Seasons LG Wk3 LO's pt.4

Intro to Pharm

Background context (definitions)

• pharmacology

• pharmacokinetics

• pharmacodynamics

• toxicology

• pharmacogenomics

• Pharmacology: the study of drugs and their properties

• Pharmacokinetics: the study of Absorption, Distribution, Metabolism, and Elimination (ADME) aka body effect on drug

• Pharmacodynamics: the study of the actions of chemicals on the organism aka drug effect on body

• Toxicology: the study of the harmful effects of drugs (shoutout Dr.Dyer)

• Pharmacogenomics: relation of personal genetics to drug response

Background context: Pharmacokinetics ADME

• describe what ADME stands for

• Absorption

• Distribution

• Metabolism

• Excretion

Background context: Pharmacokinetics ADME

• Absorption what it is

• when is it bypassed

• Absorption — a drug's ability to pass through barriers such as the intestinal lining, nasal lining, lungs, or skin

• Absorption is BYPASSED when drugs are administered intravenously

Background context: Pharmacokinetics ADME

• distribution what it is & how drugs are distributed

• Distribution — how the drug is distributed around the body and its propensity (natural inclination) to accumulate in certain tissues and organs

• Drug is distributed by blood plasma

Background context: Pharmacokinetics ADME

• metabolism what it is & what organ is it usually done by

Metabolism — how the body breaks down the drug, normally done by the liver

Background context: Pharmacokinetics ADME

• excretion what it is

• what is half-life

• Excretion — the rate and process by which a drug exits the body

• Half-life (t½): the time it takes for a drug's active substance in your body to reduce by half

LO 1: what does the route of administration determine

The chosen route of administration determines how quickly the drug reaches the systemic circulation and how much of it remains active after passing through the body’s initial metabolic barriers.

LO 1: absorption routes of administration

• what is absorption

• enteral route: 2 types & what they are, type of metabolism the drugs face

• Absorption: the process whereby a drug enters the circulatory system

• Enteral Routes: These involve the gastrointestinal (GI) tract.

  • Oral (PO): The most common route; drugs are swallowed and absorbed through the intestinal walls. These drugs face first-pass metabolism, where the liver may deactivate up to 90% of the drug before it reaches the bloodstream.

  • Rectal: Used when oral is not possible; it partially bypasses first-pass metabolism.

LO 1: absorption routes of administration

• what is first-pass metabolism

first-pass metabolism, where the liver may deactivate up to 90% of the drug before it reaches the bloodstream.

LO 1: absorption routes of administration

• parenteral: types & what they are, bioavailability

Parenteral Routes: These bypass the GI tract entirely via injection.

• Intravenous (IV): Injected directly into the vein, resulting in 100% bioavailability (F = 1) because absorption is bypassed.

• Intramuscular (IM) & Subcutaneous (SC): Injected into muscle or under the skin; these require absorption into local capillaries.

• Intrathecal: Injected into the spinal space for direct CNS access.

LO 1: absorption routes of administration

• other 8 routes

Other Routes:

• Inhalation: Rapid delivery to the lungs/bloodstream.

• Topical/Transdermal: Applied to skin/mucosa for local or systemic (patch) effects.

• Sublingual/Mucosal: Placed under the tongue to bypass the first-pass effect by entering the superior vena cava directly.

• otic route is the administration of liquid medication directly into the ear canal, usually as drops

• ocular route involves delivering medications directly into or onto the eye

LO 1: absorption routes of administration

• what is fractional bioavailability (F)

• which route has the highest bioavailability

• Fractional bioavailability (F): the amount of administered drug that enters systemic circulation

Highest bioavailability → IV

IV = F = 1 = 100% bioavailability

Why? The drug goes directly into systemic circulation, so there is no absorption step and no first-pass metabolism.

Downside: Because the entire dose enters the blood immediately, you cannot take it back. Toxicity or adverse reactions can occur rapidly. IV administration is also invasive and carries risks such as infection.

LO 1:

• ___________ is the fraction of drug reaching systemic circulation; IV is always 1.0.

• ______ primarily occurs in the liver after oral absorption via the portal vein.

• Routes like ______ and ______ bypass the liver's initial "tax" on the drug.

• Bioavailability (F) is the fraction of drug reaching systemic circulation; IV is always 1.0 (means 100% reaches the blood)

• First-pass metabolism primarily occurs in the liver after oral absorption via the portal vein.

• Routes like sublingual and IV bypass the liver's initial "tax" on the drug.

LO 1: first pass metabolism & oral administration

• describe metabolism

• what happens after absorption in the GI tract

• liver’s drug metabolizing enzymes

• what the first pass effect does to oral bioavailability

• routes that bypass the first-pass effect

• Metabolism by epithelial cells of the intestine

• After absorption from the GI tract, the hepatic portal vein transports the drug directly to the liver

• The liver's drug-metabolizing enzymes can reduce active drug concentration by up to 90% before it ever reaches the bloodstream

• This first-pass effect reduces oral bioavailability to an average F of 0.7

• Other enteral routes (oral mucosa, rectal) bypass gut absorption and avoid the full first-pass effect

LO 2: hydrophilic vs hydrophobic/lipophilic

• loves water (hydrophilic)

• loves fat (hydrophobic/lipophilic).

LO 2: absorption differences

• hydrophobic drugs: how do they cross membranes & how are they best absorbed

• hydrophilic drugs: how do they cross membranes

Absorption Differences:

• Hydrophobic (Lipophilic): These drugs cross lipid-rich cell membranes easily via passive diffusion. They are better absorbed in uncharged forms.

• Hydrophilic (Water-soluble): These are "border-restricted"; they often require facilitated diffusion or active transport (using ATP) to cross membranes because they cannot dissolve through the lipid bilayer.

LO 2: volume of distribution Vd

• what is VD

• low Vd: range & what kind of molecules/drugs

• high Vd: range & what kind of molecules/drugs

• describe plasma in terms of hydrophilic vs hydrophobic

Volume of Distribution (Vd): This is a theoretical volume representing how extensively a drug spreads.

• Low Vd (< 3-5 L): Typical for hydrophilic, large, or plasma-protein bound drugs (like Warfarin) that stay in the blood.

• High Vd (> 46 L): Typical for hydrophobic, small drugs that leave the blood to hide in fat and deep tissues.

• plasma is a water-based (aqueous) environment, so hydrophilic drugs tend to remain in the plasma/extracellular fluid more than lipophilic drugs do.

LO 2: volume of distribution

• formula

• what it accounts for

• theoretical volume needed for what

• what is it used to calculate

• Vd = dose administered (mass) ÷ Cmax (mass per volume)

• A rough accounting of where a drug goes in the body

• The theoretical volume that would be needed to contain all the drug in the body at the same concentration as the plasma

• Used to calculate the dose needed to achieve a desired plasma concentration

LO 2: what factors affect VD

LO 2: factors that affect Vd

• describe plasma protein binding (albumin)

• Plasma Protein Binding: Drugs bound to albumin cannot leave the blood; only "free" drug is active.

• Blood Flow: Highly perfused organs (brain, heart) receive drugs faster than "slow" tissues like fat.

LO 2: describe blood flow effect on drug distribution

Blood Flow: Highly perfused organs (brain, heart) receive drugs faster than "slow" tissues like fat.

LO 2: bioavailability → plasma protein binding

• what state can drugs in the blood be in

• what does binding depend on

• what occurs when a few binding sites are available on plasma proteins

• what occurs when two drugs compete for the same binding sites

• examples of drugs with high plasma protein binding

LO 2: describe membrane crossing & Vd levels in hydrophilic vs hydrophobic drugs

LO 2: describe acidic environment effect on absorption of weak acids

• what are weak acids vs strong acids

• acidic environment effect on weak acids

• A weak acid only partially dissociates, so it can exist in both uncharged (HA) and charged (A⁻) forms. In an acidic environment, a weak acid stays more uncharged, allowing it to cross lipid membranes more easily.

• A strong acid almost completely dissociates into H⁺ and A⁻, so it exists mostly in the charged form and does not readily cross lipid membranes by passive diffusion.

LO 2:

Lipophilic drugs cross membranes easily and have a _____Vd, while hydrophilic drugs stay mainly in the plasma with a _____ Vd.

Lipophilic drugs cross membranes easily and have a high Vd, while hydrophilic drugs stay mainly in the plasma with a low Vd.

LO 3: metabolism

• what is metabolism

• purpose

• substance formed when drug is metabolized

• what are prodrugs

• what do some metabolites lead to

LO 3: what is elimination

Elimination refers to the body's process of removing substances (like waste, toxins, or medications) from the system

LO 3: drug metabolism (biotransformation)

• where does it occur & why

Metabolism (Biotransformation): Primarily happens in the liver to make drugs more polar (water-soluble) for excretion.

LO 3: drug metabolism

• phase 1

• phase 2

• enzymes involved

• where can drug-drug interaction occur

• Phase I: Uses CYP450 enzymes for oxidation, reduction, or hydrolysis. Think of this as "exposing" a functional group. Prepares drug for further metabolism.

• Phase II: Conjugation reactions (e.g., glucuronidation, acetylation) that "attach" a large polar molecule to the drug. Usually makes drug more water-soluble.

shout out Dr. Dyer

LO 3: excretion

• what it is

• what does the route depend

• primary routes

• other routes

• Excretion: The final exit.

  • Renal (Kidneys): Most polar metabolites leave via urine.

  • Biliary/Fecal: Some drugs are excreted into bile and leave via feces.

LO 3: what is half-life & what is used to estimate how long it takes to remove a drug from the body

• The amount of time it takes for the blood concentration of a drug to decline to half of its initial value

• Example: diphenhydramine t½ = 2-13 hours (average 9 hours)

• Five half-lives is used to estimate how long it takes to remove a drug from the body completely

• So, it would take about ~10-45 hours to completely remove diphenhydramine (average 45 hrs)

LO 3: elimination kinetics

• first order: rate equation, dependence on drug concentration, amount eliminated, example

• zero order: rate equation, dependence on drug concentration, amount eliminated, example

[A] is concentration of the drug

LO 3: elimination kinetics

• first-order: describe

• zero-order: describe

• First-Order (Most drugs): A constant fraction (e.g., 50%) is removed per unit of time. The half-life (t½) is constant.

• Zero-Order (Alcohol, Aspirin): A constant amount (e.g., 10mg) is removed per unit of time. The enzymes are saturated, so increasing the dose can lead to rapid toxicity.

It's always 10 mg, regardless of how much drug is present.

Why? The enzymes are essentially working at maximum capacity.

Think of a checkout line with every cashier busy:

More drug arrives → enzymes can't work any faster → drug starts accumulating → toxicity risk increases.

LO 3: what is steady state & when is it reached

• Steady state is when the rate you're giving the drug equals the rate the body is eliminating it.

• Steady state is usually reached after 4-5 half-lives

LO 4: describe in simple terms

• potency

• efficacy

• therapeutic index

In pharmacodynamics:

• "How strong is the drug?" (potency)

• "How much can it actually do?" (efficacy).

• We then check the Therapeutic Index to see if that dose will kill the patient.

LO 4: what is efficacy & what is greater efficacy on a graph

• Efficacy: maximum possible effect

• Efficacy (Emax): The maximal effect a drug can produce. On a graph, this is the height of the curve. A drug with higher efficacy is more "powerful" at its ceiling.

LO 4: what is potency & what is greater potency on a graph

• Potency: amount of drug needed to produce an effect

• Potency (EC50 or ED50): The amount of drug needed to produce 50% of the maximal effect. On a graph, this is the left-to-right position. The further to the left a curve is, the more potent the drug (it takes less dose to work).

• EC₅₀: The drug concentration that produces 50% of its maximum effect; a lower EC₅₀ means higher potency.

• ED₅₀: The drug dose that produces the desired therapeutic effect in 50% of a population.

LO 3:

• therapeutic window: what it is & formula

• therapeutic index: what it is & formula

• large vs narrow TI

• TI<2

Therapeutic Index (TI): A ratio of safety: TI = TD50 / ED50.

• Large TI: Wide safety margin (e.g., Penicillin).

• Small/Narrow TI: Dangerous; requires close blood monitoring (e.g., Warfarin, Lithium, Digoxin).

• TI < 2 is considered very narrow and risky.

• ED₅₀ = dose that is effective in 50% of people (median effective dose)

• TD₅₀ = dose that is toxic in 50% of people (median toxic dose)

Dose Response Curves

• Emax: what it is

• what does it mean for a drug to have a higher Emax

• Potency: what it is

• what does it mean for a drug to be more potent

• Emax: the maximum effect of the drug — efficacy is a measure of the maximal response a drug can produce

• A drug with a higher Emax is more effective at its ceiling

• Potency: the concentration at which a drug produces its half-maximal effect (EC50, or 50% of Emax)

• A more potent drug achieves its EC50 at a lower concentration — less drug is required for it to act

Lo 4:

• what do drug act on to work

• what are agonists

• what are antagonists

• Drugs work by acting on receptors.

• An agonist is a chemical or drug that binds to a cell receptor and activates it to produce a biological response.

• An antagonist binds to the same receptor but blocks or dampens the response, preventing other molecules or natural signals from activating it

LO 4: agonists

• primary agonist

• full agonist

• partial agonist

• inverse agonist

• allosteric agonist

• Primary agonist: binds the same site as the endogenous agonist.

• Full agonist: activates signaling to maximum capability. Produces 100% of the possible response (Emax).

• Partial agonist: only partly as effective as a full agonist. Only produces a sub-maximal response, even at 100% receptor occupancy. It can act as an antagonist if it competes with a full agonist.

• Inverse agonist: stabilizes constitutively active receptors in an inactive conformation — receptor activity drops below baseline levels

• Allosteric agonist: binds a distinct, non-overlapping site from the endogenous agonist

→ allosteric agonist binds to a different site on the receptor than where the body's natural (endogenous) agonist binds and activates the receptor

LO 4: antagonists

• what it is

• competitive antagonist: can it be overcome, agonist potency & Emax

• noncompetitive antagonist: can it be overcome, Emax

• Antagonist: a drug that binds a receptor without activating signaling, and interferes with agonist activation

• Competitive antagonist (most common): competes for the same binding site as the agonist — binding is mutually exclusive

→ Increasing agonist concentration can overcome it

→ Reduces agonist potency, but not maximum efficacy

• Noncompetitive antagonist: binds an allosteric site, blocking agonist action without affecting agonist binding

→ Reduces potency; max efficacy is unchanged if enough agonist is given

Noncompetitive antagonist binds/blocks receptor function → agonist can't fully activate signaling → adding more agonist cannot overcome it → ↓ maximum efficacy (Emax).

Compare that with competitive antagonism: they're fighting for the same seat, so adding enough agonist can win the competition.

LO 4:

• Competitive antagonists change________ (_______).

• Noncompetitive antagonists change _______ (______).

• Competitive antagonists change ED50 (potency).

• Noncompetitive antagonists change Emax (efficacy).

LO 5: lidocaine

• what is it

• what is infiltration anesthesia

• what is nerve block/field block anesthesia

• what is spinal (intrathecal) anesthesia

• what is the lidocaine Vd=50 what does this mean

• Topical anesthesia

• Infiltration anesthesia — the most common route for local anesthetics – Epinephrine can be added to decrease dose and prolong duration of action

• Nerve block / field block anesthesia — blocks conductivity of sensory nerves from an area; injected into or adjacent to a peripheral nerve or plexus

• Spinal (intrathecal) anesthesia — blocks somatosensory and motor fibers, e.g., for lower-limb or pelvic surgery

• Volume of distribution: ~50 L

LO 4: lidocaine

• volume of distribution: what occurs & which organs show higher concentrations

• metabolism

• elimination

• Absorption: Can be topical, infiltration (injection), or nerve blocks. Epinephrine is often added to cause vasoconstriction, which keeps lidocaine at the site longer and reduces systemic toxicity.

• Distribution: Vd is ~1.5 L/kg (~50 L total), meaning it spreads through total body water.

• Metabolism: 70% first-pass in the liver (Phase I) 30% reaches systemic circulation unchanged from first pass

→ first-pass metabolism mainly matters when a drug is absorbed from the GI tract and travels through the portal vein to the liver. Lidocaine used by injection, nerve block, or topically does not undergo that same initial GI → portal vein first pass.

• Excretion: Via the kidneys (urine).

LO 4: lidocaine mechanism of action

• Mechanism of Action (MOA):

  • The non-ionized form of lidocaine crosses the axonal membrane ((R-NH2)

  • Inside the cell, it becomes ionized (R-NH3+)

  • This ionized form binds to voltage-gated Sodium (Na+) channels in the open state on the inside & inactivates it

  • It stabilizes the channel in the inactivated state, preventing Na+ entry and stopping the action potential (pain signal) from firing.

LO 4: what does lidocaine’s degree of block depend on (4 components)

• Concentration of local anesthetic

• Open state of the Na+ channel — a higher firing rate gives lidocaine more access to its binding site within the pore, prolonging inactivation

• Myelinated neurons are harder to block (myelin impedes drug entry)

• larger diameter nerves are harder to block than smaller ones

LO 4: which phase of the action potential does lidocaine act on & why

Depolarization (Phase 0).

• During Phase 0, voltage-gated Na⁺ channels open, allowing Na⁺ to rush into the neuron.

• Lidocaine preferentially binds to open/inactivated Na⁺ channels, stabilizes the inactivated state, and prevents further Na⁺ entry and action potential propagation.

LO 4: lidocaine adverse effects

• when do side effects occur

• CNS toxicity: what occurs

• unintentional intravascular injection: what occurs

• if epinephrine is co-administered what occurs

• Side effects occur more commonly near or above the toxic dose, or with accidental intravascular injection

• CNS toxicity: numbness/tingling around the lips and tongue, tinnitus, blurred vision, agitation, disorientation

• Unintentional intravascular injection: toxicity can occur suddenly, even at low doses, if injected directly into an artery or vein

• If epinephrine is co-administered, the patient will also experience tachycardia and hypertension

LO 4: lidocaine

• drug class

• generic

• absorption

• metabolism/elimination

• protein bound state

• MOA

• indication

• side effects/contraindications

• special notes

Lidocaine in blood	What it means
Protein-bound lidocaine 🔒	Attached to plasma protein → not immediately available to enter tissues or act
Free lidocaine 🔓	Not attached → can leave blood, enter tissues, and exert effects

lidocaine has an affinity for certain plasma proteins