Any chemical that has adverse effects on biological processes

(all drugs are toxins if taken in sufficient amounts)

Pharmacokinetics

Pharmacodynamics

Movement of drug from where it enters to the body to the blood stream

-from extravascular site of administration into the blood

Inactivation of a drug due to its metabolism (change in drug molecule) or its excretion (removal of drug in unmetabolized form

excretion or biotransformation

Phospholipid

-head region is a phosphor connected to 2 fatty acid lipid chains

-head region is polarized (lipids are nonpolarized)

-head region is hydrophilic (lipid portion is hydrophobic)

Polarized molecule= water soluble

nonpolarized molecule=not water soluble

Polarized = hydrophilic

non polarized = hydrophobic

Lipid bilayer

Phosphos that like water point out and lipids that dislike water stay inward creating a barrier

Proteins made of chains of amino acids bound by carbon and nitron molecules to create chains

-structure of a protein is the sequence of the amino acid chains

Alpha Helix: when amino acids chains spiral (secondary structure)

Tertiary structure or subunit: the bending and combination of alpha helixes

Subunits are distinct protein models that combine w/ each other to make elongated cylindrical structure w/ channel

Quadro structure: combination of subunits

Intrinsic: embedded in lipid bilayer and sticks out of both sides

Extrinsic: usually on inside of cell but doesn't push all the way through

1. receptor
2. transporter
3. channel protein

Changes function of cell

-receives chemical messages from other cells

-endogenous substance binds to receptor and changes function of cell

-all created for endogenous substances (not made for drugs)

Acts as a pump

-helps movement of substances in/out of cell

-chemical message opens it up

-active transport: when a transporter requires energy to open

Opens Channels

-connects intra and extracellular fluid 

AKA peripheral protein

-often an enzyme (protein that catalizes a chemical reaction)

Simple passive diffusion is how drugs move across the membrane

-diffuse through passive means across concetration gradient through the lipid portion of the cell

Molecule attaches to protein and alters the structure to let molecules through

-doesn't use any energy, movement is still due to diffusion

Simple Diffusion: linear relationship

greater concetration = greater diffusion

Facilitated Diffusion: upper limit due to the number of transporters available

-starts with a steep increase and then levels out after all transporters are in use

Energy is used to move molecules across membrane

-phosphorilation: process by which proteins are activated

-protein is binded shut and a solute attaches to it

-one of phosphates of ATP moved to transporter protein (ATP becomes ADP) and it changes activity of transporter

-protein changes shape and pumps binded solute across membrane

Determines absorption by simple passive diffusion

J=P*A*X(C1-C2)

J=rate of diffusion across cell membrane

P=permeability coefficient

A=surface area of membrane

(C1-C2)=concentration gradient

P = permeability coefficient (Frick's Law)

P=the drugs ability to penetrate the cell membrane

P is affected by:

-lipid solubility: oil/H2O partition coefficient

high lipid solubility=high permeability

-Ionization

greater ionization = worse permeability

-Polarization

polar or uncharged molecules = better permeability

-Size of molecule

The pH levels of fluid it is dissolved into

-same molecule will have diff ionization depending on where in the body it is and pH of that fluid

Bases get more ionized as pH decreases (in acid fluid)

Acids get more inozed as pH increased (in alkalines) 

The hydrogen ion concentration of water

H2O or neutral = H30+ and OH- = pH of 7

Acidity and alkalinity are determined by relative concentration of H30+ and OH-

Acidic = H30+>OH- = pH<7 = more protons

Alkalin = H30+<OH- = pH>7 = less protons 

Base- proton acceptor- ionizes as pH decreases (in acids)

Acids- proton donor- ionizes as pH increases (alkalines)

pKa of a drug is the pH where 50% of molecules are ionized

-if pKa of a drugs is too extreme it won't ionize even if it is in correct soltion

pH - pKa is what matters (the relation of pH to the molecules pKa)

If pH = pKa then half of molecules will be ionized

Acids: when pH-pKa is greater than zero then ionization is greater (100% at about 2)

Bases: when pH-pKa is less than zero then ionization is greater (100% at about -2)

Differential movement across a cell membrane due to pH differences across membrane

-some movement is unidrectional bc the pH levels changes and creates more ionization after it crosses the membrane, making it harder to cross back over

-e.g. bases get trapped on acidic side and acids get trapped on alkaline side

-In stomach aspirin (slightly acidic) is nonionized bc it is in the stomach which is also acidic

-so it can cross barrier into blood

-blood is not as acidic so it ionizes the aspiring

-so it can't cross back into blood

Enteral: placing in GI tract

Parenteral: bypassing the GI tract

-oral

-rectal

-sublingual

-intravenous (no rising phase, rapid effects, fast drop off, and high levels of blood concentration)

-intramuscular

-subcutaneous

-intraperitoneal

-inhalation (curve similar to IV)

-transdermal (skin patch)

-epidural (right ouside of duramater in spine)

-intrathecal (in the thecal fluid w/in dura mater of spine)

IV & Inhalation are most addictive bc of high intensity and fast drop off

Time on X (starting w/ drug administration), concentration of drug in blood on Y

-IV & Inhalation: immediate rise, high peak and little variability in concentration b/ ppl so you can set it at precise values

-Oral: long rising phase (slow absorption) and a low peak lots of variability b/ ppl

-IM: curve between IV and oral (some absorption time, mid peak), curve depends on type of liquic drug is injected into and blood flow to muscle selected (eg depo provera injection, slow steady absorption)

Job is to break down foreign substances in the blood

Majority of drug metabolism  happens here

5 functions:

-makes bile salts that emulsify fats for absorption

-makes most plasma proteins

-trashes worn out blood cells

-processes and stores glucose

-contains enzymes that break down poisons/drugs

Drug is absorbed into blood, carried into liver that can break down drug

-if enough is metabolized in liver it won't enter CNS and you don't get drug effect

Gastric emptying: how fast drug is omved from stomach to intestine

-one of the most imp factors

-faster it is moved the faster the drug effect

-faster on an empy stomach (faster effect)

Concentration: dilution of drug or dose

Metabolism: alteration of a drug that deactivates it (faster metabolism = less drug effect)

Index of the amount of drug that enters systemic circulation

-amount of drug left after metabolism in liver and proteins in intestine break it down

Oral

Rectal

Intraperitoneal

First pass metabolism

-metabolism of drug by the liver after it is absorbed but before it reaches systemic circulation

-if too much of drug is lost at first pass metabolism it can't be taken orally

F=AUC_oral/AUC_iv

AUC = area on the curve on concentration time curve

F=1 means complete bioavailability

F=.75 means 75% of drug enters systemic circulation

• local blood flow
• capillary permeability
• plasma protein binding

The more blood flow an area gets the more of the drug will get there

-drugs go to the brain first but if it is highly lipid soluble it will quickly go to the fat and stop drug effect

-distribution is not static, moves around constantly

Capillaries in braine are more impermeable than othe rareas which contributes to the BBB

Normal cells have:

-intracellular clef- juction b/ endothelia cells that make up wall of capillaries

-pinocytosis- membrane engulfing fluids w/ solutes

-fenestration- place where stuff can freely move in/out

BBB cells have a much smaller intracellular cleft called a tight junction and no pinocytosis and fenestration

-astrocytes used to be though tto help w/ BBB by stimulating tight junction

-active transport gets extracellular stuff that is needed (ATP)

Passive diffusion through the lipid bilayer

-drugs don't use active transport

-why psychotropic drugs are usually lipid soluble, bc they ahve to diffuse across barrier

Drugs with a strong affinity to proteins have less drug available for extracellular tissues

High protein affinity = less distribution

Albumin: pain protein in blood that drugs bind to

• Limits rate and amount of distribution
• might still have som eeffect but it does slow it down
• May facilitate elimination
• slowing down distribution means it might be eliminated before it becomes active
• can cause dangerous drug reactionsa nd interaction
• drug 1 binds to protein, take drug 2 and there isn't enough room on plasma protein for it to bind, so drug 2 has increased presence in extracellular fluid
• or drug 1 and 2 can compete for plasma and concentration of both will increase

Removal of unchanged drug (excretion) and drug metabolites from the body

Excretion: removal of unchanged molecules

Elimination: getting rid of drug in any possible way (excretion is a type of elimination)

• Urine: most imp, how most drugs are eliminated
• Feces
• Expired air
• Sweat
• Saliva
• Breast Milk

• regulate concentrations of constituents of body fluids
• excretes most end products of bodily metabolites, including drug metabolites and unchanged drug 

Nephron: about 1,000 in each kidney and each one functions independently & creates urine

2 parts:

-golmerulus

-tubule

Blood-->glomerulus (tangled interconnected blood vessles that are highly permeable) ->tubule ->connecting ducts->bladder ->out of body

-Almost everything is filtered out at golmerulus

-tubules are in really close contact to vessles so a lot of substance filtered from glomerulus and sent to tubules ends up leaking back into blood

-reabsorption of fluids crucial to avoid dehydration

-drugs are also filtered back into blood

Lipid Solubility

-incrases lipid solubility = increased amount leaking out of tubule= never gets to urine and less leaves body

-reason that very few psychotropic drugs get out in unchanged form (they are all lipid soluble)

• Nonsaturable so no ceiling effect, as concentration increases the filtration increases
• amount of plasma filtered each min = 10% of plasma flow through kidney (rest is leaked out in tubule)
• affected by protein binding
• Kidney function declines w/ age so lower dose needed
• measured by creatine clearance 

• Active transport of drug from blood into tubule w/out passing glomerulus
• potentially more imp than glomerular filtration
• can achieve high clearance even when high fraction of drug is bout to plasma proteins 

Non ionized drug = pass membrane=less filtered out

Ionized drug=can't pass membrane=more filtered out

• Most psychotropic drugs eliminated from urine
•  Can't eliminate them in unchanged form bc they are usually nonpolar
• nonpolar (nonionized) drugs are reabsorbed from urine after filtration by kidney
• Drug has to be metabolized to polar metabolite for elimination
• changing urin pH can affect elimination
• tubular secretion can eliminate drugs highly bound to plasma

AKA metabolism

Alteration of a drug molecule into metabolites

Nonsynthetic (catabolic, Phase I):breaking down into multiple parts that are simpler

3 possible processes:

-oxidation

-reduction

-hydrolysis

Synthetic (anabolic, Phase II): combining drug w/ other molecules making a more complex molecule called a conjugate (process is called conjugation), conjugates are generally eliminated (not always, st more potent)

-synthetic uses glucuromic acid

• Liver is most important for metabolism but it can take place in any tissue
• microsomal enzymes are used in the liver to metabolize drugs
• most imp  is cytochrome P450 family
• Microsomal metabolism usually creates inactive, polar, metabolites that can't get out of tubules so are excreted in urine
• they can ST produce active metabolites
• Prodrugs are drugs that are inactive in parent form and require metabolism to produce effect

1. body as a bucket of water, insert drug, immediate and sustained effect
2. body as a bucket w/ a leak, insert drug, immediate effect that slowly & steadily decreases
3. body as 2 compartments, insert drug, immed effect , sharp decrease as it diffuses to other container then levels off when it's equal
4. body as 2 compartments w/ leak, insert drug, immed effect, sharp decrease w/ distribution, longer decline as it is leaked out (most accurate model)

Rate of removal is porportional to drug concentration

-increased blood concentration means faster drug removal

-relative amont of drug eliminated remains constant

half life: time needed to eliminate 1/2 of drug

e.g. 100mg inject, half life is 1 hour

(first half a fast decline for the distribution phase, then the elimination phase follows first-order through excretion of unchaged or metabolites)

Decline of drug is linear

Elimination is not porportional to concentration

Curve that occurs from saturating mechanism of elimination

-if blood levels go up no more can be removed bc mechanism of elimination is saturated

Half life is not relevant

e.g., Alcohol (BAC is grams/100ml of blood)

First order: variable rate of removal, constant fraction of removal

Zero order: fixed rate of removal, variable fraction of removal

volue of fluid needed to disolve all of the drug in your body at a concentration level equivalent to the concentration of the drug in the plasma

Vd=amount of drug in body/plasma concentration

hypothetical volume (often more than volume in body) so it is called "apparent Vd)

When drug is only in plasma the Vd=plasma volume

When Vd is evenly distrubeted b/ vascular & exctravascular the Vd will equal the total amount of volume in the body

When drug is more concentrated in the extrafascular deparment Vd>total physiological volume

Volume of blood from which drug must be completely removed to accout for the loss in a period of time

Index of elimination

CL_total=CL_kidney+CL_liver+CL_other

CL_(ml)=amount of drug removed per min divided by drug concentration in blood

e.g. .1mg removed/min and .001 mg/ml in blood

then CL_(ml)=.1/.001=100ml

Assuming 1st order elimination Cl is constant over a range of concetrations

Zero order elimination, Cl varies with concetration

• Dose
• clearance is dose dependent if drug doesn't follow 1st order- increased dose can saturate organs
• blood flow
• liver and kidney function
• Clinically important: affected by kidney and liver function 

T_1/2=.693 x Vd/Cl

T_1/2= half life

.693 = constant

As Cl increases half life decreases

As Vd increases half life increases

If Vd is high when you filter some out there is more left in extracellular that goes into blood and needs filtered out

more drug in extravascular = higher Vd

more drug in plasma = lower Vd

Concentration of drug in blood that is constant, different doses will give diff steady state values

maintenance dose: dose needed to maintain a specific steady state blood concentration

Dose rate x F = Cl x Css

Dose rate=maintenance, F=porportion actually getting into blood

Dose rate x F = amount of drug in body

Cl=clearance, Css=steady state concentration

ClxCss = amount of drug leaving blood

Assumes first order elimination

• curve evens out because of first order processes: the higher the blood concentrations are the more drug is eliminated 
• as time passes, constant amount of drug enters blood, but even more is removed because it is accumulating
• eventually amount in will equal amount out
• steady state is achieved after about 5 half lives if drug is given at each half life time

If half life is long it will take a long time to reach steady stead concentration, px in clinical setting

Loading dose: initial high dose given then smaller doses given to maintain it

Loading dose = Vd x Css

Loading dose is the total amount of drug in the body at the steady state dose concentration

Rates will fluctuate between administrations

Half life administrations are still going to increase overal rate (decrease by half but then administering full dose)

Keep going until the magnitude of rise and fall are equal (decrease is the same as the dose)

-Latency to steady state

-concentration at steady state

-variability at steady state

• Higher dose rate means a higher concentration of drug in the blood @ steady state
• giving smaller doses more often (but keeping dose rate the same) decreases variability but keeps steady rate the same
• smaller interdose intervals = less variability
• Important to keep levels in therapeutic window (b/ therapeutic & toxic levels)