Exam 1 Principles of Drug Action

what are pharmacology, pharmacy, and therapeutics

pharmacology: study of the fate and actions of drugs in the body

pharmacy: the preparation of drugs

therapeutics: the treatment of disease with drugs

what are the drug classifications

natural preparation (galenicals): drying or extracting plant or animal materials, dosing issue

pure compounds: isolated from natural sources and purified, compounds are found in nature, known doses

semisynthetic compounds: imporved and modified versions of naturally occurring compounds

fully synthetic compounds: lab created molecules that don’t resemble anything in nature, discovered accidentally or computationally

types of drug nomenclature

chemical or manufacturer name

non-proprietary name (generic)

proprietary name

common (street) name

what are the goals of drug administration

1. get a therapeutic but NOT toxic concentration of drug to the site of action quickly and maintain that concentration as evenly and continuously for as long as needed

2. route of administration determines how quickly it reaches the site of action and concentration there

what are the routes of drug administration

topical: localized effect at the site of administration, small volumes and low [drug] at only the local site (intrathecal injections, ointments, etc.)

percutaneous: absorption through the skin for a systemic effect, often times drugs is suspended in an oily medium

oral mucosa (sublingual and buccal): no first pass effect, not subject to an alkaline environment, rapid

stomach and intestine (oral, p.o.): FIRST PASS EFFECT, absorption from stomach depends on pH, gastric emptying rate (pyloric sphincter), intestinal mobility, large surface area in intestines causes greater absorption

rectal mucosa (suppositories): up the butt, no first pass effect, not degraded by digestive enzymes

subcutaneous (s.c): injected under skin for non-irritating drugs in small quantities, slow even absorption

intramuscular (i.m.): inject into muscle, aqueous solutions are rapidly absorbed, slow absorption if dissolved in lipid depot

intravenous (i.v.): inject into vein, rapid influsion (desired [drug] achieved immediately, slow (blood levels titrated and maintained)

intra-arterial (i.a.): used to achieve [drug] at a specific site

injection into body cavities (i.p.): rare in humans, but peritoneum has a high surface area, risk of infection

how does drug solubility determine particle movement and other ways into cells

the partition coefficient P_m/b = (C_oil/C_water) is determined by substituent groups

low P_m/b but small uses facilitated diffusion via aquaporins

High P_m/b can diffuse through cell membrane

• rate depends on [drug], pH, surface area

• in small intestine, there has to be an apprecheable water solubility to allow passive diffusion

pinocytosis (cell drinking) allows in non-specific large molecules using ATP

gap junctions connect the cytoplasm of adjacent cells of the same tissue through 6 connexins (connexon)

pH is important for organic amines and organic acids (want the same to be uncharged and therefore can pass)

types of barriers to drug movement

epithelial (skin) barriers: occluding zonulae (continuous tight junctions) seal off the outside world, the only route is through cells

capillary barriers:

• maculae (majority): junctions have patches so drugs can pass between cells

• fenestrated: small holes where only small molecules can leave

• occluding capillaries: intercellular space is completely blocked (blood-brain barrier), only high P_m/b can pass or via transporter, CSF is within barrier, certain parts of brain don’t have barrier (pituitary, pineal, vomiting center)

what is drug distribution and how is it determined

body fluids act as a solvent and carrier of drugs

total body water = extracellular + intracellular

extracellular (determine using mannitol inulin) = plasma (determine using evans blue) + interstitial fluid

V_d = volume occupied by drug = mass/concentration (L)

plasma and serum protein binding

many drugs bind to proteins (albumin) in the blood

only the unbound drug is active

the bound drug acts as a drug reservoir that contributes to a lower maximal effect by a prolonged duration of action (protection from metabolism)

the affinity of binding is represented by K_d

K_d = k₂/k₁ (mol/L)

K_d = [free drug] when 50% of binding sites are occupied

the % of drug bound to protein is dependent on [drug], [albumin], k_d

fat and tissue binding

adipose tissue can store large amounts of high P_m/b drugs

• this takes a while to equilibrate with the [blood] due to low perfusion of adipose tissue

if [tissue] is higher than [blood] of a drug tissue localization has occurred

• if there is a lot of tissue binding sites this can greatly prolong the half life

functions and anatomy of the liver

functions: 1. detoxification of drugs and toxins 2. formation of bile for fat absorption 3. creation of plasma proteins

anatomy:

receives second-hand blood from the portal veins (lower [O₂])

blood flows from portal vein → sinusoids (contact with hepatocytes) → central veins of lobules → hepatic vein → vena cava

kidney functions

remove body wastes and low P_m/b toxins/drugs

how does kidney filtration occur

squeezing of the glomerular capillary bed passively filters all small molecules

• to maintain hydrostatic pressure with a filtration rate (GFR) of 125 ml/min, glomerular arterioles expand and contract

reabsorption by the proximal tubule

the proximal tubule reabsorbs vital contents of the solute and water

• solute reabsorption (glucose, amino acids) is active

• water is reabsorbed passively by osmosis

actions at the loop of henle

location where urine is concentrated due to the high concentration of solute in the interstitium of the medulla

descending loop:

• impermeable to solute but permeable to water and water moves out by osmosis making the tubule hypertonic

thin section of ascending loop:

• impermeable to water but permeable to solute (Na⁺, Cl^-)

• solutes diffuse out making it hypotonic

thick section of ascending loop:

• impermeable to water but Na⁺ and Cl^- actively transported out

• becomes very hypotonic

overall leads to the concentration of low P_m/b compounds

actions at the distal tubule and collecting duct

antidiuretic hormone causes the distal tubule and collecting duct to become permeable to water

due to the interstitium being hypertonic, water moves out of the lumen of the duct forming concentrated urine

• absence of ADH the tubule is minimally permeable (more dilute urine)

alcohol inhibits ADH release leading to more dilute urine

clinically important aspects of plasma protein binding

1. when [free drug] is lower, pharmacological activity os lower and so are drug clearance rates

2. competitive interaction between endogenous substances and drugs can displace drugs from protein binding sites

3. disease states characterized by hypoalbuminenia can cause an increase in [free drug]

drug distribution following rapid i.v. injection

three stages: initial dilution, distribution, elimination

the first 2-3x circulating around the body the drug travels as a bolus which can cause a danger of toxicity for low safety margin drugs

drug redistribution in tissues

different tissues have different perfusion rates and reach equilibrium with plasma [free drug] at different rates

vessel-rich groups (brain, heart, liver) equilibrate fastest

muscle group is slower

vessel-poor groups (fat, skin, bone, etc) equilibrate slowest

rates of drug decline follow the same patter (VRG fast, VPG slow)

consequences of biotransformation of drugs

1. inactivation

2. activation

3. maintenance of activity

most commonly occurs in the liver

Phase I reactions

Phase I reactions: oxidation, reduction, hydrolysis

• typically introduces or unmasks a polar functional group (lowering P_m/b)

Oxidation:

• microsomal mixed-function oxidase catalyzes reactions

• requires cytochrome P450s, NADPH-cytochrome P450 reductase, and NADPH

• transfers one oxygen to the substrate, lowering P_m/b

• Cyt P450s are versatile due to enzyme multiplicity and low substrate specificity

• can create a highly reactive epoxide intermediate that is neutralized by epoxide hydrolase (can damage DNA)

Reduction: lowers P_m/b

Hydrolysis: esterases, amidases, peptidases, lowers P_m/b

phase II reactions

coupling the drug to an endogenous substance inactivating it

glucuronidation: conjugation to glucuronic acid

• many functional groups (hyroxyl, carboxyl, amine, sulfhydryl) are susceptible

• UTP + glucose-1-phosphate → UDPGA

• UDPGA is conjugated to the drug by UDP-glucuronysyltransferase

glutathione conjugation

first pass effect

orally administered drugs can be metabolized before reaching systemic circulation by gut lumen enzymes, gut bacterial enzymes, gut wall enzymes, and hepatocyte enzymes

bio transformation enzymes are mainly located in the endoplasmic reticulum

enterohepatic drug circulation

drug absorbed from the gut enters the portal vein

liver metabolizes the drug

drug transferred to the gallbladder

metabolized drug transferred back to the g.i. tract

gut bacteria deconjugate the drug

principles of pharmacokinetics and complications

drug concentrations

rate of the various ADME steps

high dose = higher [free drug] at the site of action and a greater intensity of effect

complications: irreversibly acting drugs, tolerance, combinations with other drugs, active metabolites

one-compartment model

following i.v. administration [drug] decreases at a rate proportional to the concentration: rate = kC k = rate constant

C_t = C₀e^-kt

half-life of drug elimination = t_1/2 = 0.693/k

assumes that all body water is evenly distributed

two-compartment model

blood is in a separate compartment from tissues

excretion only occurs in the blood

• brain concentration lags behind blood concentration because the blood concentration has lowered by the time it reaches the brain again

zero-order excretion

occurs once the enzymes are fully saturated

linear excretion

constant amount of drug is excreted per unit time

what is the goal of repeated drug administrations and how is this achieved

goal: C_ther < [drug] < C_tox

use an loading (priming) dose followed by a maintenance dose

ways of determining bioavaliability

percent of the drug that enters systemic circulation following administration

plasma concentration measurements

• after oral dose, serial blood plasma measurements

• area under the curve (AUC) reflects absorption extent

• bioavailibilty = AUC (oral)/ AUC (i.v) %

correlation of drug dose with pharmacological extent

• only possible for drugs with measurable effects

urinary excretion

• used for drugs that are largely excreted unchanged

• determined via measuring drug accumulation in urine

• less drug accumulation in urine reflects lower bioavailability due to first pass

factors influencing bioavailability of oral drugs

1. formulation of drug product (tablet disintegration/dissolution)

2. interaction with other substances in the g.i. tract

3. biotransformation prior to entering systemic circulation

drug clearance

quantitative measurement of rate of removal

routes: hepatic biotransformation, kidney and bile excretion, exhalation, fecal excretion

measured as the volume of fluid from with drug is removed per unit time (mL/min, L/hour)

equations for calculating drug clearance

Cl = kV (rate constant of elimination * volume of distribution)

Cl = dose/AUC (AUC at a given time)

Cl = F*dose/AUC (F = fraction absorbed (bioavailability))

constant rate IV infusion calculations

at a steady state Q(drug input) = k * V_d * C_ss (steady state concentration)

• or Q = Cl * C_ss

• Q = mg/min

often times a loading dose is used to quickly establish C_ss

• loading dose: L = V_d * C_ss

time to steady state concentrations and the plateau principle

*assumes first order kinetics and continuous i.v. administration

the rate of approach to steady state concentration depends only on the elimination rate: plateau principle

the time to reach any fraction of C_ss = fractional attainment (f)

f = 1 - e^-kt or f = 1 - e^{-0.693t/half-life}

the time to plateau is roughly 5 half-lives

dosing regiments for repeated i.v. administration

fluctuates around an average concentration

• C_avg = (D_m/T_m)/Cl

• D_m = K x V_d x T_m x C_avg

• D_m = maintenance dose

• T_m = maintenance inrerval

the maintenance dose should keep [blood] between therapeutic and toxic levels

• D_m = (C_tox - C_ther)*V_d (maximum dose)

• loading dose: L = V_d * C_tox

clearance by multiple organs

clearance by an individual organ is the volume of body fluid from with that organ completely removes drug in unit time

first order rate constants are additive: k = k_H + k_R

so clearance is additive: Cl = Cl_H + Cl_R

calculating clearance by the liver

R: volume of blood flowing through the liver

C_a = arterial concentration C_v = venous concentration

amount of drug removed = R * (C_a - C_v)

extraction ratio: fraction of drug removed by the liver

• E = (C_a - C_v)/C_a

Cl_H = E * R

hepatic clearance properties

designed for rapid extraction

1. large size (1500g)

2. high blood flow (1 mL/g of tissue/min)

3. high hepatocyte cell surface area

first pass properties:

it is drug-specific, saturable, it can cause complete extraction, liver disease can diminish the first-pass effect, if the liver bioactivates a drug, oral administration may yield a greater response

factors affecting hepatic clearance

• liver blood flow

• dependent on enzyme concentration and affinity

clearance by the kidney (renal)

depends on glomerular filtration rate + rate of tubular secretion - rate of tubular reasborption

glomerular filtration

• passive process at ~ 125 ml/min

• inulin is used to measure GFR

tubular secretion

• proximal tubule actively transports certain substances from plasma to tubular urine

• occurs against the drug concentration gradient

• competition can occur (can be used to increase t_1/2)

• ionized molecules are transported (fast, first-order)

tubular reabsorption

• occurs to prevent the loss of nutrients and vitamins

• both passive and active mechanisms

• charged molecules can’t be reabsorbed

  • altering urine pH can alter the rate of reabsorption

if Cl_R > GFR: net tubular secretion

if Cl_R < GFR: net tubular reabsorption