.
Half-life is variable
what happens during first order elimination?
Constant proportion of the drug is eliminated over time.
For example 50% of drug is removed every hour, therefore the graph is exponential.
what happens during zero order elimination?
Constant amount of the drug is eliminated over time.
For example 25 mg of drugs is removed every hour, therefore the graph is linear.
what happens during metabolism in patients under 1 year old?
decreases
what happens during phase 1 drug metabolism?
catabolic
non-synthetic
formation of new functional group
what happens during phase 2 metabolism?
synthetic
conjugated with endogenous substance
anabolic
what is a prodrug?
biologically inactive compound that is metabolised to produce an active form of the drug
