Pharmacology Block 3

What do physicochemical characteristics of a drug determine?

they determine the drug’s ability to move through the body and initiate a cellular response, the structure-activity relationship, and the molecular mechanisms of drug action

the molecular mechanisms of a drug’s movement through the body and its actions are explained by what?

physiological transporters, receptors, and effector mechanisms

drug-receptor interactions are described in quantitative terms using graded dose-response curves that do what?

they compare efficacy and potency of drugs and determine appropriate dosage ranges for patients

The drug dose determines _____, which determines ________, which determines ________

The drug dose determines the concentration of drug in plasma, which determines the concentration of drug at the site of action, which determines the magnitude of pharmacologic effect, as reflected on graded dose-response curves

What do the graded dose-response and the graded dose-receptor relationship assume?

that the magnitude of the response to a drug is proportional to the concentration of receptors that are bound

What can be deduced from the graded dose-response curve?

efficacy and potency

What is the idea behind spare receptors and how do you know if there are spare receptors?

Some drugs can elicit a maximal response by occupying a fraction of the receptors in the total receptor pool. The remaining unbound receptors are referred to as “spare receptors”

you can use irreversible antagonists to see if in their presence you can still elicit a maximal response, if you can then there are spare receptors

What is the structure-activity relationship?

the relationship between the chemical or 3D structure of a molecule and its
biological activity

A drug’s action may persist until what? (4 different things)

dissociation of the drug from the receptor

activation of second messengers

drug-receptor complex is destroyed

desensitization mechanisms are incorporated

What three things does the concentration of occupied receptors depend on?

drug concentration, drug-receptor association rate, drug-receptor dissociation rate

What is equilibrium binding?

when half of the recptors are free and the other half are bound to drug

What is the EC50?

this is the concentration of drug that produces 50% of maximal response

What is Kd?

the concentration of free drug at which half-maximal binding is observed

What is intrinsic activity?

the ability of a drug bound to its receptor to activate downstream effector mechanisms

What is efficacy?

the quantitative ability of a drug to elicit a physiologic response when it interacts with a receptor (it is related to intrinsic activity)

What is potency? what is it related to?

the concentration of drug required to produce an effect

it is related to the drug’s affinity for its target

What is the difference between pharmacodynamics and pharmacokinetics?

pharmacodynamics: this is what the drug does to the body and how it does it

pharmacokinetics: what the body does to the drug and how it does it (ADME)

Traditional receptor occupancy theory rests on the assumption that what?

the proportion of occupied receptors is related to the effect of the drug

What is toxicology?

the branch of science that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems

What is the idea behind rational drug design?

the development of drugs is based on knowledge of the 3D structure of the receptor site

What is pharmacogenetics?

the relation between an individual’s genetic makeup to his or her response to specific drugs

what is a drug that binds to and activates a receptor but does not evoke a maximal response, no matter how high the concentration of drug?

partial agonist

what is a drug that binds to a receptor, competes with and prevents binding by other molecules?

an antagonist

What is a drug that has a much stronger affinity for the Ri than for the Ra state and stabilizes a large fraction in the Ri–D pool, reducing constitutive activity?

inverse agonist

what is a drug that binds to and activates the receptor in some fashion, which directly or indirectly brings about the effect?

an agonist

What is the difference between two-state receptor occupancy model and the classic receptor occupancy model explaining drug-receptor interactions?

The two-state receptor occupancy model posits that receptors in the  receptor pool exist in an inactive and active conformation in the absence of ligand with equilibrium favoring the inactive state. Drug binding to receptors shifts the equilibrium depending on the drug’s relative affinities for the active and inactive states. 

The classical model posits that the receptors in a receptor pool are quiescent (inactive/dormant) unless activated by a ligand.  

How does receptor desensitization and downregulation affect response to
a natural or drug agonist?

Diminished response to continued or repeated exposure to an agonist can lead to fewer receptors or desensitized receptors on the cell surface. After withdrawal of the agonist, cells recover full responsiveness to a subsequent addition of the agonist (resensitization) 

How does receptor supersensitivity affect response to a natural or drug
agonist?

Continuous or repeated exposure to an antagonist can cause upregulation of receptors and insertion of an increased number of receptors on cell surfaces. After the antagonist is withdrawn, the increased receptor density can result in an exaggerated response to a natural or drug agonist- supersensitivity  

What is the median effective dose (ED50)?

the dose of a drug required to produce a specified effect in 50% of the population

What is the median lethal dose (LD50)?

the dose of a drug that is lethal in 50% of the population

What is the median toxic dose (TD50)?

the dose of the drug that produces a specifies toxic effect in 50% of the population

What is the therapeutic window? Does it guarantee safety and/or efficacy in individual patients?

it is the concentration/dose range where efficacy likelihood is high and the probability of adverse effects is low

this range does not guarantee safety or efficacy in individual patients

What is the two-state receptor occupancy model?

it is a model that postulates that receptors in the receptor pool exist in
equilibrium in two interchangeable conformational states in the absence of a ligand: Ra (active) and Ri (inactive).

What is the classical receptor occupancy model?

postulates that receptors are quiescent unless activated by a ligand.

An increased density of membrane receptors – receptor supersensitivity – can result from what?

continuous or repeated exposure to an antagonist

After the antagonist is withdrawn, activation by the agonist can cause an exaggerated response

What is an estimate of a drug’s safety?

therapeutic index

Receptor desensitization (insensitivity) occurs due to what?

phosphorylation of the receptors, or other mechanisms, which decreases the coupling efficiency of receptors

What is receptor downregulation?

Internalization and degradation of receptors, including bound ligands, decreases the number of receptors.

What is an acute, sudden decrease in response after continuous or repeated administration of a drug?

tachyphylaxis

Increased expression of receptors can cause cells to be what?

more sensitive to the agonist when the antagonist is withdrawn

What physicochemical property determines the ability of a drug to passively diffuse through lipid membranes?

The lipid-water coefficient of a drug (the ratio of the concentration of the drug in the lipid and aqueous phases) determines how readily the drug molecule moves across lipid membranes. Lipid-soluble drugs passively diffuse through lipid membranes (not saturable). The rate of transfer across the membranes from an area of higher concentration to lower concentration is directly proportional to the lipid water coefficient

By what mechanism can a hydrophilic drug cross physiologic barriers?

A hydrophilic drug can cross physiologic barriers via transport proteins- passive diffusion or facilitated transport down the concentration gradient or by energy-using active transport. Transporters are saturable- full occupation of transporters ---> maximum rate of transfer

For drugs that are weak acids and weak bases, why is the pH of biologic fluid clinically important? 

Weak acids and weak bases either gain or lose charge-bearing protons depending on their pKa and the pH of the medium. Only the uncharged form of the drug will passively diffuse across the lipid bilayer, while the charged form does not. This is called ion trapping. Manipulation of urine pH may be appropriated for increasing the rate of excretion by ion trapping of certain drugs, such as toxic concentrations of salicylates

What is the first-pass effect?

A fraction of an oral dose may be inactivated by drug-metabolizing enzymes in the GI tract and liver before reaching the systemic circulation

what is bioavailability?

The fraction of the dose of active drug that reaches the systemic circulation

Oral drugs are absorbed mainly from what part of the intestine? 

The upper small intestine. The intestine has very large surface area from absorbing nutrients and drugs because of the villi along the length of the small intestine 

What is the clinical significance of the phenomenon of redistribution when applied to highly lipophilic drugs, such as anesthetics?

A single I.V dose of a highly lipophilic drug (such as an anesthetic) rapidly produces the CNS effect. The effect is terminated as the drug redistributes to peripheral tissues, which reduces the plasma drug concentration in the CNS

What is the concern about drugs that can cross the blood-placenta barrier? 

Drugs able to cross the blood-placenta barrier leads to fetal exposure to drugs. Practitioners need to know what drugs are safe or toxic to the fetus and at which stages of pregnancy 

What is the clinical relevance of drug binding to plasma proteins and tissue macromolecules?

Plasma proteins and tissue macromolecules are inert- they do not regulate cellular actions. Drugs reversibly bound to plasma proteins and/or tissue macromolecules are sequestered- they are not free to be metabolized, excreted, or reach the site of action. As the concentration of free drug decreases due to elimination, drug molecules dissociate, which maintains the free-drug concentration at a constant fraction 

Enzymes of phase 1 metabolic reactions do what?

catalyze the oxidation, reduction, and hydrolysis of exogenous molecules (xenobiotics), as well as endogenous molecules, by exposing a polar functional group. The cytochrome P450 mixed-function oxidases (CYPs) are the predominant enzymes involved in oxidative metabolism

Enzymes (transferases) of phase 2 metabolic reactions do what?

catalyze the transfer of a functional group from an endogenous cofactor onto a nonpolar drug or metabolite, resulting in a hydrophilic drug conjugate that is readily excreted. Phase 2 metabolites are largely
inactive, with a few exceptions

CYP metabolism requires what three elements? 

Heme, NADPH (Reducing agent), and oxygen (CYP 450 enzymes are monooxygenases) 

CYPs are susceptible to alterations in rates of drug elimination by what?

Inhibition or induction of CYPs and by pharmacogenetic variabilities 

How do phase 2 reactions differ from phase 1 reactions?

Phase 1: Reactions are oxidation reactions; Enzymes expose a functional group; Metabolites may be inactive, active, or toxic 

Phase 2: Reactions are conjugation reactions; Enzymes transfer a substance from an endogenous cofactor; Metabolites are hydrophilic, readily excretable, and almost always inactive 

True or false: phase 2 reactions must follow phase 1 reactions

false, drugs that have polar functional group already exposed on their structures may directly undergo a phase 2 conjugation reaction 

What types of drug metabolites frequently undergo enterohepatic circulation?

Glucuronide metabolites are secreted into the bile canaliculi by P-gp efflux passive diffusion. Bacteria that express beta-glucuronidase cleave the glucuronide releasing the free drug which is reabsorbed in the terminal ileum 

What are the processes involved in renal excretion of drugs and metabolites?

Molecules not bound to plasma proteins enter the kidney via glomerular filtration (small molecules dissolved in plasma) or active secretion  into the proximal tubule. If lipophilic, they may be passively reabsorbed in the distal tubule. If not, drugs and metabolites are excreted in urine.

What is the most frequently used biomarker of kidney function? 

Serum creatinine. Also, urine creatinine, which requires urine collection over time. 

What component of kidney function does serum creatinine reflect?

GFR- glomerular filtration rate shows how well the kidneys are filtering 

What is the clinical relevance of glomerular filtration rate (GFR) on drug therapy?  

A low GFR means kidney function is impaired, which means drugs may not be excreted at the usual rate and can accumulate in the blood increasing the risk of toxicity. Drug therapy may need to be adjusted. This is called renal dosing. 

What is clearance?

the proportionality factor that predicts the rate of elimination in relation to the drug concentration

what is the volume of distribution?

the proportionality constant that relates the total amount of drug in the body to the plasma concentration at a given time.

What impacts the rates of drug distribution to tissues?

change in blood flow to various tissues

so, the effect of a drug at various sites of action can vary depending on perfusion of these sites

What is the extraction ratio?

the fraction or percentage of the drug removed from the perfusing blood
during one passage through the organ

The area under the concentration vs. time curve (AUC) describes what?

the measured concentration of drug in the systemic circulation as a function of time (from zero to infinity) – the concentration of drug appearing in plasma occurs over time.

what is the elimination half-life a measurement of?

time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%

In first-order elimination kinetics, the drug elimination rate is directly
proportional to

plasma free drug concentration.

In zero-order elimination kinetics, the metabolic enzymes eventually will
become what?

saturated as the concentration of substrate increases. The rate of
drug elimination is constant (a constant amount) and independent of plasma drug concentration

When a drug that exhibits first-order pharmacokinetics is administered to a
patient continuously or intermittently, the drug will?

accumulate until it reaches a plateau – a dynamic equilibrium = steady-state plasma drug concentration

How many half-lives does it take to reach steady state?

4

What is a loading dose versus a maintenance dose?

A loading dose rapidly raises the plasma drug concentration to the target
concentration

The maintenance dose is administered after the loading dose to maintain the desired steady state concentration

What is neonatal abstinence syndrome?

A drug-withdrawal syndrome that follows in utero exposure to maternal opioids, alcohol, benzodiazepines, barbiturates, others

What is fetotoxicity?

njury to the fetus from a substance that enters the maternal and
placental circulation, which may cause fetal malformations, altered
growth, or in utero death

What is a teratogen and teratogenicity?

Any agent that acts during embryonic or fetal development to produce a
permanent alteration of form or function

The induction of defects of the fetus; exposure must occur during
a critical developmental period

What are haptens? How do they elicit an allergic reaction?

Small chemicals (drugs or their metabolites) that are not reactive in their
original state become immunogenic by covalent binding to host proteins
on cells or in plasma forming hapten-carrier complexes. Hapten-peptide
fragments are presented by antigen presenting cells to T cells, ultimately
eliciting allergic reactions

The pregnancy and lactation Drug labeling guide has what three subsections?

pregnancy (labor and delivery), lactation, and reproductive considerations for females and males

What is the difference between additive, synergistic, and potentiation?

additive: the combined effect of two drugs equals the sum of the effect of each agent given alone

synergistic: combined effect exceeds the sum of teh effect of each drug given

potentiation: accentuation of the effect of one drug due to the presence of another drug that alone has no effect

What is physiological antagonism? Example?

Two xenobiotics produce opposite effects on the same physiological function

insulin and glucagon

What is a chemical antagonist? example?

reaction between two chemicals neutralizes their effects

antacids chelating tetracycline (preventing its absorption)

What is receptor antagonism?

blockade of the effect of one drug by another drug that competes at a common binding site or acts at an allosteric site

Drug A is taken orally to increase gastric pH. The absorption of Drug B requires an acid stomach for optimal absorption. What is the potential effect on blood levels when the two drugs are administered concomitantly?

PK absorption: Systemic levels of Drug A are decreased, which could reduce its therapeutic efficacy

A drug that is a positive allosteric modulator enhances the inhibitory effects of a chloride ion channel in the CNS. Alcohol is also a positive allosteric modulatory at the same target acting at a different site. What is the likely adverse drug effect when the two chemicals are used simultaneously?

PD: Synergistic CNS depressant effects may lead to death, especially when combined with a mu opioid agonist.

A patient is taking an antiplatelet drug following a heart attack and an anticoagulant due to recent knee replacement surgery. What is the potential adverse drug event that could result from this drug-drug interaction?

PD: Additive or synergistic effects can lead to potentially serious bleeding, including hemorrhagic stroke

A patient with several comorbidities treated with various drugs is evaluated for an antiviral drug that contains a potent CYP3A4 inhibitor for the treatment of COVID-19. What effects may be anticipated when the antiviral is taken together with the patient’s chronic medications?

PK metabolism: Inhibiting the metabolism of the concurrent drugs (CYP3A4 substrates) can lead to elevated blood levels of the substrate drugs and increase the risk of adverse effects

An 87 year-old patient with compensated congestive heart failure takes a medication that is a P-glycoprotein substrate, has a narrow therapeutic window and potential for serious toxicity. She is evaluated for antibiotic therapy for a bacterial lung infection. The preferred drug is a P-glycoprotein
inhibitor. What is the potential effect of this drug-drug interaction?

PK distribution / excretion: P-gp inhibition decreases P-gp drug efflux by intestinal epithelial cells and decreases drug secretion into the proximal tubule, resulting in elevated blood levels of the heart drug. This interaction could lead to serious toxicity by the heart drug.

A 57-year-old patient with longstanding type 2 diabetes mellitus takes a drug that reduces glomerular filtration pressure. Patient education (in easy to understand language) includes the caution that he should not take any over-the-counter pain medications that also decrease glomerular filtration pressure. What is the potential effect of this drug-drug interaction?

Drug-disease interaction and PD interaction: Additive or synergistic effects resulting in decreased glomerular filtration rate could lead to acute kidney injury in the vulnerable (at risk) patient

A patient with hypercholesterolemia is taking a drug that is not absorbed from the GI tract. It acts by complexing and sequestering bile acids (synthesized from cholesterol) in the gut and excretes the drug-bile acids complex in the feces. The patient has not achieved goal levels of serum
cholesterol so agrees to take an add-on drug, which is orally absorbed and acts by preventing cholesterol absorption at the level of the enterocytes. Thinking about the mechanism of action of the bile acid sequestrant, what is the likely effect of this drug-drug interaction?

PK absorption: Cholestyramine sequesters many drugs in the GI tract – not only bile acids – preventing absorption, resulting in reduced blood levels of the orally absorbed drugs

Strong inducers of CYP3A4 and P-glycoprotein include?

carbamazepine, phenobarbital, phenytoin, rifampin, and St. John’s wort

CYP1A2 isoenzymes are induced by?

tobacco smoking

Clinically relevant CYP3A4 and P-glycoprotein inhibitors include

cimetidine, macrolide antibiotics (erythromycin and clarithromycin), azole antifungal agents, ritonavir, grapefruit juice

What do antimicrobial agents target?

Microbial molecules that are essential components of biochemical
reactions in the microbes

What is the effect of antimicrobial agents on target microbial molecules?

interference with physiological pathways kills the microorganisms or slows their growth allowing host immune mechanisms to eradicate them

What is selective toxicity with relation to antimicrobial agents?

The extent to which an antimicrobial agent harms microbial cells, but
does not damage host cells, at therapeutic concentrations determines its relative safety

Which organisms are more susceptible to drug action than others?

Actively and rapidly growing organisms are more susceptible to drug action than those in the resting phase

What are the 5 main contributors to the emergence of resistance?

evolution, natural selection, selection pressure, clinical practices, and environmental practices

Frequent of long-term use of a particular drug increases the risk of what?

microbial mutations that produce resistance to the drug

what are the 4 mechanisms of antimicrobial resistance?

1. the drug does not reach target (efflux pumps or altered porins)

2. drug inactivation

3. target alteration

4. organism expresses alternative metabolic pathways

What is the minimum inhibitory concentration (MIC)?

The lowest concentration of an antibacterial agent that inhibits visible
growth

What is the minimum bactericidal concentration (MBC)?

The lowest concentration of an antibacterial agent that either totally
prevents growth or results in a greater than 99.9% decrease in the initial
inoculum

What do we use susceptibility testing for?

to determine the likelihood that a particular antibiotic or antifungal agent will be effective in stopping the growth of the bacteria or fungi causing the infection