Pharmacology Kinetics Flashcards
What factors determine the drug’s plasma concentration versus time profile
-absorption, distribution, metabolism, excretion
->metabolism and excretion refers to elimination
What is the importance of ADME for clinicians
-prescribing errors are made in 7% of prescriptions written
->with 50% of patients admitted to hospitals
-many errors are dosing errors, resulting in not understanding ADME principles
What is absorption
-the net movement of drug from the site of administration into the bloodstream
-> no absorbption after intravenous injection
What is distribution
-net movement of drug from the bloodstream into organs and tissues
What are routes of administration
Parenteral
->bypassing the intestine
Enteral
->intestinal
What are the different types of parenteral administrations
-IV
->intravenous injection
-Intramuscular injections
-Subcutaneous injections
-Topical
->transdermal, inhalation, insufflation, eye/eyedrops
-Buccal/sublingual(goes straight to systemic circulation, initially avoiding the liver)
What are the different types of enteral administrations
-Oral(by mouth)
-Rectal
->can be absorbed parenterally by going through GI to lymphatic and bypassing the liver and going to the systemic circulation
What are pharmaceutics
-pharmaceutics accounts for a drugs GI tract transit time
What are the pharmaceutics of the stomach, proximal small intestine and the large intestine
Stomach
-pH of 1-2 with food, pH of 3-5 when fasting, it takes 0.5-3 hours
Proximal small intestine
-pH of 6
->it takes 3 hours
Large intestine
->pH of 6.8-7
->it takes 12-24 hours
What is drug formulation
-it is used to optimise absorption
What sort of factors play into drug formulation
-drug particle size affects
dissolution extent and rate
->small drugs packed into a pellet will have a large surface area and dissolve faster or be available sooner to the body
-protective coatings on tablets and capsules
->protect them from dissolving in stomach and only when it reaches the small intestine
-slow and fast release pellets, polymers, osmotic technology
-depot injections
->lipid soluble injections
->oil droplets will sit in the muscle and will have slow release over many days and many weeks
->this is used with drugs treating schizophrenia
Where must all drugs absorbed from the stomach and intestines into the blood enter
-they enter the portal vein
->they then pass through the liver before reaching the systemic(general) circulation
Does metabolization in the liver result in loss of drug activity
-yes but now always
->you lose a certain percentage of the dose on one pass through the liver
Do orally-administered drugs pass through the liver before entering the systemic circulation
-yes
->drugs may pass through the liver on each circuit
->on average, about once every four circuits, the drug passes through the liver again
What is first pass metabolism
-the loss of drug to metabolism on its first passage through the liver
What is the definition of oral bioavailability
-the fraction of an oral dose of a drug that reaches the systemic circulation as an intact drug
How would you calculate oral bioavailibility
-fraction escaping the gut x fraction escaping the liver
->f(g) x f(H)
How does lymphatic absorption occur
-some drugs can interact with a lipoprotein chylomicron
->the chylomicron carries through lymphatic vessel, bypassing the liver
->this will increase the oral bioavailability of that drug
Do drugs need to be lipid soluble
-yes
->because they need to have an ability to diffuse through lipids
->they must also be water soluble to an extent
Do charged drugs diffuse across lipid bilayers
-no
Are most drugs weak acids or weak bases
-yes
->they can exist in a charged form
->charged molecules do not diffuse across the lipid bilayers
->they are in the form depending on the pH and the pKa
What is the pKa
-the pH at which 50% of the drug is ionized
What does a weak acid do in the stomach
-it is rapidly and extensively absorbed from the stomach
What does the absorption of weak bases look like in the stomach
-they are slowly and unpredictably absorbed from the stomach
->in the small intestines, they are better absorbed
When is concurrent use of drugs like laxatives problematic
-when they reduce GI transit time reducing absorption
->problematic for drugs which dissolve very slowly(griseofulvin)
->drugs that are absorbed by active transport(vitamin B)
->polar drugs with low lipid solubility(antibiotics)
How does polarity affect a drug
-more Nitrogen and Oxygen atoms=higher polarity=less lipid-soluble
What is a logP value
-how effectively a drug will partion from a water layer into an oil layer
-logP 0 means that it is in equlibirum in water and oil
->anything above 0 means that it dissolves more extensively in oil
-higher logP value means the drug is more lipid soluble in its neutral form or non-charged form
What is polar surface area
-it refers to 3 dimensional diagram of the drugs
-it is the area of composed of red and blue(outer shells of electrons)
->the more red and blue, the larger the polar surface area
-the lower the polar surface area, the more lipid soluble the uncharged form of the drug is
What is Fick’s Law of Diffusion
-a drug will flow from an area of high concentration to an area of lower concentration
->with the rate of flow being higher with a larger gradient
Can drugs that are more lipid soluble move more quickly and distribute more rapidly in cells, tissues, etc?
-yes
How does equilibrium differ between a highly-perfused tissue and a poorly-perfused tissue?
-drug reaches peak tissue concentration (equilibrium) soon after drug concentration peaks in the plasma for a highly perfused tissue
-for a poorly-perfused tissue, there is a lag
->it needs a continuous dose to reach that equilibrium
->but after a single dose, drugs may never reach equilibrium concentration in the tissue
How does drug diffusion back to plasma from tissue differ from a highly perfused tissue to a low perfused tissue
-it is much more rapid for the highly perfused tissue
What does it mean for the plasma concentration of the drug if the drug more extensively distributes from the plasma into the tissues
-it means there is a smaller amount of the drug remaining in the plasma
->and a lower concentration of the drug remaining in the plasma
What is the apparent volume of distribution of drugs
-the apparent volume of plasma that would contain the total body content of the drug at a concentration equal to that in the plasma once distribution is complete
What are the factors that determine the AVd or the apparent volume of distribution?
-fat is present
->drug is lipid soluble and will distribute into the fat
-there is soluble plasma proteins as well
->they have binding sites for acidic and basic drugs
->they are significant in the plasma and can bind to the drugs in the plasma, preventing absorption into the tissue
What happens to tissue water in an elderly person and fat and plasma albumin? What impacts does this have
-tissue water is reduced, fat isn increased and plasma albumin is reduced
-if administered same dose as in a younger healthy individual, you get reduced plasma protein bounding and more protein present in fat but lower concentrations in plasma(unbound) and tissue water
-the apparent volume distribution is increased because there is more of the drug in the fat
What is the definition of drug elimination
-the irreversible removal of a drug compound from the blood so that it is no longer able to exert a pharmacological effect
->excretion fo unchanged drug into urine, faeces, expired air, sweat
->most important is renal elimination
Can metabolites be produced during drug elimination
-yes
->enzymatic metabolism of the parent drug into a different chemical compound is a metabolite
->it goes through the liver to produce this metabolite
What is drug clearance
-refers to the volume of plasma cleared of drug in inut time
->ml/min or l/h
-each organ clearing its drug has its own drug clearance value
-for most drugs, the total body clearance is sum of renal clearance and hepatic clearance
->if others involved too, you add those organ clearances too
What is the organ extraction ratio
-the proportion of drug removed by a single transit of that drug through the organ
->it is between 0 and 1
How do you calculate clearance
-clearance=Q(bloodflow through organ) x organ extraction ration
How much of the blood volume is leaked from nephron into Bowman’s capsure in terms of the drug
-10%
->the 90 % of the blood containing the 90% of the drug passes out of the Bowman’s capsule and the walls of the capillaries
What factors affect renal drug clearance
-clearance by glomerular filtration
->drugs of MW<20, 000 pass from the blood into the filtrate in the Bowman’s capsule
->only drug molecules not bound to plasma proteins can be filtered
-clearance by secretion
->transporters exist for acidic and basic drugs that pump these drugs from the circulation into the tubules
->this is a major route of excretion
->only drug molecules that are not bound to plasma proteins can be secreted
What factors affect GFR
-it changes with age, sex and disease
What happens to fraction of drugs unbound with age and disease
-it changes in a variety of conditions due to age and disease
->for example, serum albumin drops 20% from 20 to 80 and acidic drugs are most affected
Does fraction of drugs reabsorbed change with urinary pH
-yes
->a possible increase in pH can reduce the drug reabsorption
What does the hepatic extraction ratio depend
-fraction of drugs unbound
->only drug molecules that are not bound to plasma proteins can be metabolized
-hepatic bloodflow
->with slower blood flow, drug is in contact with liver enzymes for longer
->this increased contact means with enzymes means increased metabolism and extraction from the liver
-intrinsic clearance
->theoretical maximum limit of liver enzyme activity versus a particular drug
->it has a value of litre/hour
Why are drugs metabolized
-so it is easier to excrete
What are the different phases of drug metabolism
-there are two phases
-phase 1 is the functionalisation step
->phase 1 gets the drug ready for phase 2
->for example, it can introduce a hydroxyl group
->making the metabolite easier to excrete
Phase 2
->it is a conjugation step
->creates a conjugate that is very water soluble
What are the major conjugation steps in Phase 2 of metabolism
-glucuronic acid(major)
-sulphate(major)
-acetyl group(minor)
-glutathione(detoxification)
Is phase one a major determination of the Clint value
Is there significant phase 1 enzyme variability in different individuals
-yes
->causing differences in drug responses for different individuals
What are the different types of phase 1 reactions
-oxidations, reductions, hydrolysis, hydrations, isomerisations
What enzymes carries out most oxidations?
-they are carried out primarily by the cytochrome P450 enzyme
Where are cytochrome 450 enzymes mostly found
-in the liver
-cytochrome P450 3A4 is one of the most important and 2D6
->note CYP450(3A4) makes up 30% and CYP450(2D6) makes up 5%
->these two are involved in 60% of all oxidation processes
What are some endogenous factors affecting CYP enzymes
-genetic polymorphisms
->differences between races/ethnicity
->poor/extensive metaboliser phenotypes
-age
->some CYPs are low or missing in neonates
->CYP also decreases with age
Sex
->differences in drug metabolism due to hormones
Bodyweight
->hepatic clearance varies with bodyweight due to liver size
Disease
->CYP reduced with liver diseases
->infections, endocrine disorders often reduce CYP
What is the area under the curve of a concentration time profile after oral administration mean
-it is the oral bioavailability
Can CYP inhibition occur
-yes
->grapefruit juice inhibits CYP3A4 irreversibly
What are external factors affecting CYP enzymes
-cigarettes, charcoal-broiled beef, cruciferous vegetables affect CYP1As
-pesticides, barbiturates affect CYP2B
-many drugs, including St. John’s wort affect CYP3As
