Pharmacology #1 – Fundamentals of Clinical Pharmacology

Pharmacokinetics = What the ____ does to the ____
What the BODY does to the DRUG

4 main concepts of pharmacokinetics
1) Absorption
2) Distribution / Redistribution
3) Transfer / Transport
4) Elimination

Definition of bioavailability
Relative amount of drug that reaches systemic circulation

Parenteral routes of administration
1) Intravascular (IV)
2) Intramuscular (IM)
4) Intradermal
5) Intrathecal
6) Epidural
7) Subcutaneous

What is the usual bioavailability of drugs given parenterally?
1 (all of it reaches circulation)

Does the bioavailability of IV fentanyl = 1?
No, it is less than 1 because it goes through a first pass metabolism in the lungs

Does the bioavailability of IV succinylcholine = 1?
No, it is less than 1 because it goes through a first pass metabolism by pseudocholinesterases

When does first pass metabolism occur?
Before the drug reaches systemic circulation / target site

What is the site of significant first pass metabolism for enteral drugs?
Liver

Enteral routes of administration
1) Oral
2) Rectal
3) Sublingual

When using the sublingual route of administration, where does the drug absorb into? Is there a first pass effect?
Direct absorption into systemic venous system, no first pass effect because it avoids portal circulation and bypasses hepatic metabolism

What are the 4 classic tissue groups?
1) Vessel-rich group (VRG)
2) Muscle
3) Fat
4) Vessel-poor group (VPG)

What percentage body weight is the VRG?
10%

What percentage body weight is the muscle?
50%

What percentage body weight is the fat?
20%

What percentage body weight is the VPG?
20%

What percentage cardiac output does the VRG get?
75%

What percentage cardiac output does the muscle get?
19%

What percentage cardiac output does the fat get?
6%

What percentage cardiac output does the VPG get?
~0%

Which equilibrates quicker into CNS tissue – lipophilic or lipophobic drugs?
LipoPHILIC drugs

What is the pathway of redistribution through the tissue groups?
Plasma –> VRG –> Muscle –> Fat –> VPG

What effect does multiple doses of a drug have on duration of action?
Increases duration of action

In small doses of a drug, what does a decrease in plasma concentration depend on?
Redistribution to other tissues

With multiple doses of a drug, what does a decrease in plasma concentration depend on?
Drug elimination from the body

What drugs does albumin bind?
1) Acidic drugs
2) Neutral drugs
3) Some basic drugs (benzodiazepines, SSRIs)

What drugs does alpha-1-acid glycoprotein bind?
Most basic drugs

What does low protein levels indicate in regards to drug availability?
More free drug levels (more potent)

What can cause a patient to have a greater response to a typical dosage of a drug?
Low protein levels from malnutrition or chronic illnesses

What kind of drugs can easily pass through the lipid bilayer cell membrane?
Small, lipophilic drugs

True or False: Hydrophilic drugs can easily pass through the lipid bilayer cell membrane?
FALSE – needs a transmembrane protein to make a hydrophilic channel

True or False: Hydrophilic drugs can use a passive transmembrane protein to pass through the cell membrane in the CNS
FALSE – needs active transport

What is passive transport of a drug?
Movement of drug down a concentration gradient

What is facilitate diffusion of a drug?
Drug needs carrier proteins but doesn’t need energy

What is active transport of a drug?
Drug needs a carrier protein and energy (ATP) to move against a concentration gradient

Acid Equation
H+ + A- <--> HA

Base Equation
H+ + B <--> HB+

What is passive transport limited by?
Blood flow (not lipid solubility), meaning the drug will diffuse across as quickly as it can be delivered to the tissue

Acidic environments will drive H+ + A- <--> HA to which side?
To the RIGHT, towards HA

Acidic environments will drive H+ + B <--> HB+ to which side?
To the RIGHT, towards HB+

Which crosses membranes easier, charged or uncharged species?
Uncharged (non-ionized)

What does pKa tell you?
Tells you the pH where the ionization occurs (“50-50” point)

If pH is more acidic (lower than) pKa, which way do the acid base equations go?
Goes to the RIGHT (acidic environment)

If pH is less acidic (higher than) pKa, which way do the acid base equations go?
Goes to the LEFT (basic environment)

If a basic drug with pKa of 4.2 is in the blood (pH of 7.4), will it be ionized or non-ionized in the blood?
Non-ionized

If an acidic drug with pKa of 11 is in the blood (pH of 7.4), will it be ionized or non-ionized in the blood?
Non-ionized

What is the definition of biotransformation?
Alteration of the drug via a metabolic process

Where does biotransformation usually take place?
Liver

True or False: Most drugs have to be hydrophilic for excretion
True

What biotransformation process(es) is/are in Phase I?
1) Oxidation
2) Reduction
3) Hydrolysis

What is the purpose of Phase I biotranformation?
To increased the polarity of the molecule to make the drug water soluble for excretion in urine

What enzyme system catalyzes most Phase I reactions?
Cytochrome P450 (CYP)

Does CYP activity increase or decrease with ongoing drug exposure?
Increase

What happens when drugs compete for the same CYP subtype?
CYP activity can be inhibited (Example: cimetidine inhibits metabolism of meperidine, propranolol, and diazepam)

If a patient has been on Drug A that is metabolized by CYP 3A4 for many months, and is given another Drug B that is metabolized by CYP 3A4, what effects on duration and metabolism does this have?
CYP 3A4 activity will be increased from prolonged exposure to Drug A, so it will metabolize Drug B faster than usual and the duration of Drug B will be shorter than usual as well

What biotransformation process(es) is/are in Phase II?
Conjugation with polar substance

What is the purpose of Phase II biotransformation?
To make the drug water soluble for excretion in urine

Do Phase I and Phase II polymorphisms exist?
Yes, for example a pseudocholinesterase deficiency

What age group has diminished Phase I and Phase II activities?
Neonates – 1 year old

What does hepatic drug clearance depend on?
1) Hepatic blood flow
2) Extraction ratio

What is the hepatic extraction ratio?
The fraction of drug removed when blood passes through the liver

What is the equation for hepatic drug clearance?
Hepatic drug clearance = hepatic blood flow * extraction ratio

What is intrinsic hepatic clearance (ClI) based on?
1) Metabolic activity of the liver
2) Hepatobiliary excretion

True or false: High intrinsic clearance drugs will have flow-limited hepatic clearance
True, hepatic clearance will be almost the same as hepatic blood flow and will have a high extraction ratio

True or false: Low intrinsic clearance drugs will have flow-limited hepatic clearance
False, hepatic clearance is limited by the instrinsic hepatic clearance of the drug and will have a low extraction ratio

True or false: Autoregulation normally maintains constant renal blood flow
True

True or false: Etomidate and propofol have high intrinsic clearance
True

True or false: Thiopental and diazepam have high intrinsic clearance
False

Glomerular filtration rate (GFR) = ___% of renal blood flow (RBF)
20%

True or false: Only unbound drugs will be filtered into the kidneys for excretion
True, passive filtration is insufficient due to protein binding

What allows renal clearance to approach renal blood flow?
Renal tubular active transporters

True or false: Pancuronium and rocuronium have significant renal excretion and should be avoided in renal-insufficient patients
True

True or false: Rocuronium has a high hepatic extraction ratio
False, it has a low hepatic extraction ratio

True or false: Fentanyl has a low hepatic extraction ratio
False, it has a high hepatic extraction ratio

True or false: Propofol has a high hepatic extraction ratio
False, it has an intermediate hepatic extraction ratio

What order pharmacokinetics has a fixed percentage (“k”) of existing drug that is removed per unit of time?
First-order kinetics

If 10% of a first-order kinetics drug is removed per minute, what does k = ?
k = 0.1 min^-1

True or false: In first-order kinetics, the fraction of drug removed per minute depends on serum levels
False, it does NOT depend on serum levels. The amount of drug removed per minute depends on serum levels.

True or false: In first-order kinetics, the amount of drug removed per minute depends on serum levels
True

Is the slope of a first order kinetics drug a curved or straight line on a concentration vs time graph?
Curved

Is the slope of a zero-order kinetics drug a curved or straight line on a concentration vs time graph?
Straight

What order pharmacokinetics has a fixed amount of drug removed per unit time?
Zero-order kinetics

True or false: In zero-order kinetics, the fraction of drug removed per minute depends on serum levels
False, it is independent of serum concentration

True or false: Alcohol has zero-order kinetics
True

If 7% of a first-order kinetics drug is removed per minute, what does k = ?
k = 0.07 min^-1

At high serum concentrations of drugs, what order kinetics do they have?
Zero-order (concentration exceeds body’s capacity to metabolize drug)

What is the time required for serum concentrations to change by a factor of 2?
Half-life

Equation for half-life
Half-life (t_1/2) = ln 2 / k

After 5 half-lives, what percentage of the process is complete?
97%

What does volume of distribution (Vd) quantify?
The extent of drug distribution (describes the capacity of tissues for absorbing a certain drug)

Which type of drug has a larger Vd, lipophilic or hydrophilic?
Lipophilic drugs have larger Vd

Equation for volume of distribution (Vd)
Vd = amount of drug given / serum concentration

Equation for loading dose
Loading dose = Vd x target concentration

What is the theoretical volume of blood from which drug is completely and irreversibly removed in a unit of time?
Elimination clearance (Cl_E)

What is the difference between elimination half life (t_1/2B) and half-life (t_1/2)?
Elimination half life is the amount of time it takes for the drug in the body (not just in the serum) to decrease by factor of 2

Equation for elimination half-life
t_1/2B = ln 2 * (Vd/Cl_E)

True or false: Thiopental duration is prolonged in the elderly because of decreased metabolism
False, it is because the volume of distribution is increased. Clearance is unchanged.

Does termination of drug effect depend on body concentration or serum concentration?
Serum concentration

What are the two parts of the Two-compartment Model?
1) Central compartment (Plasma + VRG)
2) Peripheral compartment

What is the alpha phase of the two-compartment model?
Distribution phase

What is the beta phase of the two-compartment model?
Elimination phase

Which is faster, distribution or elimination?
Distribution

Pharmacodynamics = What the ____ does to the ____
What the DRUG does to the BODY

What is ED50?
Dose required to produce a specific effect in 50% of the population (like MAC)

What is LD50?
Dose required to cause death (or toxicity) in 50% of the population

What is the therapeutic index?
A measure of safety (room for error) – LD50/ED50

True or false: The lower the therapeutic index, the safer a drug is
False, the more dangerous a drug is

What is the receptor model?
Drug + Receptor <--> Drug-Receptor –> Effect

True or false: Maximum effect typically occurs at far below maximum receptor binding
Yes due to redundancy (excess of receptors)

What percentage receptors need to be bound by ACh in the neuromuscular junction for clinical strength?
25%

What percentage receptors need to be blocked to produce clinical weakness?
>75%

Agonist definition
Bind to receptor and produce an effect

Potency definition
How much drug you need to get an effect

Partial agonist definition
Produces a lower maximal response than a full agonist (lower efficacy) and can competitively inhibit the response produced by a full agonists

Efficacy definition
Maximum degree of effect a drug can cause

Tolerance definition
Diminished response to a drug due to chronic exposure

What are the ways tolerance can come about?
1) Cellular tolerance (adaptation)
2) Enzyme induction (change in metabolism)
3) Depletion of neurotransmitters

Tachyphylaxis definition
Acute tolerance after only a few doses

What is the x axis of the dose-response curve?
Log dose

What is the y axis of the dose-response curve?
Intensity of effect

Antagonist definition
Bind to receptor without producing an effect

Competitive antagonist definition
Bind reversibly to the same binding site

True or false: Competitive antagonists be completely overcome by increasing the concentration of an agonist
True

On the dose-response curve, does the x or y axis measure potency?
The x axis – the further right the change in slope is, the less potent the drug is (takes greater dose to achieve effect)

On the dose-response curve, does the x or y axis measure maximal effect?
The y axis – the higher the curve is, the greater effect the drug has

True or false: Non-competitive antagonists can be completely overcome by increasing the concentration of an agonist
False

Competitive antagonists increase or decrease agonist potency?
Decrease

Competitive antagonists increase or decrease agonist efficacy?
Does not change

Non-competitive antagonist definition
Bind irreversibly to the receptor or bind to a separate (allosteric) binding site

Non-competitive antagonists increase or decrease agonist potency?
Decrease

Non-competitive antagonists increase or decrease agonist efficacy?
Decrease

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