Lecture 4

Question 1

What is the importance of pharmacokinetics (PK) and pharmacodynamics (PD)

Answer 1

Individualize patient drug therapy
Monitor medications with a narrow therapeutic index
Decrease the risk of adverse effects while maximizing pharmacologic response of medications
Evaluate PK/PD as a diagnostic tool for underlying disease states

Question 2

What is pharmacokinetics
State four Factors affecting drug absorption related to patients

State four Drug characteristics that affect absorption

Answer 2

The science of the rate of movement of drugs within biological systems, as affected by the absorption, distribution, metabolism, and elimination of medications

Drug characteristics that affect absorption:
Molecular weight, ionization, solubility, & formulation(whether it’s a tablet,syrup,infusion,etc)

Factors affecting drug absorption related to patients:
Route of administration, gastric pH, contents of GI tract

Acidic Environment: The stomach’s acidic pH (around 1.5 to 3.5) can affect the solubility and stability of drugs. Weakly acidic drugs (e.g., aspirin) are more soluble in the acidic environment, enhancing their absorption. Conversely, weakly basic drugs may be less soluble and poorly absorbed in the stomach.

You’re correct in that the solubility and ionization of weak acids in an acidic environment affect their excretion:

1. Weak Acid in Acidic Environment:
   
   • In an acidic environment, weak acids remain non-ionized (neutral). This non-ionized form is more lipophilic (fat-soluble) and can easily cross cell membranes, enhancing absorption in the stomach.
   • Because they remain non-ionized, they are less likely to be excreted through urine directly, as they do not dissolve in urine as polar substances.
2. Excretion via Urine:
   
   • For excretion in urine, weak acids are often better excreted in a more alkaline (basic) urine environment. In alkaline urine, weak acids become ionized (charged), which makes them more polar and thus more water-soluble. This increased polarity enhances their solubility in urine, promoting excretion.

• Weak acids are better absorbed in acidic environments due to their non-ionized form.
• They are more effectively excreted when urine is alkaline, as they become ionized, polar, and water-soluble.

So, weak acids can dissolve in an acidic environment but may not be effectively excreted until they are ionized in a more basic environment.
So weak acid in acidic environment will make it uncharged or neutral making it more hydrophobic but weak acid in basic environment will make it charged or polar making it more hydrophilic to be excreted in the urine
Same for weak bases

Presence of Food: Food can alter gastric pH and affect drug dissolution. For some drugs, food can enhance absorption by increasing gastric emptying or by promoting bile secretion. For others, food can delay gastric emptying or bind with the drug, reducing absorption.

Question 3

What happens to drug forms when there is malnutrition?
Where do lipophilic drugs accumulate in the body?

Answer 3

Membrane permeability
cross membranes to site of action
Plasma protein binding
bound drugs do not cross membranes
malnutrition = albumin =  free drug
Lipophilicity of drug
lipophilic drugs accumulate in adipose tissue
Volume of distribution

Question 4

Drugs and toxins are seen as foreign to patients bodies
Drugs can undergo metabolism in the lungs, blood, and liver
Body works to convert drugs to less active forms and increase water solubility to enhance elimination

Liver - primary route of drug metabolism
Liver may be used to convert pro-drugs (inactive) to an active state
Types of reactions
Phase I (Cytochrome P450 system)
Phase II

True or false

Answer 4

True

Question 5

Where do phase I reactions occur

State four examples of phase I reaction types

Answer 5

Cytochrome P450 system
Located within the smooth endoplasmic reticulum of hepatocytes
Through electron transport chain, a drug bound to the CYP450 system undergoes oxidation or reduction
Enzyme induction
Drug interactions

Types:
Hydrolysis
Oxidation
Reduction
Oxidation: Addition of oxygen or removal of hydrogen (e.g., cytochrome P450 enzymes).
• Reduction: Gain of electrons, often involving the conversion of double bonds to single bonds or the addition of hydrogen.
• Hydrolysis: The addition of water to cleave chemical bonds, often seen in esters and amides.

• Enzymes Involved:
• Cytochrome P450 enzymes: The most significant group involved in oxidation reactions.
• Flavin-containing monooxygenases (FMOs): Involved in oxidative metabolism.
• Hydrolases: Enzymes that catalyze hydrolysis reactions

Question 6

State three types of phase II reactions

Answer 6

Polar group is conjugated to the drug
Results in increased polarity of the drug
Types of reactions:
Glycine conjugation
Glucuronide conjugation
Sulfate conjugation

Question 7

State three ways elimination of drugs occur

Answer 7

1.Pulmonary = expired in the air
2.Bile = excreted in feces.
enterohepatic circulation
3.Renal
-glomerular filtration
-tubular reabsorption
-tubular secretion

Question 8

Why do neonates have prolonged elimination of medications?
Which drugs have a longer dosing interval

Answer 8

Glomerular filtration matures in relation to age, adult values reached by 3 yrs of age
Neonate = decreased renal blood flow, glomerular filtration, & tubular function yields prolonged elimination of medications
Aminoglycosides, cephalosporins, penicillins = longer dosing interval

Question 9

What is the steady state of a drug under pharmacokinetic principles
Between drugs with short half life and drugs with long half life, which reach steady state quickly
What is half life
How many half lives does it take to reach steady state

Answer 9

Steady State: the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant serum drug level. In this case, the difference in there will be the amount of drug that stays in your serum.

Drugs with short half-life reach steady state rapidly; drugs with long half-life take days to weeks to reach steady state

Half-life = time required for serum plasma concentrations to decrease by one-half (50%)
4-5 half-lives to reach steady state

Question 10

Loading doses allow rapid achievement of therapeutic serum levels
Same loading dose used regardless of metabolism/elimination dysfunction
true or false

Answer 10

True.

A loading dose is a higher initial dose of a drug given to rapidly achieve therapeutic serum levels. It is designed to quickly reach the desired drug concentration in the bloodstream, particularly for drugs with a long half-life or when immediate drug effects are needed.

The loading dose is calculated based on the desired drug concentration in the body and the drug’s volume of distribution (Vd). It does not depend on the drug’s metabolism or elimination rate, which primarily affects the maintenance dose.

Therefore, the same loading dose is generally used regardless of metabolism or elimination dysfunction, such as in patients with renal or hepatic impairment. However, care must still be taken in these patients, as subsequent maintenance doses may need adjustment to avoid toxicity.

Question 11

What is linear pharmacokinetics

Answer 11

Linear = rate of elimination is proportional to amount of drug present

Dosage increases result in proportional increase in plasma drug levels
you’ll have a straight line when you plot concentration dose graph

So the two values to be looked at here are dOsage and concentration of drug not the amount of the drug

proportional” in this context means that the rate at which the drug is removed from the body increases with its concentration. So if you have a very highly concentrated drug, it’s eliminates rapidly As the drug is eliminated and its concentration decreases, the rate of elimination also decreases, but the overall effect is a steady decrease in drug amount in the body.

Question 12

What is non linear pharmacokinetics
What shape do yoj see on the concentration dose graph
Explain this statement:

Dosage increases saturate binding sites and result in non- proportional increase/decrease in drug levels.

Answer 12

Nonlinear = rate of elimination is constant regardless of amount of drug present
Dosage increases saturate binding sites and result in non- proportional increase/decrease in drug levels.
When a drug dosage is increased, more of the drug is introduced into the body. This drug often binds to proteins in the blood, such as albumin or α1-acid glycoprotein. These proteins help transport the drug through the bloodstream and also affect how much of the drug is available to act on the body.

Here’s how saturation of binding sites affects drug levels:

1. Saturation of Binding Sites: There are only so many binding sites on these proteins. When the drug dosage is increased, it can reach a point where all these binding sites become filled or saturated.
2. Impact on Drug Levels:
   
   • Initially, as dosage increases, the amount of free (unbound) drug in the bloodstream increases proportionally.
   • However, once all binding sites are saturated, further increases in dosage don’t lead to a proportional increase in free drug levels. Instead, more of the drug remains unbound because all the protein binding sites are already occupied.
3. Clinical Implications:
   
   • Risk of Toxicity: Saturation of binding sites means more free drug is available to cause effects, potentially increasing the risk of side effects or toxicity.
   • Monitoring: It’s important to monitor drug levels, especially in situations where binding sites may be saturated, to ensure the drug is effective without causing harm.
   • Dosing Adjustments: Healthcare providers may need to adjust dosages based on how much of the drug is bound to proteins versus free in the bloodstream.

In summary, saturation of protein binding sites can alter how drugs distribute in the body, impacting both their effectiveness and potential for side effects. If you have more specific questions or need further clarification, feel free to ask!
You’ll see a parabola when you draw a concentration dose graph
It gets to a point that As dose increases, the concentration may plateau

Question 13

What is the Michaelis Menten pharmacokinetics

Answer 13

Follows linear kinetics until enzymes become saturated
Enzymes responsible for metabolism /elimination become saturated resulting in non-proportional increase in drug levels
Phenytoin was used in the graph to show this type of pharmacokinetics

I can help clarify that. In Michaelis-Menten pharmacokinetics, small increases in drug doses can lead to disproportionately large increases in plasma concentrations due to the saturation of metabolic enzymes. Here’s how it works:

1. Enzyme Saturation:
   
   • When a drug is metabolized by enzymes (like those in the liver), these enzymes work at a certain rate to break down the drug.
   • At low drug concentrations, there are plenty of enzymes available to metabolize the drug. The metabolism rate is directly proportional to the drug concentration — this is first-order kinetics.
   • As drug concentrations increase, the enzymes gradually become saturated. When saturation occurs, the enzymes are working at their maximum capacity (Vmax). At this point, any further increase in drug concentration does not result in a proportional increase in the rate of metabolism.
2. Transition to Zero-Order Kinetics:
   
   • Once the enzymes are fully saturated (i.e., the concentration of the drug is much higher than the Km), the metabolism of the drug changes from first-order to zero-order kinetics.
   • In zero-order kinetics, the rate of drug metabolism becomes constant and independent of drug concentration. The body can only metabolize a fixed amount of the drug per unit time because the enzymes are already operating at full capacity.
3. Consequences of Enzyme Saturation:
   
   • When you increase the dose slightly beyond the point where enzymes are saturated, the body cannot increase the metabolism rate to handle the extra drug. As a result, the additional drug stays in the bloodstream longer.
   • This can lead to a large increase in plasma concentration, even with small increases in dosage. For example, if the drug’s dose is increased by 10%, the plasma concentration might increase by 30%, 50%, or more, depending on how saturated the enzyme system is.

Consider phenytoin, a drug that exhibits Michaelis-Menten kinetics:

• At low doses, phenytoin is metabolized efficiently. As you increase the dose, the enzymes metabolizing phenytoin become saturated.
• Once saturation is reached, any small increase in dose cannot be effectively metabolized. The unmetabolized drug accumulates in the plasma, causing a sharp rise in plasma levels.
• This is why careful monitoring and small dose adjustments are crucial when dosing drugs like phenytoin — to avoid toxic levels.

The concept of small increases in doses leading to large increases in plasma concentrations is due to the capacity-limited metabolism of drugs. Once metabolic pathways are saturated, the body cannot increase the clearance rate, resulting in drug accumulation and the potential for toxicity.

Question 14

If you have a patient with renal disease,how does this impact the dosing interval of the drug you’ll give?

If you have a patient with hepatic disease,how does this impact the dosage and the dosing interval of the drug you’ll give?

If you have a patient with cystic fibrosis ,how does this impact the dosage and dosing interval of the drug you’ll give?

Answer 14

Renal Disease: same hepatic metabolism, same/increased volume of distribution and prolonged elimination: so you increase dosing interval

Hepatic Disease: same renal elimination, same/increased volume of distribution, just that there is slower rate of enzyme metabolism cuz of the liver damage so you reduce the dosage and increase the dosing interval because of how slowly the drugs are clearing and being metabolized

Cystic Fibrosis Patients: increased metabolism/ elimination, and larger volume of distribution so you increase the dosage and you reduce the dosage interval

Question 15

What is pharmacogenetics
Why is it useful?
What is pharmacodynamics

Answer 15

Science of assessing genetically determined variations in patients and the resulting affect on drug pharmacokinetics and pharmacodynamics
Useful to identify therapeutic failures and unanticipated toxicity
It forms the baseline for personalized medicine. The different genetic makeup in different people are largely responsible for the different pharmacological therapy that are tailored for these different people

Dynamics:
Study of the biochemical and physiologic processes underlying drug action
-Mechanism of drug action:
Drug-receptor interaction
-Efficacy
-Safety profile

Focused on What the drug does to the body at the:
Cellular level
General level

Question 16

What happens when drugs bind to cellular receptors

Answer 16

Most drugs bind to cellular receptors:
-Initiate biochemical reactions
-Pharmacological effect is due to the alteration of an intrinsic physiologic process and not the creation of a new process

Question 17

What are drug receptors made up of?
Where are the found in the cell?
There is an infinite number of receptors in a given cell true or false

Answer 17

Receptors are Proteins or glycoproteins
They are Present on cell surface, on an organelle within the cell, or in the cytoplasm.
False. they have a Finite number of receptors in a given cell
Therefore, Receptor mediated responses plateau upon saturation of all receptors

Question 18

When does the action of a drug occur in the body?

Answer 18

Action occurs when drug binds to receptor and this action may lead to:
-Ion channel being opened or closed
-Second messenger being activated
cAMP, cGMP, Ca++, inositol phosphates, etc.
these Initiates a series of chemical reactions
-Normal cellular function being physically inhibited forcing Cellular function to be “turned on”

Question 19

What is drug receptor affinity

Answer 19

Affinity:
Refers to the strength of binding between a drug and receptor. The Higher the strength of binding,the stronger the affinity

Number of occupied receptors is a function of a balance between bound and free drug

Binding affinity refers to the strength of the interaction between a drug (ligand) and its receptor. It indicates how tightly the drug binds to the receptor.
• Measurement: High binding affinity means the drug binds very tightly to the receptor, while low affinity indicates a weaker interaction.

Question 20

What does the dissociation constant of a drug measure?
Define the dissociation constant of a drug?

Answer 20

Dissociation constant (KD)
-Measure of a drug’s affinity for a given receptor
-Defined as the concentration of drug required in solution to achieve 50% occupancy of its receptors
so when you plot dose response curve and you’re asked to deduce the dissociation constant, you can just use half of the concentration of the drug and this gives you a clue

Question 21

What are drug agonists
What are partial agonists (we also have full agonists and they’re the opposite of partial ones)

Answer 21

Drugs which alter the physiology of a cell by binding to plasma membrane or intracellular receptors(types:cytoplasmic or nuclear intracellular receptors)

Partial agonist:
A drug which does not produce maximal effect even when all of the receptors are occupied

It produces a sub maximal effect or below the maximum effect

Question 22

What is a drug antagonist
What is competitive antagonist
What is a non competitive antagonist
What are irreversible antagonists
What’s the difference between an irreversible antagonist and a non competitive antagonist

Answer 22

Antagonists:
Inhibit or block responses caused by agonists
Competitive antagonist:
Competes with an agonist for receptors
High doses of an agonist can generally overcome antagonist
Noncompetitive antagonist:
Binds to a site other than the agonist-binding domain
Induces a conformation change in the receptor such that the agonist no longer “recognizes” the agonist binding site.
High doses of an agonist do not overcome the antagonist in this situation

Irreversible Antagonist:
Bind permanently to the receptor binding site therefore they can not be overcome with agonist

So for competitive, it’s a competition. May the best man win. If the antagonist wins cool. The agonist will only be able to win if it puts in more effort to overcome the antagonist. It’s reversible.

For non competitive, there’s no competition 😂. No matter how much you fight, you’ll never overcome the antagonist. Like Satan fighting us but we already have victory.
So for non competitive, the agonist can never overcome because the antagonist has changed the sensitivity of the receptors and the receptors no longer recognize the agonist. So the receptors are plenty but they don’t recognize the agonist anymore. The agonist can bind but it will never overcome the antagonist because the receptors don’t recognize it anymore. So the antagonist binds to the allosteric site(a site different from where the orthosteric or actual site where the receptors are) and causes the change so that when the agonist binds to the actual site where the receptors are, the receptors won’t recognize the agonist again. The antagonist doesn’t bind to the site where the agonist binds to.

So Jesus translated us from the kingdom of darkness into the kingdom of light. He changed our status.

For irreversible, it has reduced the number of receptors for the agonist doesn’t have a chance to bind anymore so even if you increase the effort of the agonist, there’s no receptor for it to go and meet so it can’t work.

Irreversible antagonists and non-competitive antagonists both inhibit the effects of agonists, but they differ in how they interact with the target receptor:

• Binding: They bind permanently or with very high affinity to the receptor, often through covalent bonds.
• Effect: This binding leads to a permanent inactivation of the receptor, even if the agonist concentration is increased.
• Receptor Function: Irreversible antagonists reduce the total number of available receptors, which decreases the maximal response that an agonist can achieve.
• Example: Phenoxybenzamine is an irreversible antagonist of alpha-adrenergic receptors.

• Binding: They bind to a site on the receptor that is different from the agonist’s binding site (allosteric site) or modify the receptor in such a way that the agonist cannot produce its effect even if it binds.
• Effect: They do not prevent the binding of the agonist but inhibit the receptor’s response to the agonist, which means increasing the concentration of the agonist cannot overcome the effect of a non-competitive antagonist.
• Receptor Function: They decrease the efficacy (the maximal effect) of the agonist without affecting the binding affinity.
• Example: Ketamine is a non-competitive antagonist of the NMDA receptor.

• Site of Action: Irreversible antagonists bind directly to the active site (or another critical site) irreversibly, while non-competitive antagonists typically bind to allosteric sites.
• Overcoming Antagonism: The effects of irreversible antagonists cannot be overcome by increasing the agonist concentration, whereas non-competitive antagonism cannot be overcome either, but due to different reasons (allosteric modification rather than receptor availability).
• Receptor Numbers vs. Function: Irreversible antagonists reduce the number of functional receptors, while non-competitive antagonists reduce the receptor’s ability to respond to an agonist without changing receptor availability.

These differences are crucial in pharmacology for understanding how drugs interact with their targets and the implications for therapeutic use and side effects.

Yes, the allosteric site is indeed a different site from the orthosteric (actual) site on a receptor.

• Orthosteric Site: This is the primary or active site where the endogenous ligand (such as a neurotransmitter or hormone) or an agonist binds to activate or inhibit the receptor.
• Allosteric Site: This is a secondary site on the receptor that is distinct from the orthosteric site. When a ligand (e.g., an allosteric modulator or non-competitive antagonist) binds to the allosteric site, it induces a conformational change in the receptor.

• Positive Allosteric Modulators (PAMs): Enhance the effect of the agonist without activating the receptor by themselves.
• Negative Allosteric Modulators (NAMs) or Non-competitive Antagonists: Decrease the receptor’s response to an agonist without directly blocking the agonist-binding site.

• Non-competitive antagonists usually bind to allosteric sites. Their binding changes the receptor’s shape or function in such a way that it reduces the effect of the agonist even though the agonist can still bind to the orthosteric site.
• Because these antagonists do not compete directly with the agonist for the same binding site (orthosteric site), their effects cannot be overcome by increasing the concentration of the agonist.

The allosteric site is a distinct location on the receptor that allows for different forms of regulation (either enhancement or inhibition) without directly competing at the active site where the endogenous ligand binds.

Question 23

What is efficacy of a drug
What is potency of a drug
How is potency determined on the Response dose curve?

Answer 23

Efficacy:
Degree to which a drug is able to produce the desired response

Potency:
Amount of drug required to produce 50% of the maximal response the drug is capable of inducing
Used to compare compounds within classes of drugs

If drug A uses a low concentration to produce 50% of the max response and B uses a high dose, A is more potent than B.

Based on the dose-response curves shown in the image, let’s analyze the questions:

Question 29: Which of the following drugs above is the most potent assuming all the drugs act on the same receptor?

Potency is determined by the position of the curve along the x-axis (log [Drug]). The further to the left the curve, the more potent the drug, cuz as you’re going to the left, the doses are lower and a lower concentration is needed to achieve the same effect as the one more on the right.

• Drug A (red curve) is to the leftmost.
• Drug B (green curve) is slightly to the right of Drug A.
• Drug C (black curve) is further right.
• Drug D (blue curve) is the rightmost.

Answer: A. Drug A (most potent, as it requires the lowest concentration to achieve the effect)

Question 30: Which of the following drugs above is the most efficacious assuming all the drugs act on the same receptor?

Efficacy is determined by the maximum effect a drug can produce, represented by the plateau of the dose-response curve.

• Drug A reaches a maximum effect of around 80%.
• Drug B reaches a maximum effect of around 60%.
• Drug C reaches a maximum effect of around 100%.
• Drug D reaches a maximum effect of around 40%.

Answer: C. Drug C (most efficacious, as it produces the highest maximum effect)

So, the answers to the questions are:
- Question 29: A. Drug A
- Question 30: C. Drug C

Question 24

What is the effective concentration 50% of a drug?
What is the lethal dose 50% of a drug
What is EC50 not ED50?
Diff between EC50 and ED50?

Answer 24

Effective Concentration 50% (ED50)
Concentration of the drug which induces a specified clinical effect in 50% of subjects

Lethal Dose 50% (LD50)
Concentration of the drug which induces death in 50% of subjects

ED({50}) (median effective dose) is similar to EC({50}), but it applies to a different context:

• ED(_{50}): This is the dose of a drug that is required to produce a therapeutic effect in 50% of the population. It is commonly used in pharmacology to determine the dose at which a drug is effective for half of the people who take it.
• EC(_{50}): As mentioned earlier, this is the concentration of a drug that produces 50% of its maximum effect. It is typically used in vitro or in experimental settings where concentration can be precisely controlled.

In summary:
- ED({50}) is used in the context of dosing in populations (in vivo).
- EC({50}) is used in the context of concentration-response relationships (often in vitro).

Both are measures of drug potency, but they are applied in different scenarios.

EC(_{50}) and potency are related but distinct concepts:

• EC(_{50}): This is the concentration of a drug that produces 50% of its maximum effect. It is a specific quantitative measure used to compare the effects of different drugs or the same drug under different conditions.
• Potency: This refers to the amount of drug needed to produce a given effect. It is a broader concept that often uses the EC({50}) value as an indicator. A drug is considered more potent if it requires a lower concentration to achieve a certain effect, typically represented by a lower EC({50}) value.

In summary, EC(_{50}) is a specific measure, while potency is a general concept describing a drug’s effectiveness at a given concentration.

No, EC({50}) (half maximal effective concentration) is not the maximum concentration. It is the concentration of a drug that produces 50% of the maximum possible response in 50% of the population or test subjects. It is a measure of a drug’s potency: the lower the EC({50}), the more potent the drug, as less of the drug is needed to achieve half of its maximum effect.

TD50 (Median Toxic Dose):
• The dose at which 50% of the population experiences toxic effects. It is used to assess the safety margin of a drug.

Therapeutic Index (TI):
• The ratio of the TD50 (or LD50) to the ED50. It indicates the safety margin of a drug; a higher therapeutic index means a safer drug. TI = TD50/ED50.

Margin of Safety:
• The difference between the effective dose (ED50) and the toxic dose (TD50) of a drug. It provides additional insight into drug safety.

Potency is often described as the amount of drug required to produce a certain level of effect, such as 50% of the maximal response. It reflects the effectiveness of a drug at inducing a response at a given dose or concentration.

EC50 (Effective Concentration 50) is the specific concentration of a drug that produces 50% of its maximum effect (Emax)

EC50 is a specific metric for quantifying that potency.

Question 25

What is therapeutic index?
How is it calculated?
What is margin of safety?

Answer 25

Therapeutic Index-
Measure of the safety of a drug
Calculation: LD50/ED50

Margin of Safety:
Margin between the therapeutic and lethal doses of a drug

Margin of Safety:
• The difference between the effective dose (ED50) and the toxic dose (TD50) of a drug. It provides additional insight into drug safety.

The Margin of Safety does refer to the “margin” or gap between the therapeutic and lethal doses of a drug, but it’s more accurately described as a ratio rather than a simple numerical difference. Here’s a clearer explanation:

• The Margin of Safety is a measure of how safe a drug is by comparing doses that produce therapeutic effects to those that produce lethal effects. It provides a more conservative safety measure compared to the Therapeutic Index (TI).
• Definition: It is the ratio of the dose that causes a lethal effect in a small percentage of the population (e.g., LD1) to the dose that is therapeutically effective in nearly all of the population (e.g., ED99).

[
\text{Margin of Safety} = \frac{\text{LD1}}{\text{ED99}}
]

• LD1 (Lethal Dose for 1% of the Population): The dose at which 1% of the population would experience lethal effects.
• ED99 (Effective Dose for 99% of the Population): The dose at which 99% of the population experiences the desired therapeutic effect.
• The Margin of Safety shows how much higher the lethal dose is compared to the effective dose for nearly all patients. A larger Margin of Safety indicates a safer drug because there is a wider gap between the effective and potentially lethal doses.

• When we say “margin” in this context, it can be misunderstood as a simple difference (subtraction) between lethal and therapeutic doses. However, in pharmacology, the “margin” is typically expressed as a ratio to quantify the safety of a drug more meaningfully.

• If a drug has an LD1 of 100 mg and an ED99 of 10 mg:

[
\text{Margin of Safety} = \frac{100 \, \text{mg}}{10 \, \text{mg}} = 10
]

• This means the lethal dose for 1% of the population is 10 times higher than the effective dose for 99% of the population, indicating a relatively safe drug.

The Margin of Safety is indeed the “margin between the therapeutic and lethal doses of a drug,” but it is typically expressed as a ratio rather than a simple difference to provide a clearer understanding of drug safety.

The term Margin of Safety can indeed be described as the difference between the effective dose and the toxic dose, though it’s more commonly expressed as a ratio in pharmacological contexts. Here’s a detailed breakdown:

Margin of Safety:

•	Definition: The Margin of Safety represents the difference between the dose that causes a therapeutic effect and the dose that causes toxic effects. It helps to gauge how much higher the toxic dose is compared to the effective dose.

\text{Margin of Safety} = \text{TD50} - \text{ED50}

where:

•	TD50 is the dose at which 50% of the population experiences toxic effects.
•	ED50 is the dose at which 50% of the population experiences the desired therapeutic effect

Question 26

An increase in a drug may cause what two effects?

Answer 26

Drug induced responses are not an “all or none” phenomenon.
Many drug effects are not strictly all-or-none but rather follow a dose-response curve where a minimal dose is needed to achieve a noticeable effect. effects can vary incrementally with dose.

Increase in dose may:
-Increase therapeutic response
-Increase risk of toxicity

Question 27

What should you focus on when prescribing drugs for an ill patient

Answer 27

-Select appropriate drug for clinical indication
-Select appropriate dose
Consider pathophysiologic processes in patient such as hepatic or renal dysfunction
Consider developmental and maturational changes in organ systems and the subsequent effect on PK and PD
-Select appropriate formulation and route of administration
-Determine anticipated length of therapy
-Monitor for efficacy and toxicity
-Pharmacogenetics Will play a larger role in the future

For a critically ill child or infant, consider the fact that they won’t have matured livers,kidneys,etc and won’t have enzymes in optimum proportions for metabolism of drugs so you must becareful about the dosage and dosing interval of drugs

Question 28

Why will you consider drug drug interactions when prescribing drugs for patients

Why will you consider drug food interactions when prescribing drugs for patients

Answer 28

Other factors
-Drug-drug interaction: cause the drugs they are taking and the drugs you want to give with their interactions can cause the following:
Altered absorption
Inhibition of metabolism
Enhanced metabolism
Protein binding competition
Altered excretion

Other factors (con’t)
-Drug-food interaction:
NG or NJ (naso jejunal feeding when you want to by pass acidic content In stomach ) feeds
Continuous vs. intermittent
Site of optimal drug absorption in GI tract must be considered

Question 29

Under absorption in the effect of disease on drugs,Why will per os or nasogastric administered drugs have altered absorption!

Answer 29

Absorption
PO/NG administered drugs may have altered absorption due to:
Alterations in pH
Edema of GI mucosa
Delayed or enhanced gastric emptying
Alterations in blood flow
Presence of an ileus
Coadministration with formulas (I.e. Phenytoin)

Question 30

Why will the drug distribution be affected when someone has a disease?(3 reasons)

Answer 30

Drug distribution may be affected:
-Altered organ perfusion due to hemodynamic changes:
May effect delivery to site of action, site of metabolism and site of elimination.
Inflammation and changes in capillary permeability may enhance delivery of drug to a site
-Hypoxemia affecting organ function:
Altered hepatic function and drug metabolism

Question 31

How will alterations in protein synthesis as a disease affect a drug given?
How will substrate deficiencies as a disease affect a drug given?

Answer 31

-Alterations in protein synthesis:
If serum albumin and other protein levels are low, there is altered Vd(volume of distribution) of free fraction of drugs that typically are highly protein bound therefore a higher free concentration of drug. The bound form does not freely cross cell membranes to enter tissues.Free (Unbound) Drug: This is the portion of the drug that is not attached to proteins. It is the free drug that is pharmacologically active and capable of entering tissues to exert its effects.
-Substrate deficiencies:
.Exhaustion of stores
.Metabolic stress

Question 32

What is the effect of disease on pharmacodynamics

Answer 32

-Up regulation of receptors: ### Upregulation of Receptors:
- Definition: When cells sense that there aren’t enough receptors to respond to a certain signal (like a hormone or neurotransmitter), they can make more receptors.
- Example: Imagine a cell that normally has a few “locks” (receptors) for a specific “key” (signal). If the cell senses it needs more of that signal, it can make extra locks to catch more keys. This is upregulation.

-Down regulation of receptors
Decreased number of drug receptors: ### Downregulation of Receptors:
- Definition: Sometimes, cells have too many receptors or are getting too much of a signal. To protect themselves, they can take some locks away.
- Example: If a cell has too many locks for a signal, it might remove some to avoid being overwhelmed. This is downregulation.

• Drug Effects: Drugs can influence these processes. For example, some drugs might cause cells to upregulate their receptors, making them more sensitive to a signal. Others might lead to downregulation, reducing the cell’s response to a signal.

Upregulation and downregulation of receptors refer to adaptive changes in the number or sensitivity of receptors on cell surfaces in response to various stimuli, including drugs.

-Altered endogenous production of a substance may affect the receptors. The factors below are how altered endogenous production of a substance can affect drug receptors or This altered endogenous production of a substance affecting receptors will due to :
Acid-base status(alkalosis and acidosis influencing how receptors respond to signals and this influences your drug choice)
Electrolyte abnormalities
Altered intravascular volume: changes in blood volume and blood pressure can affect receptor responsiveness. Low blood volume can reduce receptor activation in response to hormones like aldosterone
Tolerance: Prolonged exposure to certain substances (like drugs or hormones) can lead to receptor desensitization or downregulation, reducing their responsiveness over time.

• Mechanism: Tolerance develops as cells adapt to constant stimulation by reducing the number or sensitivity of receptors, requiring higher doses to achieve the same effect.

• Understanding how these factors influence receptor function helps clinicians manage conditions where receptor signaling plays a crucial role.
• Monitoring acid-base balance, electrolytes, and intravascular volume is essential for optimizing receptor responsiveness in various physiological and pathological states.

Question 33

How will you manage drug therapy using target effect strategy

Answer 33

Target-effect” strategy:
Either you get a Pre-determined efficacy endpoint
or you Titrate drug to desired effect
so in titrating:
-Monitor for efficacy and
If plateau occurs, you may need to add additional drug or choose alternative agent
-Monitor for toxicity and in this case you May require decrease in dose or alternative agent

Question 34

How will you manage drug therapy using target concentration strategy
What is first order and zero order pharmacokinetics

Answer 34

Target-concentration strategy:
-There is a Pre-determined concentration goal. This goal is Based on population-based PK and the
Target concentration is also based on efficacy or toxicity
-you need to Know the PK of the drug you are prescribing:
answer questions like
Is there a Presence of an active metabolite?
Should the level of the active metabolite be measured?
is it Zero-order or first-order kinetics?(Does it change with increasing serum concentrations?)
Does it follow linear kinetics or it follows Michael mentens kinetic principles

In pharmacokinetics, the terms “first-order” and “zero-order” refer to different types of kinetics that describe how drugs are eliminated from the body:

1. First-Order Kinetics:
   
   • Definition: First-order kinetics describe a process where the rate of elimination of a drug is directly proportional to its concentration in the body.
   • Characteristics: In first-order kinetics, as the concentration of the drug decreases over time (due to metabolism and excretion), the rate of elimination also decreases proportionally.
   • Example: Most drugs follow first-order kinetics because enzymes responsible for drug metabolism and renal clearance are usually not saturated at therapeutic doses.
2. Zero-Order Kinetics:
   
   • Definition: Zero-order kinetics describe a process where the rate of elimination of a drug remains constant regardless of its concentration in the body.
   • Characteristics: In zero-order kinetics, the enzymes responsible for drug metabolism or the mechanisms of drug excretion become saturated at higher concentrations. Therefore, the rate of elimination does not increase with increasing drug concentrations.
   • Example: Some drugs, especially at high doses or when the enzymes responsible for their metabolism are saturated, exhibit zero-order kinetics. For instance, alcohol metabolism follows zero-order kinetics when the alcohol dehydrogenase enzyme is saturated.

Zero-Order Kinetics: Also known as saturation kinetics.
• Michaelis-Menten Kinetics: Describes both zero-order (at saturation) and first-order (at low concentrations) processes.

Question 35

State five critical aspects of target concentration therapy

No drug produces a single effect!!!

Answer 35

Critical aspects of “target-concentration” therapy
-Know indications for monitoring serum concentrations
AND when you do not need to monitor levels especially when doing therapeutic drug monitoring
-Know the appropriate time to measure the concentration
-If the serum concentration is low, know how to safely achieve the desired level
-Be sure the level is not drawn from the same line in which the drug is administered
-Be sure drug is administered over the appropriate time
AND Treat the patient, not the drug level cuz some patients will need a higher dose to achieve therapeutic effect while some will need lower dose to achieve therapeutic effect

Question 36

JB is a 5 y.o. male with pneumonia. He has a history of renal insufficiency and is followed by the nephrology service. His sputum gram stain from an ETT shows gram negative rods. He needs to be started on an aminoglycoside. Currently, his BUN/SCr are 39/1.5 mg/dL with a urine output of 0.4 cc/kg/hr. You should:
a) Start with a normal dose and interval for age
b) Give a normal dose with an extended interval
c) Give a lower dose and keep the interval normal for age
d) Aminoglycosides are contraindicated in renal insufficiency

Answer 36

In the case of JB, a 5-year-old male with pneumonia and renal insufficiency requiring an aminoglycoside, the best choice would be:

b) Give a normal dose with an extended interval.

1. Renal Insufficiency: Since JB has renal insufficiency (BUN/SCr of 39/1.5 mg/dL) and reduced urine output (0.4 cc/kg/hr), the clearance of aminoglycosides would be impaired. Aminoglycosides are primarily eliminated by the kidneys, so adjusting the dosing regimen is necessary to avoid toxicity.
2. Dosing Adjustments:
   
   • Aminoglycosides have a narrow therapeutic window, and the risk of nephrotoxicity and ototoxicity increases with accumulation due to impaired renal function.
   • Extended-interval dosing is often preferred in patients with renal impairment because it allows for higher peak concentrations while reducing the risk of accumulation and toxicity during the trough phase.
3. Dosing Recommendations:
   
   • Starting with a normal dose would not be safe due to the risk of accumulation.
   • A lower dose with a normal interval may not provide adequate therapeutic levels for treating the infection effectively.
4. Contraindications: Aminoglycosides are not strictly contraindicated in renal insufficiency but require careful dosing adjustments based on renal function.

Thus, b) Give a normal dose with an extended interval is the best option to manage JB’s pneumonia while accounting for his renal insufficiency.

Question 37

MJ is a 3 y.o. female with a history of congenital heart disease. She is maintained on digoxin 10 mcg/kg/day divided bid. She has a dysrhythmia and is started on amiodarone. You should:
a) Continue digoxin at the current dose
b) Decrease the digoxin dose by 50% and monitor levels
c) Increase the digoxin dose by 50% and monitor levels
d) Discontinue the digoxin

Answer 37

In the case of MJ, a 3-year-old female with congenital heart disease who is on digoxin and has been started on amiodarone, the best choice would be:

b) Decrease the digoxin dose by 50% and monitor levels.

1. Drug Interactions: Amiodarone can significantly increase the serum concentration of digoxin. This is because amiodarone inhibits P-glycoprotein, which can lead to increased absorption and reduced clearance of digoxin, raising the risk of digoxin toxicity.
2. Dosage Adjustment:
   
   • Given the interaction between digoxin and amiodarone, it is advisable to reduce the digoxin dose to avoid potential toxicity.
   • A reduction of 50% is a common practice when starting amiodarone in a patient already taking digoxin.
3. Monitoring: Close monitoring of digoxin levels is essential after making any adjustments. This ensures that the levels remain within the therapeutic range and helps to detect any signs of toxicity early.
4. Other Options:
   
   • a) Continue digoxin at the current dose: Not advisable due to the risk of increased digoxin levels from the interaction with amiodarone.
   • c) Increase the digoxin dose by 50%: This would further increase the risk of toxicity, which is contraindicated.
   • d) Discontinue the digoxin: This is not appropriate as MJ requires digoxin for her heart condition.

Therefore, the best course of action is b) Decrease the digoxin dose by 50% and monitor levels to ensure safe and effective management of her treatment.

Question 38

AC is a 4 y.o male on a midazolam infusion for sedation in the PICU. He is currently maintained on 0.4 mg/kg/hr. You evaluate the child and notice that he is increasingly agitated. You should:
a) Increase the infusion to 0.5 mg/kg/hr
b) Bolus with 0.1 mg/kg and increase the infusion to 0.5 mg/kg/hr
c) Bolus with 0.4 mg/kg and increase the infusion to 0.5 mg/kg/hr
d) Bolus with 0.1 mg/kg and maintain the infusion at 0.4 mg/kg/hr

Answer 38

In the case of AC, a 4-year-old male on a midazolam infusion for sedation in the PICU who is becoming increasingly agitated, the best choice would be:

a) Increase the infusion to 0.5 mg/kg/hr.

1. Midazolam Infusion: Midazolam is a short-acting benzodiazepine commonly used for sedation in pediatric patients. An increase in agitation suggests that the current dose may not be providing adequate sedation.
2. Dose Adjustment:
   
   • Increasing the infusion rate: Given that AC is showing signs of agitation while on 0.4 mg/kg/hr, increasing the infusion to 0.5 mg/kg/hr is a reasonable step to enhance sedation.
   • Safety and Efficacy: Increasing the infusion rate allows for a continuous effect rather than a bolus, which may lead to fluctuations in sedation levels.
3. Considerations for Bolusing:
   
   • b) Bolus with 0.1 mg/kg and increase the infusion to 0.5 mg/kg/hr: While this could provide a quick effect, it may not be necessary to bolus if the goal is to achieve more consistent sedation through the infusion.
   • c) Bolus with 0.4 mg/kg and increase the infusion to 0.5 mg/kg/hr: This is too high a bolus dose and could lead to oversedation and respiratory depression.
   • d) Bolus with 0.1 mg/kg and maintain the infusion at 0.4 mg/kg/hr: This does not address the underlying issue of increasing agitation effectively.

Therefore, the most appropriate action is a) Increase the infusion to 0.5 mg/kg/hr to provide better sedation while monitoring the patient closely for response and any potential side effects.

Question 39

JD is a 10 y.o. child on phenytoin NG bid (10 mg/kg/day) for post-traumatic seizures but continues to have seizures. He is on continuous NG feeds. His phenytoin level is 6 mcg/ml. You should:
a) Increase his phenytoin dose to 12 mg/kg/day divided bid
b) Load him with phenytoin 5 mg/kg and increase his dose to 12 mg/kg/day
c) Change his feeds so they are held 1 hr before and 2 hrs after each dose, give him a loading dose of 10 mg/kg, continue his current dose of 10 mg/kg/day and recheck a level in 2 days (sooner if seizures persist).
d) Add another anticonvulsant

Answer 39

In the case of JD, a 10-year-old child on phenytoin who continues to have seizures and has a low phenytoin level of 6 mcg/ml, the best choice would be:

c) Change his feeds so they are held 1 hour before and 2 hours after each dose, give him a loading dose of 10 mg/kg, continue his current dose of 10 mg/kg/day, and recheck a level in 2 days (sooner if seizures persist).

1. Phenytoin Level: JD’s phenytoin level of 6 mcg/ml is below the therapeutic range (typically 10-20 mcg/ml for seizure control). This indicates that his current dosing regimen is insufficient to maintain effective drug levels.
2. Nutritional Interference: Continuous NG feeds can interfere with the absorption of phenytoin. Holding the feeds for 1 hour before and 2 hours after administering the phenytoin will help improve its absorption and effectiveness.
3. Loading Dose: Administering a loading dose of 10 mg/kg is appropriate to quickly raise the serum phenytoin level into the therapeutic range. The current maintenance dose of 10 mg/kg/day may then be reassessed after ensuring proper absorption.
4. Other Options:
   • a) Increase his phenytoin dose to 12 mg/kg/day divided bid: This option does not address the absorption issue and may not adequately resolve the low levels and persistent seizures.
   • b) Load him with phenytoin 5 mg/kg and increase his dose to 12 mg/kg/day: A 5 mg/kg loading dose is insufficient given his current low level.
   • d) Add another anticonvulsant: While this may be a consideration if phenytoin levels are optimized and seizures persist, it is important first to address the absorption issue and raise the phenytoin level.

Thus, the most appropriate action is c) Change his feeds so they are held 1 hour before and 2 hours after each dose, give him a loading dose of 10 mg/kg, continue his current dose of 10 mg/kg/day, and recheck a level in 2 days (sooner if seizures persist) to ensure adequate phenytoin absorption and therapeutic effect.

Question 40

LF is a 12 y.o. with sepsis and a serum albumin of 1.2 mg/dL. She has a seizure disorder which has been well controlled with phenytoin (serum concentration on admission was 19 mcg/ml). You notice she is having clonus and seizure-like activity. You should:
a) Administer phenytoin 5 mg/kg IV now
b) Order a serum phenytoin level now
c) Obtain an EEG now
d) Order a total and free serum phenytoin level now

Answer 40

In the case of LF, a 12-year-old with sepsis and low serum albumin, who is experiencing clonus and seizure-like activity, the best choice would be:

d) Order a total and free serum phenytoin level now.

1. Low Serum Albumin: LF’s serum albumin level is significantly low (1.2 mg/dL), which can affect the binding of phenytoin. Since phenytoin is highly protein-bound, a low albumin level will increase the free (unbound) fraction of the drug in the serum, potentially leading to toxicity, even if the total phenytoin level appears to be in the therapeutic range.
2. Seizure Activity: The presence of clonus and seizure-like activity suggests that LF may be experiencing breakthrough seizures. It’s important to assess the current status of phenytoin therapy.
3. Total and Free Levels: Ordering both total and free phenytoin levels will provide critical information to evaluate whether she is in the therapeutic range for the free fraction of the drug, which is the pharmacologically active form. This will help guide further treatment decisions.
4. Other Options:
   • a) Administer phenytoin 5 mg/kg IV now: This option might be considered later, but without knowing the current free level of phenytoin, it could risk further increasing toxicity if the free levels are already high.
   • b) Order a serum phenytoin level now: This would only give the total level, which is not sufficient due to her low albumin. It’s important to get both total and free levels.
   • c) Obtain an EEG now: While this may be useful for monitoring seizure activity, it does not address the immediate concern of phenytoin levels and the potential need for adjustment of her medication.

Therefore, the most appropriate action is d) Order a total and free serum phenytoin level now to assess her current drug status and make informed decisions regarding her treatment.

Question 41

KD is a 12 y.o. child admitted with status asthmaticus who is treated by her primary physician with theophylline (serum concentration is 18 mcg/ml). Based on her CXR and clinical findings, you treat her with erythromycin for presumed Mycoplasma pneumoniae. You should:
a) Continue her current dose of theophylline.
There is no need to monitor serum concentrations.
b) Lower her dose of theophylline and monitor daily serum concentrations
c) Increase her dose of theophylline by 10% and monitor daily serum concentration
d) Continue her current dose of theophylline and monitor daily serum concentrations

Answer 41

In the case of KD, a 12-year-old child with status asthmaticus who is being treated with theophylline and is starting erythromycin for presumed Mycoplasma pneumoniae, the best choice would be:

b) Lower her dose of theophylline and monitor daily serum concentrations.

1. Drug Interaction: Erythromycin is known to inhibit cytochrome P450 enzymes (specifically CYP1A2), which are involved in the metabolism of theophylline. This inhibition can lead to increased serum concentrations of theophylline, raising the risk of toxicity.
2. Current Theophylline Level: KD’s current theophylline concentration is 18 mcg/ml. While this level is within the therapeutic range for asthma, starting erythromycin could increase theophylline levels significantly, potentially leading to adverse effects such as nausea, vomiting, tachycardia, and CNS stimulation.
3. Monitoring and Dose Adjustment: Lowering the theophylline dose is prudent to account for the potential increase in its concentration due to the erythromycin interaction. Monitoring daily serum concentrations is essential to ensure that theophylline levels remain safe and effective.
4. Other Options:
   • a) Continue her current dose of theophylline. There is no need to monitor serum concentrations.: This is not appropriate because it ignores the risk of elevated theophylline levels due to erythromycin.
   • c) Increase her dose of theophylline by 10% and monitor daily serum concentration.: This is contraindicated because it would further elevate the risk of toxicity in the context of a drug interaction.
   • d) Continue her current dose of theophylline and monitor daily serum concentrations.: This does not account for the interaction with erythromycin and the potential for increased levels.

Therefore, the most appropriate action is b) Lower her dose of theophylline and monitor daily serum concentrations to mitigate the risk of toxicity while ensuring effective management of her asthma.

Question 42

BJ is a 13 y.o. S/P BMT for ALL. She is admitted to the PICU in septic shock. She has renal insufficiency with a BUN/SCr of 45/2.1 mg/dL and is on fluconazole, cyclosporine, solumedrol, vancomycin, cefepime and acyclovir in addition to vasopressors.
a) Identify the drugs which may worsen her renal function
b) Identify the drugs which require dosage adjustment due to her renal dysfunction
c) Identify the drugs which require serum concentrations to be monitored and project when you would obtain these levels

Answer 42

In the case of BJ, a 13-year-old female with a history of bone marrow transplant (BMT) for acute lymphoblastic leukemia (ALL) who is now in septic shock and has renal insufficiency, let’s analyze the medications she is receiving:

1. Cyclosporine: This immunosuppressant can cause nephrotoxicity, especially in patients with existing renal impairment.
2. Vancomycin: This antibiotic is associated with nephrotoxicity, particularly at higher doses or with prolonged use, especially in the setting of renal insufficiency.
3. Acyclovir: High doses or rapid infusion can lead to crystalline nephropathy, which can worsen renal function, especially in the context of dehydration or renal impairment.
4. Cefepime: While generally safe, cefepime can cause neurotoxicity and renal impairment in cases of significant renal dysfunction.

1. Vancomycin: Dosing should be adjusted based on renal function. It is crucial to monitor renal function and adjust the dose accordingly to avoid toxicity.
2. Acyclovir: Dosage should be adjusted in renal impairment due to the risk of nephrotoxicity.
3. Fluconazole: The dose of fluconazole may need to be reduced in patients with renal insufficiency.
4. Cefepime: The dose of cefepime should be adjusted based on creatinine clearance to avoid toxicity.
5. Cyclosporine: Dosing may need adjustment based on renal function and therapeutic drug monitoring, but the need for adjustment may depend on the specific renal status and target levels.

1. Cyclosporine: Requires monitoring of trough levels to maintain therapeutic efficacy and avoid toxicity. Levels should be obtained just before the next dose (trough) and may need to be monitored frequently (daily or every other day) in the setting of renal insufficiency.
2. Vancomycin: Monitoring of serum levels (troughs) is essential to ensure effective dosing while minimizing toxicity, especially in the context of renal impairment. Trough levels should be obtained just before the next dose, ideally after a few doses (typically after the third or fourth dose).
3. Acyclovir: Monitoring is not typically routine unless there are concerns for toxicity; however, levels can be checked if there is suspicion of renal-related toxicity.
4. Fluconazole: While routine monitoring may not be required, it can be helpful in adjusting the dose based on renal function.

• Drugs that may worsen renal function: Cyclosporine, vancomycin, acyclovir, cefepime.
• Drugs requiring dosage adjustment: Vancomycin, acyclovir, fluconazole, cefepime, cyclosporine.
• Drugs requiring serum concentration monitoring: Cyclosporine (daily or every other day), vancomycin (trough levels after a few doses).

In BJ’s case, it’s essential to closely monitor her renal function and adjust her medication regimen accordingly to manage her septic shock while preventing further renal deterioration.