Fundamentals of Clinical Pharmacology Flashcards
Pharmacokinetics
what the body does to the drug
Enteral
something that goes through the gi tract
First-pass metabolism
anytime a drug is metabolized before the drug reaches systemic circulation/target site
First-pass metabolism is very significant for which organ? Why?
Liver: very significant for enteral (oral, rectal) administration
Where does first-pass metabolism occur and what is metabolized at these locations?
- Liver: very significant for enteral (oral, rectal) administration
- Lung (some fentanyl uptake, propofol metabolism)
- Plasma esterases in the blood/pseudocholinesterase (succinylcholine goes thru first pass metabolism in the blood via plasma esterases)
Bioavailability
= the fraction of drug that reaches systemic circulation
What is the bioavailability for drugs given IV or IM?
= 1 (100%) for parenteral (IV, IM) drugs because there's is no hepatic first-pass effect
Sublingual route
– direct absorption into systemic venous system (vena cava) Ex: nitroglycerin and fentanyl)
- Avoids portal circulation, therefore there is no hepatic first-pass effect because it bypasses hepatic metabolism
Different routes of drug absorption:
- enteral (oral, rectal)
- parenteral (IV, IM)
- sublingual
- transcutaneous (through the skin)
- subcutaneous (unreliable, injected under the skin),
- intramuscular (reliable but slower)
- Intrathecal (CSF)
- epidural
- perineural (around a nerve)
- inhalational
Once the drug is absorbed around the body what happens?
- The drug is distributed to one of four groups of tissue per the body’s cardiac output.
- The four main categories of tissue include:
- Vessel rich group
- Muscle
- Fat
- Vessel poor group
Four Classic Tissue Groups
- VRG (vessel-rich group) = gets most cardiac output even though it makes up a small percentage of body weight
- Muscle
- Fat
- VP (vessel-poor group) gets almost no cardiac output even though it makes up about 20% of body weight
Lipophilic drugs rapidly equilibrate where? And why is this important?
Lipophilic drugs rapidly equilibrate into CNS
tissue. This is important bc our anesthetic drugs work in the CNS tissue
Can protein-bound drugs get taken up by an organ?
No. Therefore they also cant be taken up by the kidneys for excretion either.
Which protein binds most drugs in the body?
Albumin - binds most acidic / neutral drugs, some basic drugs (ex: benzodiazepines, SSRIs)
What does a pt’s protein levels have anything to do with how our drugs are distributed?
Low protein levels (due to malnutrition, chronic illness) = less protein-bound drugs in circulation that cant be absorbed into organs = higher free drug levels in circulation = pt will be affected by a drug to a greater degree or require less of a drug to obtain the same effect
What happens once a drug gets to its target site?
It needs to get transported into its target cell
Unlike in the rest of the body, what type of transport must hydrophilic drugs undergo in the CNS?
active transport
Passive transport
= passive movement of a drug down a concentration gradient across the cell membrane into the cell
- Generally limited by blood flow (not lipid solubility)
- This means the drug will diffuse across as quickly as it can be delivered to the tissue
Facilitated diffusion
= requires carrier proteins to transport a drug across the cell membrane and into the cell, but no energy (ATP) is required to do so
Active transport
= carrier proteins require energy (ATP) to move the drug across the cell membrane into the cell. It can be done even against a concentration gradient
- Both lipophilic and hydrophilic drugs need active transport to deal with concentration gradients
Acid
A substance that can lose a proton and become negatively charged
H+ + A– ↔ HA (substance)
Base
a substance that can gain a proton and become positively charged
H + + B (substance) ↔ HB+
Why do we care about the concept of acids and bases when it comes to the drugs we administer?
- Because CHARGED (ionized) species don’t cross membranes very well. Most drugs work best when they are non-ionized.
- We determine whether an environment is acidic or basic based on the drug molecule’s pka value.
- pka = the pH at which half of the drug species is ionized and half is non-ionized
Remember…
Acids: H+ + A– ↔ HA
Bases: H+ + B ↔ HB+
…Acidic (H+) environments drive these equations to the RIGHT
Ex: If pKa = 6 and the pH is 2 (much more acidic)
———Then the “excess protons” will drive the equation to the RIGHT
Ex: If pKa = 6 and the pH is 7.4, the equation will be driven to the LEFT
What happens to a drug after its inside its target cell?
Biotransformation = alteration of the drug via a metabolic process (usually in liver)
- Most drugs need to be hydrophilic (water-soluble) for excretion to occur
- Some drugs do NOT require biotransformation in order to be excreted in the urine
Biotransformation
= alteration of the drug via a metabolic process (usually in liver)
- Most drugs need to be hydrophilic (water-soluble) for excretion to occur
- Some drugs do NOT require biotransformation in order to be excreted in the urine
- The body performs different types of reactions to transform a drug into a form that can be excreted like…
Phase I rxns: oxidation, reduction, hydrolysis → increase polarity of molecule to make the drug water soluble for excretion in urine
——-Cytochrome P-450 (CYP) enzyme system catalyzes most Phase I reactions
——-CYP activity increases with ongoing drug exposure – can alter metabolism of other medications that are metabolized by the same CYP enzyme subtype
—————-> Ex: CYP3A4, CYP3A5: many opioids, benzodiazepines, local anesthetics, others
——– CYP activity can be inhibited when drugs compete for the same CYP subtype
—————-> Ex: cimetidine inhibits metabolism of meperidine, propranolol, diazepam
Phase II rxns: conjugation with a polar substance (ex: attachment of a glucuronate, acetate, glutathione group) → water soluble for excretion in urine
- —–Many CYP as well as other Phase I and Phase II polymorphisms exist.
- ———->Ex: pseudocholinesterase deficiency
- —-Neonates thru 1 yr of age have diminished Phase I and Phase II activities
- Biotransformation rxn types
Phase I rxns: oxidation, reduction, hydrolysis → increase polarity of molecule to make the drug water soluble for excretion in urine
- ——Cytochrome P-450 (CYP) enzyme system catalyzes most Phase I reactions
- ——CYP activity increases with ongoing drug exposure – can alter metabolism of other medications that are metabolized by the same CYP enzyme subtype
- —————> Ex: CYP3A4, CYP3A5 metabolize many opioids, benzodiazepines, local anesthetics, others. So let’s say a pt is chronically exposed to benzos, they may have a very active form of CYP3A4 or CYP3A5 which means that when we give our own dose of benzos it will be metabolized much more quickly than normal.
- ——- CYP activity can be inhibited when the body is overloaded with drugs competing for the same CYP subtype
- —————> Ex: cimetidine inhibits metabolism of meperidine, propranolol, diazepam and make them have a longer effect than normal
Phase II rxns: conjugation with a polar substance (ex: attachment of a glucuronate, acetate, glutathione group) → water soluble for excretion in urine
- —–Many CYP as well as other Phase I and Phase II polymorphisms exist.
- ———->Ex: pseudocholinesterase deficiency (pts who cant metabolize sux)
—–Neonates thru 1 yr of age have diminished Phase I and Phase II activities so we may need to adjust dosing for them not just based on their weight and body fat but also on the fact their metabolic capabilities can be limited
Which enzyme catalyzes most Phase I reactions of biotransformation?
Cytochrome P-450 (CYP) enzyme
Hepatic drug clearance:
Hepatic drug clearance= the volume of blood that the liver could cleanse completely of drug in a given amount of time
Hepatic drug clearance = hepatic blood flow × extraction ratio
——— Hepatic blood flow: depends on cardiac output, blood pressure
——— Hepatic extraction ratio: fraction of drug removed from the blood as it passes through the liver
o Some drugs are more easily “extracted” by the liver (and metabolized) than others
What does hepatic blood flow depend on and how does it relate to pharmacology?
Hepatic blood flow depends on cardiac output, blood pressure.
This relates to pharm bc lots of drugs go through biotransformation (are metabolized) in the liver which means we have to understand what determines Hepatic drug clearance.
Hepatic drug clearance = hepatic blood flow × extraction ratio
Hepatic extraction ratio
= the fraction of drug removed from the blood each time it passes through the liver
——-> Some drugs are more easily “extracted” by the liver (and metabolized) than others
What does it mean when a drug is said to have a high extraction ratio?
- It means that as much drug is taken out of the blood for excretion as possible every time it passes through the liver. Therefore, the only thing that limits their rate of metabolism in the body is hepatic blood flow (which is dependent on CO) bc remember…. Hepatic drug clearance= hepatic blood flow × extraction ratio-
- They are called “flow limited” drugs (ex: etomidate, propofol) bc their extraction ratio is already set high
——– Therefore for these drugs, Hepatic clearance will be almost the same as hepatic blood flow. That is, a change in hepatic blood flow produces a nearly proportional change in clearance
Ex: In a Low CO state, these drugs will show diminished hepatic elimination
Clearance remains unchanged unless metabolic capacity (Vm) is severely compromised
What does it mean when a drug is said to have a Low hepatic extraction ratio?
- Low extraction ratio = “capacity limited” (ex: thiopental, diazepam)
- It means that very little of the drug is extracted from the blood for excretion every time it passes through the liver.
- Since the extraction ratio is set at being so low, its clearance from the body won’t change much if you change hepatic blood flow (CO)
o For these drugs, their clearance is only limited by the liver’s limited capacity to metabolize a small fraction of it at a time even under ideal conditions
o Changes in metabolic capacity (Vm) will produce a nearly proportional effect on clearance
For a Low extraction ratio drug, what happens to its drug clearance if you change hepatic blood flow (CO)?
- the drug’s clearance from the body won’t change
For a High extraction ratio drug, what happens to its drug clearance if you change hepatic blood flow (CO)?
a change in hepatic blood flow will produce a nearly proportional change in clearance
Is a pt’s liver health taken into account for High extraction ratio or Low extraction ratio drugs?
Low extraction ratio drugs bc they are “capacity limited” and as such a healthy liver can only metabolize a small fraction of it at a time. So when there’s a pt with an unhealthy liver, we worry about the liver’s capability to metabolize this type of drug at all
What is the last step in pharmacokinetics for most drugs?
the kidneys
When drugs reach the kidney, what happens?
If the drug is already biotransformed by the liver or just naturally water soluble, the kidney will excrete the drug from the body
Blood flow regulation to the liver vs. kidneys
Hepatic blood flow changes depending on CO & BP.
Kidney blood flow never changes thanks to autoregulation.
What is autoregulation (as it relates to the kidney)?
Autoregulation maintains constant renal blood flow over a wide range of cardiac output
Does the kidney’s constant high blood flow mean that it constantly excretes all the drugs in the blood that passes by it?
NO bc the kidney glomerulus can only filter and excrete drugs that are not bound to blood proteins (albumin or alpha-1-acid glycoprotein).
However, the kidney has a workaround and can actually excrete the entire [protein+drug} entity but it requires a lot of energy via lots of renal tubular active transporters that transport the [protein+drug} into renal cells where they are later eliminated.
First-order kinetics
First-order kinetics = when the same PERCENTAGE (fraction, “k”) of the existing drug is removed from the body per unit of time.
- The AMOUNT of drug removed depends on the serum levels.
- The FRACTION of drug removed does NOT depend on serum levels.
- Ex. If 10% is removed per minute, we call it a k = 0.1 per min. (‘k’ represents the rate constant that describes the drug elimination)
Zero-order kinetics
Zero-order kinetics = when the same AMOUNT of drug is removed per unit time
- the amount of drug removed is INDEPENDENT of serum concentration
- Zero-order kinetics is found in certain drugs (ex: phenytoin, alcohol)
- But many drugs that first undergo first-order kinetics will convert to zero-order kinetics at very high serum concentrations of drugs (notably, thiopental) especially when the drug concentration exceeds the body’s capacity to metabolize it
Half-life
= the time required for serum concentration to drop by a factor of 2
In first-order kinetics, does half-life remain the same at all drug concentrations or does it change?
half-life remains the same at all concentrations
How many half-lives is sufficient to clear a drug from a system?
5 half-lives where the drug elimination is 97% complete
Volume of distribution (Vd)
= its not a true volume. Its a measure of how a drug distributes to different compartments in the body. So a drug with a very large volume of distribution will have a very low concentration in the central compartment (blood).
- it helps us understand how a drug is distributed in a system by describing the capacity of tissues for absorbing a certain drug
- it depends on the pt’s tissue mass and the affinity of that drug for the tissue
- It is a numeric index of the extent of drug distribution, describing behavior of the drug in the body
A drug with a very large volume of distribution will have a very ____ concentration in the central compartment (blood). Why?
low.
Bc the drug constantly distributes out of the blood plasma due to its high affinity for distributing to tissues like fat.
In general, when we talk about a drug with a large volume of distribution we’re talking about drugs that are _______ (very soluble in ____).
lipophilic, fat
How do you calculate a drug’s volume of distribution (Vd)? Why do we care?
- Vd = amount of drug given / serum concentration.
- We care bc a drug’s volume of distribution tells us:
- ——how a drug will distribute in the body
- ——whether or not the drug will stay in blood plasma or rapidly distribute out to fat.
- —— it can help us calculate a loading dose if we wanted to give one.
- ————————-»»» Loading dose = Vd × target concentration
Elimination clearance (ClE) =
Elimination clearance (ClE)= the theoretical volume of blood from which drug is completely and irreversibly removed per unit of time by the liver & kidneys
- ——Can be calculated from the declining blood levels observed after an IV injection
- ——Clearance = dose given / Area under the concentration vs time curve
- ——Elimination clearance keeps the effect of the drugs we administer within the ‘safe zone’ and out of the ‘toxic zone’
Elimination half-life (t 1/2β) =
= the amount of time it takes for the amount of drug IN THE BODY to drop by a
factor of 2
It depends on both distribution and elimination
t1/2β = ln 2 × (Vd / ClE)
Ex: thiopental has a prolonged t1/2β in elderly – a prolonged elimination half-life means it takes a long time for old people to clear the drug by half.
In this case, Its not that old people cant metabolize it, but bc elderly people have increased body fat (larger volume of distribution, (Vd)) while the clearance (kidney function is still intact) so it takes a longer time to get the drug out of the body bc every time the amount in the serum is cleared, the same amount comes out of the fat compartment and replaces it in the central compartment.
Ex: pancuronium has prolonged t1/2β in renal insufficiency – in this case its due to clearance (renal elimination) is decreased, but not bc of a change in Vd
Elimination half-life does not say anything about termination of EFFECT (how long it takes for the drug to stop working) - (which depends on serum concentration), only the elimination of drug from the whole body (which includes all the other compartments and tissues)
What is termination of EFFECT?
= its how long it takes for a drug to stop working
- it depends on serum concentration
Central Compartment =
Plasma & Vessel Rich Group (brain, liver, kidneys,)
Pharmacodynamics = “What the drug does to the body”
“What the drug does to the body”
ED50:
Dose required to produce a specific effect in 50% of the population (like MAC)
LD50 (TD50) =
LD50 (TD50) = Dose required to cause death (or toxicity) in 50% of the population
Therapeutic Index =
= The ratio of (LD50 / ED50)
= its a measure of safety (room for error), the difference between the safe dose (ED50) and unsafe dose (LD50)
What does it mean to say that a drug has a high therapeutic index?
It’s very safe to use because the dose needed to get an adverse effect is way more than the dose needed to get the desired effect.
Agonist (X):
= a drug that binds to a receptor (R) and produces an effect
Potency
= The drug amount (mg) needed to achieve an effect.
- it’s usually dependent on receptor affinity
- Ex: If 1 mg of drug X vs 10mg of drug Z can be used to provide the same effect then the more potent drug is drug X bc less of it is required to deliver the desired effect.
Efficacy =
= the max degree of effect a drug can cause
- a drug that elicits a larger response / effect is said to have more efficacy when compared to another drug that elicited a smaller response/effect.
Partial Agonist drug=
a drug that elicits a lower maximal response than a full agonist and therefore has a lower efficacy than a full agonist drug.
it also blocks a full agonist from producing its maximal response and achieving its max efficacy
A drug with low potency has a dose-response curve that is shifted to the _____.
right
A drug with high potency has a dose-response curve that is shifted to the _____.
left
A drug with low efficacy has a dose-response curve that is shifted _____.
down
A drug with high efficacy has a dose-response curve that is shifted _____.
up
Redundancy =
= the concept that there is generally an excess of receptors
You don’t need to bind 100% of receptors to achieve the max effect of a drug.
The maximum effect typically occurs at far below maximum receptor binding
Tolerance:
= diminished response to a drug due to chronic exposure
Tachyphylaxis
= Acute tolerance after only a few doses
Antagonists
= bind to receptor without producing an effect
Competitive antagonist (Y)
It binds reversibly to its receptor
Its effect can be overcome by increasing the concentration of the agonist.
It decreases an agonist’s potency, but maximum effect (efficacy) is not changed.
What does a competitive antagonist do to the potency and efficacy of an agonist?
It decreases an agonist’s potency, but the maximum effect (efficacy) is not changed.
Non-competitive antagonist (Z)
- A drug that binds to its receptor or an allosteric site irreversibly
- They reduce both potency and efficacy of agonists
- Their effect cannot be completely overcome by increasing the concentration of agonist
What does a noncompetitive antagonist do to the potency and efficacy of an agonist?
It reduces both the potency and efficacy of agonists
How do you overcome the effect of a competitive antagonist?
increase the concentration of the agonist
How do you overcome the effect of a non-competitive antagonist?
The non-competitive antagonist’s effect CANNOT be completely overcome by increasing the concentration of the agonist because it is irreversibly bound to some receptors
