ILE 2 EXAM 1

if you failed this exam dont blame me you the one who decided to look at my cards ):

what is the definition of ADME?

An acronym standing for Absorption, Distribution, Metabolism, and Excretion. hese four physiological processes determine the movement of a drug through the body over time

what is the definition of pharmacokinetics

The quantitative, mathematical modeling of ADME over time. What the body does to the drug

what is the definition of pharmacodynamics?

The study of the relationship between drug concentration at the site of action and the resulting pharmacological response or effect. what the drug does to the body

What is the defninition of C_max (Maximum Plasma Concentration)?

The peak concentration of drug achieved in the plasma following administration

what is the definition of T_{max (Time to} C_max)?

The exact time post-dose required to reach peak plasma concentration Cmax

what is the definition of AUC (Area Under the Concentration-Time Curve)?

A plot representing total systemic drug exposure or total extent of absorption over time

what is the definition of V_d (Volume of Distribution)?

A pharmacokinetic parameter representing the apparent volume into which a drug distributes in the body relative to plasma concentration

what is the definition of CL (CLearance)

The volume of plasma cleared of unchanged drug per unit of time through elimination processes (renal, hepatic, metabolic)

what is the definition of 1_1/2 (elimination Half-Life)

The time required for the plasma concentration of a drug to decrease by 50%

what is the definition of K_a(Absorption Rate Constant)?

A rate value reflecting how rapidly a drug moves from its site of administration into the systemic blood supply

what is the definition of absolute bioavailability (F)?

The fraction of an administered drug dose that reaches the systemic blood circulation unchanged

What is the definition of MEC(Minimum Effective Concentration)

the minimum plasma drug concentration required to produce a therapeutic response

What is the definition of MSC (maximum Safe Concentration)

The ceiling plasma drug concentration above which adverse toxic effects occur

what is the definition of therapeutic Range?

The concentration window between the MEC and MSC where efficacy is optimized while avoiding toxicity

what is the definition of drug absorption?

as the movement or transportation of unchanged (unmetabolized) drug from its site of administration into the systemic circulation

Who and Why is the main organ for gastrointestinal drug absorption?

The small intestine serves as the main organ for gastrointestinal drug absorption due to the villi/microvilli giving it immense surface area, a moderate pH environment from 5-7.5, a long transit residence time of less than 3 hours and extensive vascular blood supply.

what is the defintion of transmembrane passive transport?

diffusion driven purely by a concentration gradient across the membranes

What types of drugs use transmembrane passive transport and why?

Most small molecule drugs due to their low molecular weight that is less than 500da and its sufficient ability to dissolve in the GI fluids due to high aqueous solubility

What is the definition of paracellular transport?

A minor passive pathway where small, polar, ionized, water-soluble molecules move through tight junctions between neighboring epithelial cells

what is the defintion of influx transporters (Facilitated or Active transport)

transporters from the SLC family that facilitate or actively drive drug movement from the lumen into the enterocytes and blood

what are examples of transporters from the SLC family?

OATP1A2, OATP2B1, PEPT1, PMAT

what if the definition of efflux transporters (Active Transport)

Energy-dependent pumps from the ABC family ctively pump drugs out of enterocytes back into the GI lumen, limiting systemic exposure

what are examples of transporter pumps from the ABC family

P-glycoprotein/P-gp, BCRP, MRP2

what is the defintion of endocytosis?

A minor absorption pathway of active cellular transport process where a cell engulfs extracellular fluids, macromolecules, or large particles by folding its plasma membrane inward to form an internal vesicle

what types of drugs utilize endocytosis?

Large, lipophilic drugs, vitamins, and specific drug formulation.

explain the mechanisms of solid oral dosage forms such as tablets and capsules

these dosages must go through the sequential step of disintegration into granules/particules and subsequent dissolution in GI fluids before passive membrane permeation can take place

explain the mechanism of liquid oral dosage forms?

since these dosage forms are already in a liquid solution, they bypass the disintegration and dissolution steps entirely and is rapidly absorbed by the body

what are some pre-preparations a suspension dosage form must go through before being used?

Require dissolution of suspended solid drug particles prior to absorption[

define the rate-limiting step

The slowest process among drug release/disintegration, dissolution, or membrane permeability determines the overall rate of absorption (K_a) and peak time (T_max)

explain the mechanism behind immediate release formulations such as metoprolol tartrate

The rate of absorption is governed by the drug's intrinsic dissolution rate, producing a rapid T _{max ​} and higher peak concentration (C _max ​ ) requiring multiple daily doses

explain the mechanism behind Extended-release formulations such as metoprolol succinate

Engineered with rate-controlling polymeric membranes or osmotic systems so that the rate of absorption is governed by the controlled rate of drug release from the tablet, producing a flattened plasma profile that remains within the therapeutic window over 24 hours

explain parenteral/subcutaneous formulations

Structural aggregation states dictate absorption speed from tissue sites

explain the mechanism of intravenous (IV) administration

Drugs are injected directly into the systemic venous circulation. Because the drug enters the bloodstream immediately, there is no absorption phase (F=100%) resulting in an immediate onset of action

explain the mechanism for SC and IM drug administration

Drugs must first diffuse and absorb from the tissue site of injection into local capillaries to reach systemic blood circulation. This creates a delayed onset of action relative to IV, but provides a more prolonged duration of effect

explain why different insulins such as monomeric insulin (lispro) and hexameric insulins (glargine) have different absorption rates despite simular formulations

the size of the molecule effects the insulin association state thus impacting absorption rates. the bigger the molecule, the slower the absorption rate.

how do you calculate Absolute Bioavailability

the areas under the curve of oral administration over the areas under the curve of intravenous administration

$$\mathbf{F = \frac{AUC_{po}}{AUC_{iv}}}$$

how does the GI surface area and anatomy influence absorption of drugs

The small intestine's vast surface area provided by villi and microvilli makes it the principal absorptive organ compared to the stomach

how does gastric emptying and GI motility influence absorption of drugs

Dictates the transit time and exposure duration of the drug at mucosal absorptive surfaces

how does gastric and intestinal pH influence absorption of drugs?

Stomach pH (1–3) versus intestinal pH (5–7.5) influences drug ionization state (pKa) and passive transmembrane diffusion

why does weak basic drugs such as antifungals like ketoconazole or itraconazole depend on stomach pH?

weak basic drugs require an acidic stomach environment to dissolve and absorb properly. If a weak basic drug was co-administered with a proton pump inhibitor, gastric pH will increase, causing sever suppression of dissolution and systemic absorption

what would happen if an acid-labile drug such as certain beta-lactam antibiotics was administered to the stomach environment?

it can be degraded by acidic gastric secretion

how does splanchnic blood flow/ vascularity influence absorption of drugs?

Adequate blood flow maintains sink conditions across the intestinal mucosa to sustain passive diffusion gradients

how does GI transporters and presystemic metabolism influence drug absorption?

Intestinal mucosal CYP3A4 enzymes and active P-gp efflux pumps in enterocytes metabolize or pump out drugs before they reach portal blood

how would fruit juices such as grapefruit influence drug absorption?

inhibit intestinal OATP influx transporters, reducing drug uptake (e.g., fexofenadine)

how does the drug ritonavir influence absorption of drugs?

inhibit intestinal P-gp efflux and CYP3A4 metabolism, significantly boosting the bioavailability of co-administered protease inhibitors

how does bile salts influence absorption of drugs?

it aid in solubilizing of lipophilic drugs

how doesCo-administered cations or resins influence absorption of drugs?

can bind drugs in the GI lumen (e.g., fluoroquinolones chelating with iron; cholestyramine forming insoluble complexes with acidic drugs like NSAIDs or warfarin), preventing absorption

how does disease states and surgical resectioning influence drug absorbtion?

Conditions altering mucosal integrity or surgical procedures like gastric bypass drastically reduce functional absorptive surface area and alter transit time, altering drug absorption profiles

what are intradermal (ID) injections?

Injected shallowly into the dermis layer of the skin (just beneath the epidermis)

what is the absorption and clinical use of ID injections?

Extremely slow systemic absorption with minimal blood flow; ideal for localized diagnostic testing (e.g., tuberculin PPD skin tests) or specific immunizations

what is a subcutaneous(SQ/SC) injection?

Injected into the subcutaneous adipose tissue layer beneath the dermis

what is the absorption provil for SQ injections?

Slower, sustained absorption rate due to lower blood perfusion in adipose tissue compared to muscle. This provides a flattened concentration curve over time

what are intramuscular (IM) Injections?

Injected deep into skeletal muscle tissue underlying the subcutaneous laye

what is the absorption profile IM?

Faster absorption and higher peak plasma concentrations (C_max) than SQ injections because muscle tissue possesses a significantly higher vascular blood supply.

what is the clinical use of IM?

Can accommodate larger volumes than SQ and allows for sustained-release depot formulations (e.g., oil-based suspensions).

where are the injection sites of SQ injections?

Injections target the loose subcutaneous fat matrix:
-Abdomen (at least 2 inches away from the umbilicus)
-Anterior outer thighs
-Posterolateral upper arms
-Upper buttocks/hips

what are some common enteral dosage forms?

solid oral forms such as tablets and capsules and liquid oral forms such as suspensions, syrups, powders, and elixirs

which molecules are able to easily cross the capillary membrane?

small molecules that are <500 Da

which type of molecules are restricted to vascular spaces?

Large molecules greater or equal to 500 Da.

what types of drugs can cross lipid cellular membrames?

lipophillic, non ionized drugs

what types of drugs remain in the extracellular fluids?

polar, ionized drugs

why does organs such as the brain, liver, heart and kidneys receive drugs rapidly within minutes?

these organs are highly, perfused, thus able to absorb drugs more rapidly

why does fat, bone, and skin take hours to receive drugs in in circulation?

These organs have poorly perfused tissues, thus taking longer to achieve distribution equilibrium

explain the structure of continuous capillaries in skeletal muscles and the blood-brain barrier

Tight junctions limit drug access to passive lipophilic diffusion or active transport

explain the structure of fenestrated capillaries that are found in the renal glomerulus and GI mucosa

Pores allow rapid passage of small polar drugs

explain the structure of the discontinuous capillaries found in the liver and bone marrow

Large gaps allow unrestricted movement of most plasma components and drugs

what is reversible equilibrium?

Only free (unbound) drug is pharmacologically active and capable of diffusing across capillary membranes into tissues

what are the key plasma proteins?

albumin, alpha 1 acid glycoprotein and lipoproteins

acidic and neutral drugs binds to what kind of plasma proteins?

albumin plasma proteins

basic drugs such as propranolol and lidocaine binds to which plasma proteins?

alpha 1 acid glycoproteins

lipophilic drugs binds to what plasma proteins?

lipoproteins

explain the concept of high protein binding?

Traps drug in the vascular compartment, slowing distribution and prolonging half-life. However, active tissue transport can outcompete plasma binding

explain the concept of competitive displacement

f Drug B displaces highly bound Drug A from albumin, the free active concentration of Drug A can spike drastically, potentially causing severe toxicity

explain the function of efflux active transport pumps

pumps such as P-gp and BCRP pumps drugs out of tissues such as the brain

explain the function of influx active transport pumps

transporters such as OAT and OCTs draw drugs into the surrounding cells

explain pH partitioning with basic drugs

basic drugs tend to accumulate in acidic tissue compartments whenever the pH of the plasma is higher than the tissues (pH tissue<pH plasma)

explain pH partitioning with acidic drugs

acidic drugs accumulate in alkaline compartments whenever the pH of the tissue is greater than the pH of the plasma (pH tissue > pH plasma)

what is the mathematical formula for volume of distribution

$$V_d = \frac{\text{Total Amount of Drug in Body}}{\text{Plasma Drug Concentration}}$$

what does it mean when there’s low Vd (<20 L)

Indicates the drug is heavily confined to blood plasma and extracellular water (e.g., amoxicillin, aspirin; highly polar or strongly plasma protein bound)

what does it mean when there’s high Vd (>50 L)

Indicates the drug extensively distributes out of plasma into deep tissue reservoirs and intracellular fluid (e.g., digoxin = 640 L, imipramine = 1050 L)

how does a drug pass as efficacy therapy for a patient?

free drug must achieve concentrations exceeding the Minimum Effective Concentration (MEC) at the target site of action. (e.g., crossing the blood-brain barrier for CNS disorders, or accumulating in lung tissue for pneumonia/asthma)

explain the adverse event in off-target distribution

Drug distribution into non-target tissues triggers side effects (e.g., distribution across placental/fetal membranes causing teratogenicity, or into breast milk affecting a nursing infant)

explain the adverse events during organ accumulation

Drug accumulation in eliminating organs (liver, kidney) can lead to direct organ toxicity

explain the adverse events during protein binding interactions

Drug-drug competition for plasma protein binding sites can instantly convert a safe maintenance dose into a toxic free plasma level

what types of drugs are able to cross cell membranes into tissue spaces?

Free, unbound, drug fraction

what does plasma proteins such as albumin effect systemic distribution?

plasma proteins cause restriction on systemic distribution

how does high binding proteins effect systemic distribution?

these proteins draws drugs out of the blood into deep tissue reservoirs

how does capillary membranes structure and transporters regulate drug penetration?

Tissue-specific barriers (such as tight junctions in the Blood-Brain Barrier versus porous sinusoids in the liver) and regional efflux pumps (e.g., P-glycoprotein) tightly regulate drug penetration into target organs

how does the physiological and pathological state of a patient effects distribution of drugs within the body?

Alterations in body composition (e.g., increased adipose tissue in obesity), fluid shifts (edema or dehydration), hypoalbuminemia, pregnancy, and surgical resections significantly alter the drug's apparent volume of distribution (V_d)

how does targeted delivery and systemic toxicity affect safety and efficacy of a medication?

Selecting the appropriate dosage form allows clinicians to maximize therapeutic efficacy at the target site while minimizing off-target adverse effects elsewhere in the body

how does the oral delivery of vancomycin capsules affect the safety and efficacy of the medication?

oral vancomycin is not absorbed systemically due to it being a large, polar molecule with not active transport mechanims in the intestines. This lack of absorption is utilized intentionally to safely achieve extremely high drug concentrations localized inside the GI lumen to treat Clostridium difficile colitis without systemic toxicity

how does the intravenous (IV) delivery of vancomycin capsules affect the safety and efficacy of the medication?

Because oral vancomycin cannot enter blood circulation, systemic bacterial infections (e.g., MRSA bacteremia or pneumonia) must be treated with IV vancomycin to ensure the drug reaches systemic circulation and deep tissue sites

what is the mechanism behind phase 1 reactions (Non-synthetic phase)

Introduces or unmasks polar functional groups (e.g., −OH, −NH 2 ​ , −SH) on the drug molecule via oxidation, reduction, or hydrolysis

what are the key enzymes that are related to phase 1 reactions?

cytochrome p450 monoxygenases, CYP3A4/5, Esterases, Monoamine Oxidase (MAO), Alcohol Dehydrogenase (ADH) and Flavin-Containing Monooxygenases (FMO)

what is the mechanism of action behind phase II reactions (Synthetic/Conjugation Phase)?

Attaches an endogenous, highly polar moiety (such as glucuronic acid, sulfate, amino acids, or glutathione) to the parent drug or its Phase I metabolite to make it water-soluble for renal or biliary excretion

what are the key enzymes that are related to phase II reactions?

Uridine Diphosphate-Glucuronosyltransferase (UGT—the most abundant Phase II enzyme), Sulfotransferase (ST), N-Acetyltransferase (NAT), and Glutathione S-Transferase (GST)

explain how drug inactivation occurs during the metabolism of drugs

The active parent drug is converted into an inactive metabolite that no longer binds to target receptors and is rapidly excreted (e.g., Phase I hydroxylation and Phase II glucuronidation of Naproxen)

explain how drug activation(prodrugs) occurs during the metabolism of drugs

A biologically inert parent molecule is engineered to undergo enzymatic cleavage in the body to release the pharmacologically active drug

what are prodrugs?

they are deisgned to improve GI stability enhance oral permeability, or prevent local GI irritation