PHRM 409 Exam 2

What is the goal of drug therapy?

Keep plasma concentration at a level that results in expected therapeutic effects without causing adverse side effects or toxicity

Bioavailability (F)

• How much drug gets into systemic circulation and how long does it take to get there?

• Fraction of administered drug reaching systemic circulation

• Absorption rate » elimination rate

• Unitless

What is F for intravenous (IV) injection?

F_IV = 1

Volume of Distribution (V_D)

• Abstract volume that relates the amount of drug in the body to the drug concentration in blood

• Extent to which a drug partitions between the plasma and tissue compartments

V_D value and physiological space

• Doesn’t usually correspond to an actual physiological space

• Value corresponds to a 70 kg healthy individual

• Unit: L/kg of body mass

If there is a decrease in muscle mass, what is the V_D for drugs that bind to muscle?

Decreases

If there is an increase in fat stores, what is the V_D for lipophilic drugs?

Increases

If there is a decrease in plasma protein, what is the V_D for lipophilic drugs?

Increases

If there is a decrease in body water, what is the V_D for hydrophilic drugs?

Decreases

Clinical use of V_D

Used to calculate loading dose needed to achieve a target initial plasma drug concentration (C_o)

Clearance (CL)

• Constant, hypothetical volume of fluid from which the drug is completely removed per unit time

• Reflects drug-eliminating efficiency

• Unit: Volume/time

Total clearance

Sum of clearances from all drug eliminating organs/processes

Clearance vs. rate of elimination

• First order kinetics

• Rate/C_p highly predictable

Clearance vs. rate of elimination: Constant fraction

Fraction of drug eliminated in a given time interval

What is clearance? (answer all that applies)

A. Synonymous with elimination (process)

B. Synonymous with “Rate of elimination” (dC/dt)

C. Fraction of drug that is elimination

D. Specifies a fixed amount of drug eliminated in a given time interval

E. Proportionality factor that correlates the drug concentration with the rate of elimination

C, E

The drug concentration declines exponentially. What is the rate constant k_e in the decay equation dependent on?

CL and V_d

How many half-lives does it take to completely eliminate a drug from the body?

At least 5 half lives

When is steady state C_ss achieved?

After at least 5 half lives

What is the key factor that relates dose to steady state C_ss?

CL

What are the limitation of the one compartment open model?

• Drug absorption isn’t really instantaneous

• Drug distribution isn’t instantaneous (multicompartment models)

• Drug elimination pathways may saturate

What are the non-saturable elimination processes?

Glomerular filtration, ventilation, and uncatalyzed breakdown of drugs

What are the saturable elimination processes?

Enzymatc metabolism, transporter mediated elimination

What are some clinically important drugs eliminated by saturable kinetics (zero-order kinetics, non-linear)?

Phenytoin, Valproic acid, salicylic acid, ethanol

Personalized medicine

Medical care that is tailored to the individual patient based on their predicted response

What is the significance of the pharmacogenetic approach?

• Determines effects of genetic variation on drug action

• Impacts response to therapy

• Narrows pharmacogenomics to more actionable info

Polymorphism

• Difference in DNA code that occurs in >1% of the population

• Less likely to be main cause of disease

• Often have no visible clinical impact

Mutation

• Differences in DNA code that occurs in <1% of the population

• Often associated with rare diseases

Pharmacogenetics

Effects of a single gene on drug disposition or response

Pharmacogenomics

Effects of multiple genes on drug disposition or response

Single-nucleotide polymorphism (SNP)

• DNA sequence variation when a single nucleotide (A, T, G, C) differs between members of a species

• Gives rise to multiple alleles

How can SNP affect coding sequences?

• May cause changes in protein structure or function

• I.e., enzymes, receptors, transporters

• Presence of protein isoforms between individuals

How can SNP affect non-coding sequences?

• Alter gene slicing (protein isoforms)

• Alter transcription factor binding (enhancers, promoters)

  • Alter expression of proteins

SNP: Synonymous

• Silent mutation

• Same polypeptide sequence despite changing letter

SNP: Synonymous

• Misense and nonsense

• Results in either a different AA or premature stop codon

Copy number variations (CNV)

• Abnormal # of copies of 1+ sections of DNA

• Ex

  • Entire gene

  • Insertions/deletions

• Location mattes

  • Excess functional protein

  • Dysfunctional or abnormally functional fusion protein

  • Nonfunctional protein

Pharmacogenomic effects on drug disposition

• Alter function of proteins involved in ADME

• Influence drug or active metabolite concentrations

A decrease in activity of metabolizing enzyme results in an increase in plasma parent drug concentration but decrease in metabolite concentration

• If parent drug is active, SNP may…

• If metabolites are active, SNP may…

• If parent drug is active, SNP may potentiate drug response and adverse side effects

• If metabolites are active, SNP may decrease drug response

Drug metabolism ex #1: CYP2C29 and Warfarin

• Warfarin is an anticoagulant drug with a narrow therapeutic window

• Large variability in dosage between individuals

• CYP2C9 inactivates warfarin

How can CYP2C9 affect the differences in dosage of warfarin between individuals?

CYP2C9 has many types of alleles and thus genotypes. Some people possess a genotype that causes a complete loss of metabolic activity, which means that it takes much to clear it out and can be dangerous. On the other hand, mot people possess the fully functional genotype which results in fast clearance.

Drug metabolism ex #1: CYP2D6 and antidepressants.

• Highly polymorphic

• Types of metabolizers:

  • Ultra-extensive, extensive, intermediate, poor

• Nortriptyline and amitriptyline

  • CYP2D6 inactivates nortriptyline

  • Nortriptyline is the active metabolite of amitriptyline

1. Predict effectiveness in a patient who is a poor metabolizer?

2. Predict effectiveness in a patient who is an ultra-extensive metabolizer?

3. Predict the impact of unknown CYP2D6 status on the healthcare system? On patient outcomes?

1. Very effective drug but it will cause more ADR since it’s in the system longer

2. Not effective but less ADR

3. Start with standard doses and adjust from there

Drug metabolism ex #2: CYP2D6 and opioids

• Opioids require bioactivation via CYP2D6

  • Prodrug with active metabolites

• Some 2-10% of the population cannot metabolize codeine (resistant to analgesic effects)

Ex case:

• Full-term healthy male infant

  • Uncomplicated delivery

  • Until D7: Intermittent difficulty in breast feeding and lethargy

  • D11: Issues with breast feeding resolved; regained birth weight

  • D12: grey skin; intake fallen

  • D13: baby had passed away

  • Morphine concentration 70 mg/mL (0-2.2 mg/mL typical)

• Mother

  • Tylenol #3 (APAP 500mg/Codeine 30mg) PRN for pain related to delivery

  • Instructed to continue for 14 days following delivery

  • Breast milk morphine concentration 87mg/mL (1.9-20.5 mg/mL typical)

Mother has a very fast metabolizer so there is a high bioactivation rate of codeine. Since there is a high concentration in her breast milk, the baby also has a high morphine concentration after consuming breast milk.

Empiric ABX therapy

• Chosen when an active infection is present, but the causative organism has not been identified

• Goal: To cover all of the most likely organisms causing the infection until culprit is identified

• ABX, antifungals, antivirals

• Choice dependent on:

  • Patient related factors

  • Possible bacterial pathogens’ characteristics

• Role is different with outpatient vs inpatient treatment

Targeted ABX therapy

• Chosen once causative organism has been identified

• Goal: Cover the causative organism while avoiding unnecessary ABX exposure

• Choice dependent on:

  • Patient related factors

  • Causative bacterial pathogen’s characteristics

• Common inpatient

  • After empiric therapy

  • After culture and susceptibly results

Spectrum of activity

Range of microbes that an antibiotic agent inhibits or kills

• Gram-positive vs gram negative

• Atypical pathogens

• Aerobic vs anaerobic

• MDR organisms

Ways to identify causative organisms

• Gram-staining

• Immunologic detection

• Bacterial cultures

• ABX susceptibilities

Minimum inhibitory concentration (MIC)

• Minimum amount of antibiotic conc. to inhibit organism

• If antibiotic conc increases but organisms is still there, it’s a resistant organism

Minimum bactericidal concentration (MBC)

Testing for the lowest concentration of antibacterial drug to get rid of bacterial colonies

Bacteriostatic

Inhibits growth of causative organism but don’t cause direct cell death; immune system will eventually clear the infection

Bactericidal

Actively causes direct cell death in causative organism

ABX Resistance: Anti-ABX protein induction

• Inactivating enzymes (hydrolases, catalases, etc)

• Activating enzyme inhibitors (prodrug ABX)

ABX Resistance: ABX target modification

• Mutations of target site

• Excessive target site

• Loss of target site

ABX Resistance: Limited ABX entry

• Reduced cell membrane permeability

• Loss of porins or active transporters

• Cell wall structure

ABX Resistance: Increased ABX efflux

Induction of ABX efflux pumps (pumping out)

Spectrum of Activity: Narrow-spectrum

Cover a single or limited group of bacteria

Spectrum of Activity: Extended-spectrum

Covers gram-positive bacteria and some gram-positive bacteria

Spectrum of Activity: Broad-spectrum

• Covers gram-positive and gram-negative bacteria

• Activity against a wide range of pathogenic bacteria

ABX MOA: Beta-lactams

• Penicillins, Cephalosporins, Carbapenems

• MOA: Inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), inhibiting peptidoglycan cross-linking

• MOR:

  • Beta-lactamases (hydrolytic enzyme) open the characteristic beta-lactam ring of the antibiotic, rendering it inactive before it can reach its target

  • Efflux pumps

  • PBP mutations

ABX MOA: Beta-lactamase inhibitors

• Addition to beta-lactam ABX

• Extended spectrum

• MOA: Inactivates beta-lactamases by covalently binding and inhibiting their hydrolytic activity

• MOR: Newly resistant beta-lactamases

ABX MOA: Cell wall and cell membrane targets, Aztreonam

• SoA: Narrow

• MOA: Inhibits bacterial cell wall synthesis by binding to PBPs, similar to beta-lactams

• MOR: ESBL production

ABX MOA: Cell wall and cell membrane targets, Vancomycin & Lipoglycopeptides

• Glycopeptide

• SoA: Narrow, Gram-positive

• MOA: Inhibits bacterial cell wall synthesis by binding to peptidoglycan and preventing polymerization

• MOR: Modification of peptidoglycan building blocks

ABX MOA: Cell wall and cell membrane targets, Daptomycin

• SoA: Narrow, gram-positive

• MOA: Inserts into bacterial cell membrane to make a pseudo-pore leading to membrane depolarization and cell death

ABX MOA: Cell wall and cell membrane targets, polymyxins

• SoA: Narrow, gram-negative, last resort ABX

• MOA: Displaces ions from cell membrane, hydrophobic region disrupts cell membrane integrity

• MOR: Cell membrane modifications, efflux pumps

• Narrow therapeutic window

ABX MOA: Nucleic acid synthesis targets, Fluoroquinones

• SoA: Broad

• MOA: Inhibits DNA gyrase or Topo IV, leads to double-stranded DNA breaks and downstream DNA damage

• MOR: Enzyme mutations, efflux pumps, resistance (clinical overuse)

ABX MOA: Nucleic acid synthesis targets, Metronidazole and Nitrofurantoin

• Metronidazole

  • SoA: Narrow, anaerobic

  • MOA: Prodrug reduced to highly reactive metabolites that disrupts bacterial DNA and inhibit nucleic acid synthesis

• Nitrofurantoin

  • SoA: Narrow, UTIs

  • MOA: Prodrug reduced to highly reactive metabolites capable of disrupting bacterial DNA and enzymatic processes

ABX MOA: Nucleic acid synthesis targets, Sulfamethoxazole/trimethoprim

• SoA: Broad

• MOA: Each component inhibits different enzyme in folate synthesis, depleting purine amounts and inhibiting DNA synthesis

• MOR: Enzyme mutation, enzyme induction

ABX MOA: Protein synthesis targets, Macrolides and Clindamycin

• Macrolides

  • SoA: Broad

  • MOA: Reversibly binds the 50s ribosomal subunit to inhibit peptide chain elongation ad protien synthesis

  • MOR: Ribosomal mutations, inactivating enzyme induction, efflux pumps, resistance (clinical overuse)

• Clindamycin

  • SoA: Narrow, gram-positive

  • MOA: Like above

  • MOR: Ribosomal mutations

ABX MOA: Protein synthesis targets, Chloramphenicol and Streptogramins

• Chloramphenicol

  • SoA: Broad, last resort ABX

  • MOA: Like macrolides

  • MOR: Ribosomal mutations, inactivating enzyme induction

  • Narrow therapeutic window

• Streptogramins

  • SoA: Narrow, gram-positive, for resistant infections

  • MOA: Like macrolide

  • MOR: Ribosomal mutations, inactivating enzyme induction

ABX MOA: Protein synthesis targets, Linezolid

• SoA: Narrow, gram-positive, for resistant infections

• MOA: Inhibits formation of initiation complex (tRNA + mRNA), preventing protein synthesis

• MOR: Ribosomal mutations

ABX MOA: Protein synthesis targets, Aminoglycosides

• SoA: Gram-negative, Gram-positive with synergy

• MOA: Disrupts protein elongation by causing inaccurate translation of mRNA template, making inaccurately translated proteins that are truncated/dysfunctional

• Narrow TW

ABX MOA: Protein synthesis targets, Tetracyclines

• SoA: Broad

• MOA: Binds 30S ribosomal subunit at A-site, preventing tRNA binding. so bacterial proteins can’t elongate

• MOR: Ribosomal protection proteins, efflux pumps

Which of the following correctly matches the drug or drug class with an acquired MOR, if used inappropriately?

A. Vancomycin – target modification

B. Cephalosporin – hydrolytic enzyme

C. Metronidazole – target loss

D. Sulfamethoxazole – target induction

E. A and B

F. A, B, C

G: A, B, D

G: A, B, D

Which of the following antibiotics should only be used in empiric ABX regimens when a suspected susceptible pathogen(s) is/are involved?

A. Carbapenems

B. Penicillins

C. Aminoglycosides

D. Polymyxins

E. Linezolid

F.A, D, E

G.All of the above

G.All of the above

Which of the following statements is/are correct? Select all that apply.

A. Bacteriostatic ABX inhibit the growth of bacteria, but bactericidal ABX directly kill bacteria.

B. Time-dependent killing refers to ABX that do not exhibit higher efficacy as ABX concentration increases.

C. Concentration-dependent killing refers to ABX that do not exhibit higher efficacy as ABX concentration increases.

D. Bacteriostatic ABX inhibit the growth of bacteria at the MIC but bactericidal ABX directly kill bacteria at the MIC.

A, B

Time-dependent killing

• ABX do not exhibit higher efficacy as ABX concentration increases

• Optimal effect when concentrations above MIC

• Lower, frequent dosing

Concentration-dependent killing

• Higher concentrations = greater kill

• Post-ABX effect: Persistent suppression of bacterial growth after [ABX] falls under MIC

• Higher, less frequent dosing

Heart failure

• Insufficient cardiac output to meet metabolic demands

  • inadequate contractility

  • Inadequate relaxation

• Increased LV pressure

  • Myocardial ischemia

  • Leads to increased pulmonary capillary pressure

Regulation of heart function: Baroreceptors and chemoreceptors (intrinsic)

• Baro = Pressure/mechanical

• Baroreceptors sense pressure

Arterial baroreflexes

Feeds back pressure information from arteries

Cardiopulmonary reflexes

Feeds back pressure information form heart-lung circulation

Autonomic nervous system (ANS)

• Responsible for subconscious control of organs

  • Heart, blood vessels, eye, bladder, lung

Sympathetic (ANS)

• fight or flight

• Releases Norepinephrine and epinephrine onto target organs

  • Increases blood pressure, shifts blood flow to muscles

Parasympathetic (ANS)

• Rest and digest

• Releases acetylcholine onto target organs

  • decrease heart rate, increase digestive functions

Chronotropy (heart rate)

• Positive: increase heart rate

  • Epinephrine (Symp)

• Negative: decrease heart rate

  • Beta-blockers, digoxin

Inotropic (contractility)

• Positive: Increase strength, helping pump more blood

  • Digoxin, norepinephrine

• Negative: Decrease contraction strength, reducing heart’s workload

  • Beta-blockers, acetylcholine

Norepinephrine (noradrenaline)

Most post-ganglionic sympathetic nerve terminals

Epinephrine (adrenaline)

Adrenal medulla (sympathetic)

Acetylcholine

Post ganglionic parasympathetic nerve terminals

Cholinergic receptors: Nicotinic

• Ligand gate ion channcel

• Skeletal muscle, autonomic ganglia

Cholinergic receptors: GPCR

• Target organs of parasympathetic NS

• Atropine

Alpha adrenergic receptors

• GPCRs: a1 (post synaptic), a2 (presynaptic)

• Inhibitor

Beta adrenergic receptors

• GPCRs: B1, B2, B3

• Epi more potent agonist at B2 receptor

Therapeutic use of Epinephrine

• Cardiovascular emergencies

• Anaphylaxis

• Prolong action of local anesthetics

Therapeutic use of Norepinephrine

Used to raise BP in cardiovascular crisis problems

Sympathomimetic drugs

Drugs that mimic some aspect of sympathetic nervous system stimulation

Stimulation of adrenergic receptors: Inotropic/chronotropic

• Increase BP

• Increase heart rate (B1 agonist)

• Increase vasoconstriction (a1 agonist)

Inotropic agents in cardiovascular disease: Shock states

• Goal: When a patient is in shock, blood pressure drops dangerously low, threatening organ failure.

• Effect: Inotropes squeeze the heart harder to increase blood pressure and restore adequate vital organ perfusion (blood flow to critical organs like the brain, kidneys, and liver).

Inotropic agents in cardiovascular disease: Acute/refractory heart failure

• Goal: When the heart suddenly falls or stops responding to standard treatments, it can’t pump enough blood

• Effect: Inotropes boost cardiac output, which raises BP and organ perfusion

Inotropic agents in cardiovascular disease

• Act very quickly and have a short half life

• Given as continuous IV infusions

IV Inotropic Agents: Beta agonists

• Dopamine, dobutamine, epinephrine

• Stimulate cAMP

IV Inotropic Agents: Alpha agonists

Phenylephrine