Exam 1 Pharm COMBINED

Pharmacodynamics vs. Pharmacokinetics

Pharmacodynamics: what the drug does to the body; the study of the biochemical and physiological effects of drugs and their mechanisms of action

Pharmacokinetics: what the body does to the drug; the study of the absorption, distribution, metabolism and excretion of drugs.

Define Pharmacogenomics

Study of genomic influence on drug response and side effects

Therapeutic action vs Toxic Action

Therapeutic action: the dosage at which the drug reaches its desired effect

Toxic action: the dosage at which an undesirable effect occurs; can be due to supra-therapeutic doses, genetic predispositions, inappropriate use, non-selective actions

Pharmacognosy

The study of drugs that come from plant and animal sources, alternative medicine

Drug Development Phases

• Phase 0: the first clinical trial where sub-therapetic doses are administered to 10-15 people for a limited duration <7 days

• Phase 1: drug is tested on 20-100 healthy and diseased individuals to test for efficacy, side effects, optimal dose and safety

• Phase 2: Trial conducted on several hundred individuals with the disease to test for efficacy and side effects

• Phase 3: Designed to assess the drug’s efficacy compared to the gold standard in 300-3000 individuals

• Phase 4: FDA tests the drug on hundreds to thousands of patients

The Ideal drug must have what characteristics

• Specific size, shape and charge to be able to interact with a specific receptor

• The necessary properties to travel to the site of action

• The ability to be easily inactivated and excreted by the body

Very small drug vs Very Large drug

Very small drug results in poor selectivity while a very large drug has poor absorption and distribution

• Ex. Alteplase is way too big to be distributed so it has to be directly distributed to the vascular compartment

You want it not big, not small, just right; goldilocks

What role do the types of bonds play in pharmacodynamics?

• Covalent Bonds: strong and stable/irreversible

  • Used when you want the drug to be long-acting and with broad effects

• Electrostatic: weaker than covalent but reversible (most used)

  • Used when you want a short and specific effect

• Hydrophobic: weakest

Explain the nature of drugs relating to Enantiomers

R vs S configurations may have different effectiveness

• Warfarin S is bioactive and Warfarin R is less active

4 Stages of Pharmacokinetics

• Absorption

• Distribution

• Metabolism

• Excretion

Types of Permeation Mechanisms

• Aqueous diffusion: water soluble drugs diffuse through aqueous pores, governed by Fick’s Law

  • The more ionized, the more water soluble

• Lipid diffusion: lipid soluble molecules move through the membrane

  • The greater partition coefficient the greater lipid solubility and faster diffusion

  • The less ionized (neutral), the more lipid soluble

• Carrier-mediated Transport: for molecules that are too large or lipid insoluble, a carrier or transmembrane protein/channel will help it get through

  • Passive through concentration gradient

  • Active when it uses ATP directly to carry against the concentration

• Exocytosis

Fick’s Law of Diffusion

• Rate of diffusion is directly proportional to the concentration of the substances on both sides → gradient moves from high concentration to low concentration

• Drugs are absorbed faster from organs with large surface (ex/ Intestines) areas and thinner membranes

Degree of Ionization

• An acid in an acidic environment favors ______, while an acid in an alkaline environment favors ________.

• A base in a basic environment favors _______, while a base in an acidic environment favors ________.

Degree of Ionization

• An acid in an acidic environment favors absorption, while an acid in an alkaline environment favors excretion.

• A base in a basic environment favors absorption, while a base in an acidic environment favors excretion.

Henderson-Hasselbalch Equation

• Ion trapping

FOR WEAK BASE → pH-pKa = log Un-ionized/ Ionized

FOR WEAK ACID → pH-pKa = log Ionized/ Unionized

• Ion trapping: we make the environment the opposite of the drug so it can be excreted

  • Ex. methamphetamine (basic) can be forced to be excreted by making the urine very acidic, which stops reabsorption

Multidrug Resistance Protein Type 1 (MRP1)/ P-Glycoprotein

A very common drug transporter that pumps drugs out of the cell (REVERSE TRANSPORT and uses ATP)

• Used by fetus to transport drugs back into maternal blood

• Intestines use it to transport drugs into intestinal lumen

• Brain limits access to brain-blood barrier by pumping back into circulating blood

• Cancer cells use it to pump chemotherapy drugs out of the cell

In regards to ion trapping

• ______ ______ is used to alkalinize urine in patients presenting with a weak acid overdose

• ______ ______ is used to acidize urine in patients presenting with a weak acid overdose

In regards to ion trapping

• Sodium Bicarbonate is used to alkalinize urine in patients presenting with a weak acid overdose

• Ammonium Chloride is used to acidize urine in patients presenting with a weak base overdose

Endocytosis and Exocytosis

Endocytosis: transport of solid matter or liquid into the cell utilizing a coated vacuole or vesicle

Bioavailability and ROA

• The fraction of the administered dose that reaches the systemic circulation following administration by any route

• Bioavailability may be different depending the Route of Administration (ROA)

  • IV has the highest (100%) bioavailability

ROA Classification

Systemic:

• Enteral: directly into the digestive tract

  • oral, sublingual, and rectal

• Parenteral:

  • Transdermal or Injections (IV, IM, SC, IT)

Topical/Local

• Skin, eye, mucosa, inhalational

First Pass Effect

The reduction of bioavailability of the administered dose due to metabolism by the gull wall enzymes and liver

ROA: Oral (PO)

• Advantages

• Disadvantages

Absorption can occur at any point of the digestive tract but must cross the digestive and vascular endothelium

• Advantages: safe, most convenient and economical

• Disadvantages: limited absorption, destruction of drug by digestive enzymes, first pass effect, patient compliance

ROA: Sublingual (SL)

• Advantages

• Disadvantages

Absorption occurs through oral mucosa under tongue (or buccal route)and goes into blood

• Advantages: fast absorption, avoids first pass effect

• Disadvantages: limited to certain drugs, may lose effect if swallowed, irritation on site

ROA: Rectal (PR)

• Advantages

• Disadvantages

Rectal suppository

• Advantages: Less first pass effect than oral, ideal for comatose or vomiting patients

• Disadvantages: erratic and variable absorption, irritation

ROA: Intravenous (IV)

• Advantages

• Disadvantages

Absorption not required, goes into circulation right away

• Advantages: most rapid onset, ideal for large doses, emergencies, noncompliant patients

• Disadvantages: May increase adverse effects, Must be slowly injected, aseptic techniques needed, unsuitable for oily substances

ROA: Intramuscular (IM)

• Advantages

• Disadvantages

Injected into a muscle

• Advantages: ideal for moderate volumes of a drug, good for self-administering patients, suitable for oily vehicles and irritants

• Disadvantages: can cause intramuscular hemorrhage and contraindicated in anticoagulant

ROA: Subcutaneous (SC)

• Advantages

• Disadvantages

Injected below dermis, the hypodermis

• Advantages: suitable for slow release drugs and poorly soluble suspensions

• Disadvantages: smaller volumes administered and may be painful

ROA: Transdermal

• Advantages

• Disadvantages

Placed on top of the skin in like a patch

• Advantages: avoids first pass effect, convenient duration of administration, convenient and painless

• Disadvantages: some are allergic

ROA: Inhalational

• Advantages

• Disadvantages

ROA: Inhalational

• Advantages: avoids first pass effect, rapid onset, less systemic side effects

• Disadvantages: route for abuse, effect dissipates quickly

ROA: Mucosal

• Sites

• Sites: nasopharynx, oropharynx, vagina, urethra

• ROA: Ocular

Very difficult to have good bioavailability because there are many ways to absorb the drug

Pharmacogenomics vs Pharmacogenetics

• Pharmacogenomics: study of variations in the whole genome (DNA and RNA) as related to drug response

• Pharmacogenetics: study of variations in DNA sequence of 1-2 genes as related to drug response

Intracellular receptors

• Define

• Example

Intracellular receptors have lipid-soluble ligands that can cross the cell membrane to bind the receptor (proteins, NA, enzymes such as guanylyl cyclase, transcription factors)

• Ex: Glucocorticoid/steroid receptor that needs heat shock protein (hsp90) to cross the membrane

Ligand-regulated enzyme receptors

• Define

• Usually the receptors have what kind of activity

• Example

Ligand-regulated enzyme receptors have the ligand bind the extracellular domain of the transmembrane protein and trigger a reaction within the cytoplasmic domain

• Usually they are tyrosine kinases

• Ex. the Epidermal Growth Factor Receptor (EGF) and the Insulin receptor

Tyrosine kinase associated receptors/Cytokine receptors

• Define

• Example

Tyrosine kinase associated receptors are transmembrane proteins whose cytoplastic domain is associated with tyrosine kinase units

• Ex. Cytokines act as the ligand to the receptor and the receptor activates the JK STAT pathway of the tyrosine kinase

Receptors linked to ion channels

• Define

• Examples of endogenous ligands that bind to this type of receptor

Receptors linked to ion channels are those that are ligand gated, voltage gated or 2nd messenger regulated and only open by changing conformation once it binds the ligand

• Ex. Acetycholine, GABA-A, Glycine, Glutamate (not adrenergic or muscarinic)

G- coupled Receptors

• Define

• Example

G-coupled receptors are the most abundant transmembrane receptor in humans, these receptors have a membrane subunit and a G protein attached to the cytosolic component, once the ligand binds to the outside, the G protein becomes activated and causes an effect inside

• Alpha-1 adrenergic (NE) receptor is coupled to Gq protein and increases Phospholipase C, which stimulates DAG 2nd messenger

  • Causes Vasoconstriction

• Beta-1 adrenergic (NE) receptor and Histamine-2 receptor are coupled to Gs proteins and increases Adenylyl cyclase, which stimulates cAMP 2nd messenger

  • Causes contraction of heart

Define

• Signal Transduction

• Desensitization

  • Ex.

• Tachyphylaxis

  • Ex

• Pharmacodynamic Tolerance

• Signal Transduction: A chemical message sent that leads to a physiologic response

• Desensitization: when the receptor response to a drug decreases due to being given continuously or repeatedly

  • Can be due to receptor downregulation, loss of function or reduction in receptor density

• Tachyphylaxis: rapid and reversible decrease in receptor responsiveness

  • Ex. Nitroglycerin for angina

• Pharmacodynamic Tolerance: seen in chronic drug abuse, a gradual decrease in receptor responsiveness, resulting in a higher dose needed for the same magnitude effect

Define

• Affinity

• K_D

• Fractional Occupancy

• Affinity: the ability of a ligand [L] to bind its receptor [R] and become [LR]

• K_D : Equilibrium dissociation constant that quantifies affinity, defined as the concentration at which 50% of the receptors are bound to ligand [LR]

  • The lower K_D, the greater affinity

• Fractional Occupancy: the percentage of occupied receptors [LR] compared to the total amount of receptors

  • [LR] / { [R] + [LR] } or B / Bmax

Ps: sigmoidal = cooperativity

Graded Dose Response

• Define

• EC₅₀ / ED₅₀

• E_max

• Potency

• Efficacy

Graded Dose Response: the effect of various doses of a drug in a single individual

• EC₅₀ / ED₅₀: The concentration or dose at which half the maximal response is produced

• E_max: the maximal response

• Potency: measure of strength, the concentration needed to reach EC₅₀ / ED₅₀

• Efficacy: The ability of a drug to produce a biological response; an index of the maximal response E_max

Quantal-Dose Response

• Define

• ED₅₀

• TD₅₀

• TI

Quantal-Dose Response: the concentrations of a drug that produces a certain effect in 50% of the population

• ED₅₀: Effective dose, the dose at which 50% of the population receives a therapeutic effect

• TD₅₀: Median Toxic dose, the dose at which 50% of the population receives toxic effects

• TI: Therapeutic index, the distance between ED₅₀ and TD₅₀, you want it to be as high as possible → TI = TD₅₀/ED₅₀

Agonist Classifications

• Full agonist: Binds and stabilizes the active state of the receptor (Ra)

• Partial agonist: Binds and stabilizes the active state of the receptor (RA) but at a lower maximal response than a full agonist at a similar receptor occupancy

• Inverse agonist: Binds and stabilizes the inactive state of the receptor (Ri), thus producing the opposite effect of a full agonist

Antagonist Classifications

Receptor antagonists: bind receptor and stabilize Ra and Ri equally, thus creating a constitutive state

• Active site binding antagonists:

  • Reversible antagonists (competitive): can be overcome by increasing agonist concentration → ED50 (potency) decreases, shifting curve to the right, but Emax (efficacy)stays the same

    

  • Irreversible antagonists (non-competitive): binds to the receptor active side via covalent bond; antagonist cannot be outcompeted by increasing concentration → Emax (efficacy) decreases while ED50 (potency) stays constant unless spare receptors are present

  

• Allosteric site binding (non-competitive): bind somewhere other than the active site and inhibits agonist → Emax ((efficacy) decreases while ED50 stays constant

Non-receptor antagonists:

• Chemical antagonist: a drug or endogenous ligand that interacts with another drug to block its activity

• Physiologic antagonist: blocks the activation of a receptor by an agonist

Spare Receptors

• what does it mean for the Kd vs EC50

Receptors that do not have to be occupied to achieve maximal effect

• EC50 < Kd implies less than 50% of the receptors are needed for a half maximal response

Intrinsic activity (IA)

• Define

• Difference between antagonist and agonist IA

Intrinsic activity (IA): the ability of drug-receptor complex to produce functional response

• Agonists have both affinity and IA, but antagonists only have affinity

• Full agonist IA = 1, Partial agonist IA >0 but <1, Inverse agonist IA = -ve

Define the following

• Additive effect

• Synergism

• Potentiation

• Additive effect: two drugs that when taken together are equal to the sum of the effects of the two drugs taken separately → 1 + 1 = 2

  

• Synergism: The effect of two drugs taken together is greater than the sum of their separate effect at the same doses → 1 + 1 = 4

• Potentiation: a drug that by itself has no effect can potentiate another drug when taken together → 0 + 1 = 2

60/40/20 Rule

Estimates the volume of fluid in each body compartment based on total body weight

• 60% of total weight → total body water

• 40% of total weight → intracellular fluid (ICF)

• 20% of total weight → Extracellular fluid (ECF) → 75% interstitial and 25% intravascular

Drugs are absorbed faster from organs with large ______ _____ and ________ membranes

Drugs are absorbed faster from organs with large surface areas and thinner membranes

1st Pass or Pre-systemic Metabolism

Process through which ORAL drugs lose most of their bioavailability due to pre-systemic metabolism by the gut wall or liver

Bioavailability

The fraction of the given dose that reaches the systemic circulation following administration by any route

Bioavailability of Major Routes of Administration

• Intravenous

• Intramuscular

• Subcutaneous

• Oral

• Mucous membranes

• Rectal

• Inhalation

• Transdermal

• Sublingual

• Intravenous 100%

• Intramuscular 75-99%

• Subcutaneous 75%-99%

• Oral 5-99%

• Mucous membranes ECTREMELY LOW

• Rectal 30-99%

• Inhalation 5-99%

• Transdermal 80-100%

• Sublingual EXCELLENT

Factors Affecting Oral Drug Absorption

• Blood flow to the area, the more the better absorption

• Gastric emptying time; can be increased by gastric stimulants, fatty foods, anticholinergic drugs and pyloric stenosis

• pH of gut: affects ionization and stability of drug

• Food particles that trap drug molecules

• Surface area and thinness of area increases absorption

Factors Affecting Drug Distribution

1. Drug binding to plasma or tissue proteins decreases distribution and excretion

2. Storage of lipophilic drugs in ADIPOSE TISSUE

3. Blood flow to tissues and organs

4. Physical properties

5. Chemical properties: hydrophilic vs lipophilic

6. Capillary permeability

7. Ionization

Describe how plasma protein binding affects distribution

• Why is this no longer an issue in MOST cases

Plasma protein binding such as albumin traps drug molecules in the vascular space and prevents them from reaching the site of pharmacologic action, as well as decreases clearance

• Not an issue anymore because plasma protein # far exceeds #drug molecules → also as free drug increases so does clearance

  • Only a problem if drug clearance is greatly decreased due to kidney or liver disease OR if displaced drug has low TI

Describe Capillary Permeability in terms of drug acess

• Liver endothelial cell junctions vs Brain endothelial cell junctions

• Endothelial cells lining blood vessels in the liver have large fenestrations that allow free movement of substances between the blood and the interstitium

• Blood vessels in the brain have endothelial cells with very tight junctions that only allow high lipid solubility substances to pass the BBB

Explain how redistribution terminates drug action

While the drug may distribute initially to one place to have a pharmacological effect, redistribution to other tissues can terminate the effect

• Ex. Thiopental acts rapidly crossing the BBB and causes anesthetic effect, but then it redistributes to muscle, fat, etc and the patient wakes up because the brain concentration decreased

Volume of Distribution formula

Volume of Distribution (Vd) = Dose (D) / Plasma Concentration (Cp)

Xenobiotics

• Define

• How do drugs relate

• Hydrophilic vs. Hydrophobic

• Compounds foreign to the human body, we are exposed to them every day

• Drugs are xenobiotics so they are metabolized by the same enzymes the body uses to get rid of foreign compounds

• Hydrophilic xenobiotics undergo renal or biliary excretion, while lipophilic require metabolism by liver enzymes to become more hydrophilic

Describe the two main organs of elimination

• Kidney: eliminates drugs with polar functional groups such as OH, SH, NH3 and drugs ionized/charged at physiological pH

  • Lipophilic drugs filtered by the glomeruli are not excreted, they are reabsorbed

• Liver: biotransforms drugs from lipophilic to more polar metabolites

Biotransformation

The process of biochemical reactions transforming drug molecules into inactive, less toxic and more polar metabolites

• Starts after drug is absorbed systemically but before it is eliminated

• Occurs before absorption by gut wall enzymes or on 1st pass through liver

3 Different ways biotransformation alters a drug

• Most cases: active drug is inactivated and converted into more water soluble metabolites

• Some cases inactive drug (pro drug) is activated

• Some cases active drugs are converted into other active or toxic metabolites

Phase I

• Phase I: Functionalization reaction

  • Polar groups are added or hydrolysis reactions expose them or ester linkage

  • Metabolites are excreted in urine, but very slowly

  • Mainly oxidation, reduction, deamination and hydrolysis

Cytochrome P450 Enzyme System (CYP)/ Microsomal enzyme oxidizing system (MEOS)

• Define

• Net reaction

• Phase I P450 Oxidation

• CYP P450 Nomenclature

• System of drug metabolizing enzymes that are found in lipophilic membranes of of the smooth ER of the liver and other tissues

• Net reaction:

  RH (drug) + H⁺ + O₂ + NADPH → NADP⁺ + H₂O + ROH (oxidized drug)

• Phase I P450 Oxidation: constitute about 95% of all phase I oxidation rxns by CYP

  • Not very selective, metabolize thousands of drugs

• CYP P450 Nomenclature:

  • 1st number: family

  • Capital letter: subfamily

  • 2nd number: specific enzyme

CYP P450

• Most abundant type, what does it do

• 2nd most important

• 34A is the most abundant, it is found in the liver but also in the gut wall, where it can decrease bioavailability; metabolizes 50% of Rx drugs

  • Drugs that inhibit/induce 3A4 may also induce/inhibit P-glycoprotein bc they are on the same chromosome

• 2D6 is the second most abundant

Inducers vs. Inhibitors of CYP 450

• Define

• Decrease or increase active drug?

• What must clinician do with the dose?

• Inducers: Increase P450 gene transcription or prevent degradation, which will decrease the amount of active drug

  • Clinician must increase dose

• Inhibitors: Competitively or non-competitively bind to active P450 and decreases its activity, thus increasing the amount of active drug in the system

  • Clinician must decrease dose

Grapefruit Juice (GJ) Facts

• Contains furanocoumarin, an irreversible inhibitor of CYP 3A4 in the gut

• Reduces pre-systemic metabolism and increases drug bioavailability

• Contraindicated with many drugs by the manufacturer regardless route of administration

Substrates, Inducers and Inhibitors of each CYP 450 enzyme

Non-CYP Phase I Oxidations

• Monoamine oxidase rxs: oxidative deamination of monoamines

• Xanthine oxidase: oxidoreductase catalyzes the oxidation of purines

• Alcohol and aldehyde dehydrogenase: oxidation of alcohols and aldehydes

Phase I can also activate drugs, how is this useful

Drug companies may use pro-drugs that are activated by phase I reactions in order to improve bioavailability

Phase II Reactions

• Define

• What kind of reactions are they

• Examples of Transferases and Endogenous reactants for these conjugations

• Usually follows phase I, but not always, some drugs skip phase I and go directly to phase II

• Mainly conjugations that bring together 2 molecules into 1using energy and drastically increase solubility

• Ex of Trans and End reactants:

  • UDP glucuronosyltransferase (UGT) and UDP glucoronic acid

    • MOST COMMON

  • N-acetyltransferase (NAT) and Acetyl CoA

Phase II Conjugation of 4-OH-Phenytoin

• Phase I: Phenytoin → 4-OH-Phenytoin )slightly soluble)

• Phase II: 4-OH-Phenytoin + UPD glucuronyltransferase (UGT) → Very soluble compound

Some Phase II Reactions Precede Phase I

• Due to the compound already being slightly soluble

• Most lead to inactivation but sometimes some can lead to activation

  • Ex: morphine → morphine-6-glucoronide (more active)

Clinical Applications of Inducer and Inhibitors that can be beneficial

• Ritonavir: inhibits 3A4 and can be used as booster to increase bioavailability of a substrate drug

• Phenobarbital: inducer of UDP UGT in newborns with unconjugated hyperbilirubinemia, it conjugates it and eliminates it, prevents kernicterus

Explain how acetaminophen (APAP/Tylenol) can form toxic metabolites

Acetaminophen can be metabolized either by 34A or 2E1 but 10% can convert into toxic metabolite NAPQI which is toxic to hepatocytes

• Excessive doses of Tylenol causes enzymes to be saturated and therefore more of NAPQI is produced

• Alcohol consumption also increases production of NAPQI

• Toxicity reversible within 8 hrs of reaching ER and being administered

Genetic Polymorphisms

• In regards of drug effects

• Genetic mutations with an incident of 1% in the population

  • Defects cause either too little or too much of the drug

  • Resemble drug interactions

• Examples

  • N-acetyl transferase enzyme deficiency:

    • Slow acetylators accumulate INH, which is a competitive antagonist of B6, causes Peripheral Neuropathy

    • Fast acetylators produce too much Acetylhydrazine, which is hepatotoxic

      

  • Butyrylcholinesterase deficiency:

    • Defective ester hydrolysis causes decreased metabolism of succinylcholine (anesthetic), which can cause apnea after surgery

  • Acetaldehyde dehydrogenase:

    • Defective aldehyde dehydrogenation can cause decreased metabolism of ethanol, causing flushing and hypotension

1st order kinetics vs Zero order kinetics

1st order: Drug concentration decreases by the same proportion per unit of time → Half life is a constant of 1st order kinetics

Zero order: Drug concentration decreases by the same amount but not the same proportion, thus the half life is constantly changing

• Ex. Aspirin, Ethanol and Phenytoin

Phenytoin and Gabapentin as an example of Mixed order kinetics

• Phenytoin: follows 1st order kinetics until a specific threshold where enzymes become saturated and then it becomes zero order

  • At threshold, the concentration keeps going up regardless of the dose of the drug

• Gabapentin: follows 1st order kinetics at low doses then zero order is evident due to saturable absorption (gut transporter is saturated) and then serum concentration does not increase regardless of dose

Drug elimination occurs due to 3 processes

• Liver Metabolism

• Excretion removes active or inactive metabolites

• Clearance by renal system

Drug excretion occurs in 3 ways

• Renal, Biliary or fecal → can also be lungs, breast milk or sweat tears etc

Renal excretion

1. Glomerular filtration

2. Tubular secretion

3. Tubular reabsorption

   • Amount of drug entering depends on GFR, Cp, Extent of bound protein

What does low Vd vs high Vd mean

Vd = D/ Cp

• High Vd means the drug is mostly in the extravascular compartments

• Low Vd means the drug is mostly in the vascular compartment, likely tightly bound to plasma proteins

Clearance

• Formula

• Used to determine

The removal of the drug by the body

• Clearance (Cl) = rate of elimination of a drug / Plasma drug concentration (Cp)

• Used to determine maintenance dose

Bioavailability 2 Formulas

Bioavailability (F) = AUC (non-IV) / AUC (IV)

Bioavailability (F) = Dose (IV) / Dose (non-IV)

• Bioequivalence studies compare two drugs (generic : innovator) and considers:

• Two drugs are Bioequivalent IF:

Bioequivalence studies compare two drugs (generic : innovator) and considers:

• Same ROA

• AUC

• Pharmacokinetic parameters such as Peak plasma concentrations (Cmax) and Time to Peak (Tmax)

  • Cmax and AUC most important and must be +-20% of branded drug

  • FDA requires 90% confidence interval of the AUC and Cmax ratios to fall between 80% and 125% of the branded drug

Two drugs are Bioequivalent IF:

• They are pharmaceutically equivalent

• Display comparable bioequivalence, peak plasma concentration and time to peak concentration

  
  

Steady State Concentration (Css)

Achieved when the dosing rate = clearance/rate of elimination

Css = rate of infusion / clearance (Cl)

Steady State (Css) 2 Rule of thumbs

1. At least 4 half-lives must elapse after starting a dosing regimen before full effects are seen and 90% of Css is reached

   • 1 hl = 50% Css

   • 2 hl = 75% Css

   • 3 hl = 87.5% Css

   • 4 hl = 93.75 %hl

   • 5 hl = 97% Css

2. At least 5 half-lives must elapse before functional elimination is reached

Single dose vs. Continuous dose

• Single dose: has more fluctuations in concentration between doses, may be riskier if the therapeutic window is small

• Constant: continuous injections or IV, safest and the best way to keep drug at target concentration

Loading dose vs Maintenance dose

• Loading dose is the initial higher dose used to achieve the target concentration

• Maintenance dose is the lower dose given to maintain steady state within the Therapeutic Window

Maintenance dose equation

Maintenance Dose = Dosing rate x Dosing Interval

• Dosing rate IV = CL x (Cp or TC OR Css)

  • Bioavailability (F) oral = Dosing rate IV / Dosing rate oral

Dose adjustment calculation

Corrected dose = Average x creatine clearance/100 mL/min

Reasons for Therapeutic drug monitoring

• Monitoring drugs with narrow therapeutic indices

• Monitoring drugs with marked pharmacokinetic variability

• Optimize therapy, especially if there is no easy marker for efficacy

• Drugs known to cause adverse/toxic effects

• Assessing patient compliance in taking medications