PhARM

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Questions and Answers

Which form of weak acid drugs predominates in an alkaline environment?

Neither form

Both forms equally

Nonionized form

Ionized form (correct)

What is the main reason that ionized drugs cannot diffuse back into the stomach lumen?

They are too large to pass through membranes.

The pH gradient prevents their diffusion. (correct)

The concentration gradient favors the ionized form.

They are actively secreted out of the plasma.

How does the pH of plasma affect weak acid drugs?

It has no effect on the drug's ionization state.

It favors the ionized form, trapping them in plasma. (correct)

It favors the nonionized form and enhances absorption.

It leads to a build-up of the nonionized form in the plasma.

Why might ion trapping of local anesthetics during epidural administration lead to fetal toxicity?

The more acidic fetal environment traps the anesthetic. Signup and view all the answers

What happens to base molecules in an acidic environment?

They become ionized and cannot cross membranes. Signup and view all the answers

Which factor does NOT influence the rate of absorption of a drug?

Cost of the drug Signup and view all the answers

What is the primary process by which most drugs cross cell membranes?

Passive diffusion Signup and view all the answers

Which statement about the nonionized form of the drug is accurate?

It can easily cross the lipophilic cell membrane. Signup and view all the answers

According to Fick's principle/law, which factor does NOT affect the rate of diffusion of a drug across a membrane?

Molecular weight of the drug Signup and view all the answers

Why is greater blood flow to the site of absorption important?

It enhances the rate of absorption. Signup and view all the answers

What impact does increased surface area have on drug absorption?

Increases drug absorption. Signup and view all the answers

Which of the following does NOT require energy for the transport of drugs?

Passive diffusion Signup and view all the answers

Which factor is NOT a characteristic of passive diffusion?

It requires energy. Signup and view all the answers

What does the Volume of Distribution (Vd) represent in pharmacokinetics?

The volume required to achieve equal drug concentration in all tissues and plasma Signup and view all the answers

How is Volume of Distribution (Vd) calculated?

Vd = Dose administered divided by plasma concentration before elimination Signup and view all the answers

Why is knowing the Volume of Distribution (Vd) important in clinical settings?

It estimates the loading dose required for achieving steady-state concentration Signup and view all the answers

What is the effect of a higher Volume of Distribution (Vd) on drug dosing?

It indicates a greater distribution to body tissues Signup and view all the answers

If a patient weighs 70kg and has a Gentamicin Vd of 0.28 L/kg, what is the total Vd for this patient?

19.6 L Signup and view all the answers

What is the typical naming convention for the salt form of a drug?

The cation is listed in front of the drug name. Signup and view all the answers

What happens when pH is equal to pKa?

50% of the drug is ionized and 50% is nonionized. Signup and view all the answers

Which of the following is a characteristic of drug salts derived from weak acids?

They are usually named with the drug followed by the cation. Signup and view all the answers

Which statement is true regarding weak acid drugs?

Nonionized form predominates when pH is less than pKa. Signup and view all the answers

What is the primary function of the Henderson-Hasselbalch equation?

To predict the degree of ionization of a drug in solution. Signup and view all the answers

What is the significance of small changes in pH for drug ionization?

They can lead to large changes in the extent of ionization. Signup and view all the answers

What does pKa represent in the context of drug ionization?

The pH where a drug is 50% ionized and 50% nonionized. Signup and view all the answers

Which of the following statements about weak bases is correct?

Weak bases form salts with negatively charged ions. Signup and view all the answers

For weak base drugs, which form is predominant when pH is lower than pKa?

Ionized form. Signup and view all the answers

At a normal physiologic pH of 7.4, which statement is correct regarding drug absorption?

Both weak acids and weak bases have defined ratios of ionized to nonionized forms. Signup and view all the answers

How does pH affect drug absorption?

Nonionized forms of drugs are more lipid-soluble and absorbed better. Signup and view all the answers

Which of the following drugs is a salt of a weak base?

Morphine Sulfate Signup and view all the answers

How does pKa relate to the strength of an acid or base?

Lower pKa indicates a stronger acid. Signup and view all the answers

What is the impact of nonionized drugs on absorption?

They can penetrate cell membranes more effectively. Signup and view all the answers

Which two drugs are exceptions where the acid or base status is not clear from their names?

Propofol and Etomidate Signup and view all the answers

Which scenario will likely increase the fraction of ionized weak base drug present?

Increasing pH relative to pKa. Signup and view all the answers

What happens to weak acid drugs as the pH decreases?

They become more lipid-soluble. Signup and view all the answers

At a physiological pH of 7.4, what form does Acetylsalicylic acid predominantly take?

Ionized. Signup and view all the answers

How does the pH affect the ionization of weak base drugs?

They become more ionized as the pH increases. Signup and view all the answers

In the mechanism of ion trapping, what role does pH play?

It affects the ionization status of the drug. Signup and view all the answers

Which ratio indicates favored absorption for a weak acid drug in a highly acidic environment?

1000:1 nonionized to ionized. Signup and view all the answers

When the pH is lower than the pKa for a weak acid drug, what can be expected?

It will predominantly be nonionized. Signup and view all the answers

In an alkaline environment, how do weak base drugs behave?

They become more lipid-soluble. Signup and view all the answers

What occurs when a drug is ion trapped across a membrane?

The ionized form accumulates on one side. Signup and view all the answers

Study Notes

Pharmacokinetic Principles

Pharmacokinetics is the quantitative study of absorption, distribution, metabolism, and excretion of drugs and their metabolites. These processes determine the drug concentration at the site of action.
It details the relationship between drug dose and drug concentration in the body or at the site of action.
Clinically, it describes how the plasma concentration of a drug changes over time, assuming plasma equilibrates with an effect compartment to produce a pharmacodynamic effect.

Objectives

The presenter aims to review the concept of pharmacokinetics and specific pharmacokinetic parameters.
They will review pharmacokinetic rates of reactions, types of pharmacokinetics, and relevant parameters for anesthesia.
Compartmental modeling is also included.

Pharmacokinetics - Absorption

Absorption is the passage of drug molecules through physiological/biological barriers to reach the vascular system.
It describes the process of a drug being absorbed into the body, typically from an extravascular site. (e.g., oral administration)
Systemic absorption is influenced by chemical structure and properties of the drug, the drug product, dosage form, and anatomy and physiology at the absorption site.
The non-ionized form of a drug is more lipid-soluble and can cross the lipophilic cell membrane more easily.
Factors influencing absorption rate include cell membrane characteristics, surface area at the absorption site, pH, and blood flow to the site.

Passage of Drugs Across Cell Membranes - Passive Diffusion

Passive diffusion is the main mechanism by which most drugs cross cell membranes.
It's a movement of drug molecules from an area of higher concentration to an area of lower concentration, and it doesn't require energy.
Factors influencing passive diffusion include concentration gradient, surface area, diffusion coefficient, and membrane thickness. Passive diffusion is governed by Fick's law.

Passage of Drugs Across Cell Membranes - Active Transport

Active transport is a carrier-mediated process that moves drugs against a concentration gradient.
This process requires energy.
Active transport is important in renal and biliary secretion of drugs.

Passage of Drugs Across Cell Membranes - Facilitated Diffusion

Facilitated diffusion is a carrier-mediated process that moves drugs along a concentration gradient.
It doesn't require energy, but it may involve a protein carrier.

Ionization

Many drugs in anesthesia are weak acids or weak bases and exist in both ionized and nonionized forms.
Weak acids and bases are administered as salts.
The ionized form of a drug tends to remain in the filtrate, while the nonionized form is more likely to be reabsorbed.
Ionization is influenced by the pH of the environment.

Characteristics of Ionized and Nonionized Drug Molecules

Feature	Nonionized	Ionized
Pharmacological effect	Active	Inactive
Solubility	Lipid	Water
Cross lipid barriers	Yes	No
Renal Excretion	No	Yes
Hepatic Metabolism	Yes	No

Identifying Weak Acids and Weak Bases from Drug Names

Weak acids donate H+ ions and form salts with cations
Weak bases accept H+ ions and form salts with anions.

Henderson-Hasselbalch Equation

The Henderson-Hasselbalch equation can predict the degree of ionization of a drug in solution.
It relates drug ionization to the pH of the solution and the drug's pKa.
For weak acids and bases, the pH determines the relative amount of ionized and nonionized form.

Effect of pH on Drug Absorption and Distribution

Non-ionized drugs are more lipid-soluble and easily cross cell membranes
Changes in pH affect the ionization of drugs. A drug's relative ionization or non-ionization is altered by a change in pH
Weak acid drugs are more nonionized at lower pH, and weak base drugs are more nonionized at higher pH.

Calculation Questions and pH Relationships

Drugs' ionization/non-ionization is affected by the pH related to the pKa of the drug, and this affects drug absorption
The form in which the drug predominates is determined by whether the pH is higher than or lower than the drug's pka.

Ion Trapping Mechanism

A concentration difference of total drug can be generated.
The nonionized, lipid-soluble form of a drug crosses cell membranes readily
The ionized form is less prone to cross cell membranes, therefore it will be trapped on one side of the cell membrane where it is more concentrated
This can lead to toxicities depending on the difference in pH

Classification of Drug Routes of Administration

Routes of administration include intravascular (e.g., IV, intra-arterial) and extravascular (e.g., oral, intramuscular, transdermal).
The choice of route affects the bioavailability (i.e., how much of an administered dose reaches a target site)
Absorption by extravascular routes is important for drugs to reach the circulation and action sites

Oral Administration

Oral administration is a common route, but absorption can be unpredictable.
It is affected by the rate and extent of drug absorption in different regions of the gastrointestinal tract; it can have variable absorption.
The duodenum is generally the optimum site for absorption.

Transmucosal Administration

Rapid onset.
Bypass the hepatic first pass effect in sublingual & buccal administrations.

Rectal Administration

Useful for unconscious or vomiting patients.
Depending on the location within the rectum, the drug can or cannot bypass the first-pass effect.

Transdermal Administration

Sustained drug release with reduced fluctuations in plasma levels is an advantage.
A good transdermal medication will take advantage of lipid solubility; a low molecular weight (important property) and suitable pH.

Intravascular Administration

Delivers drugs directly into the bloodstream, resulting in 100% bioavailability
It is the fastest onset route.
Administration can cause local tissue irritation.

Pharmacokinetics - Distribution

Distribution is the movement of drug molecules from blood into tissues and organs, with lipid solubility being the most important factor.
Determinants of distribution include lipid solubility, protein binding, blood flow, molecular size, and drug ionization.
Only the free, unbound drug is available to cross membranes.

Volume of Distribution (Vd)

Vd is a hypothetical volume used to relate the amount of drug in the body to the measured concentration in the plasma.
It is calculated as the dose of drug divided by the resulting plasma concentration.
Vd is affected by factors such as protein binding.
Drugs with high protein binding tend to have lower Vd.

Protein Binding

Protein binding affects drug distribution by limiting the amount of free drug available to cross membranes into tissues.
Vd is inversely proportional to protein binding: High protein binding leads to a smaller Vd, while low protein binding leads to a larger Vd
This is clinically important because alterations in protein binding can significantly affect drug concentration

Pharmacokinetics - Metabolism

Metabolism is the chemical conversion of a drug into different compounds (frequently inactive metabolites or active ones.)
Drug metabolism is typically catalyzed by enzymes in the liver (CYP 450), though other tissues play roles (e.g., kidneys, plasma, etc.)
Common enzymes in drug metabolism include CYPs and others involved with oxidation, reduction, and hydrolysis.
Metabolism can produce inactive compounds for easier excretion, or active compounds with unique effects.

Metabolic Pathways

Phase I reactions (functionalization) introduce or expose functional groups to increase polarity and prepare for further metabolism or excretion.
Phase II reactions (conjugation) involve the addition of an endogenous substrate onto a drug or metabolite, increasing polarity for kidney or bile excretion.

Cytochrome P-450 System

CYP 450 enzymes are important in drug metabolism, particularly oxidation reactions
They are found in the liver, small intestine, kidneys, brain, and lungs.
Induction or inhibition of these enzymes can alter the metabolism of other drugs, resulting in clinically relevant interactions
Drugs that have the ability to activate (inducers) or deactivate (inhibitors) this system should be known by health professionals to aid in drug administration

Excretion

Excretion is the irreversible removal of a drug from the body.
Major organs of excretion include the kidneys (water-soluble drugs and metabolites), liver (biliary excretion), and lungs (volatile anesthetics).

Clearance (CI)

Clearance is the volume of plasma or blood cleared of a drug per unit of time
Factors influencing clearance can include blood flow, enzyme activity, and drug binding
Clearance is directly proportional to the drug dose and blood flow of the clearing organ, but is inversely proportional to the drugs half life
Different elimination processes, such as zero-order kinetics and first-order kinetics, may have different drug clearance processes.

Hepatic Clearance

Hepatic clearance is the volume of blood cleared of a drug per unit of time
High ER drugs' clearance is almost exclusively dependent on blood flow to the liver, whereas low ER drugs' clearance is largely independent of blood flow.
Protein binding and enzyme activity are other factors that influence liver clearance of drugs.

Renal Clearance

The kidney filters and excretes drugs, metabolites, and other substances from the body
Renal clearance is dependent on glomerular filtration, active tubular secretion, and passive tubular reabsorption
Factors influencing renal clearance include blood flow, drug properties, and urine pH change.

One-Compartmental Models

In one-compartment models, the body is viewed as a single compartment.
Assumptions include instantaneous distribution, first-order elimination, & consistency of drug concentration at the site of action and in the plasma after equilibrium.
Useful for calculating drug concentrations and estimating doses for IV drugs

Multi-Compartmental Models

In these models, the body is divided into multiple compartments.
They are useful for describing the distribution and elimination of drugs with extensive distribution into peripheral tissues.

Redistribution

Redistribution of drugs from the central to peripheral compartments can affect both duration and site of activity and effect on peripheral tissues, which can have clinical implications
The rate of transfer declines with aging

Context-Sensitive Half-Time

Describes the time required for the plasma drug concentration to reduce by 50% after discontinuing a drug infusion
It's a useful parameter for drugs given continuously and critically relevant as a parameter in the clinical setting
Important for drugs with extensive peripheral distribution, because duration of effect can be prolonged/ prolonged distribution phase

Zero-Order Kinetics

Zero-order elimination refers to a constant amount of drug eliminated per unit of time, irrespective of concentration
Usually occurs when enzymes or transporters involved in drug metabolism or excretion become saturated

First-Order Kinetics

First-order elimination refers to a constant percentage of a drug eliminated per unit of time.
Usually a direct relationship between drug concentration and rate of elimination, which can be used for calculation purposes

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