principles of pharmacology: pharmacokinetics: lecture 2/3

pharmacodynamics

drug actions and their mechanisms

pharmacokinetics

drug movement into, within, and out of the body

what are the four key points of pharmacokinetics

absorption, distribution, metabolism, excretion (clearance)

what are the mechanisms of drug transport

passive diffusion, filtration, carrier mediated transport (active transport and facilitated diffusion), and endocytosis

passive diffusion

low molecular weight drugs that are both water and lipid soluble dissolve in membrane and cross to the other side. primary means by which drugs cross membranes

explain this image - passive diffusion (non-electrolytes)

substances will move from high concentration to low concentration and then reach equilibrium so they will be in equal concentrations in both compartments, rapid increase gradual decrease over time

electrolytes

substances that can be ionized, if they are ionize they can not cross the membrane, membranes repel ionized molecules

weak acids

can cross in certain pH but can also be repelled in different ones

weak bases

same as weak acids, can cross in certain pH but can also be repelled in different ones

explain this image - passive diffusion (electrolytes)

if there is a difference in ph across different barriers then you will see a concentrating or trapping effect on the other side

a weak base will be trapped on the...

more acidic side (lower ph) because weak bases are more ionized in lower ph environments

a weak acid will be trapped on the ...

more basic side (higher ph)

if a drug gets trapped it will become ...

less effective

if there is an infection the area becomes ..

highly acidic so a local anesthetic becomes less effective

influence of ph on ionizable drugs

many drugs are weak acids or weak bases, present in solution as both lipid-soluble, non-ionized form and lipid insoluble ionized form

weak acids can cross easily when they are in ....

more acidic solutions

weak acids have a harder time when they are in...

more basic (alkaline) solutions

weak bases can cross easily when they are in...

more basic (alkaline) solutions

weak bases have a harder time when they are in...

more acidic solutions

ion trapping: high ph differences across tissues - trapping of weak acids/weak bases in specific tissues

in an acidic stomach, weak ________ will have an easy time crossing the barrier and then they will be trapped and have trouble moving back in

acids

filtration

movement across gaps (capillaries, arteries, veins, glomerulus) for larger molecules that cant cross cell membranes

receptor mediated transport

drug combines with a transport protein in the membrane and the complex allows drug to cross the membrane

two ways: facilitated diffusion and active transport

facilitated diffusion

Movement of specific molecules across cell membranes through protein channels

active transport

Energy-requiring process that moves material across a cell membrane against a concentration difference

explain this image

some have open channels that allow movement in and out of the cell. some that are specific transport proteins that bind and can move in and out of the cell. some are pumps that require energy and will actively take the drug and move it in and out of the cell in a specific direction

receptor mediated transport - FACILITATED DIFFUSION

primary driving force is chemical gradient of molecule/drug, must move with concentration gradient (no energy), can move molecule across membrane in either direction

receptor-mediated transport - ACTIVE TRANSPORT

requires use of energy by cell (ATP), unidirectional - pumps drug in a single direction, can move AGAINST concentration gradient, usually involves drugs that are highly polar or charged (not very lipid soluble)

absorption

transfer of drugs from site of administration to systemic circulation, intramuscular, intravenous, subcutaneous, oral, etc.

what are the two parts to absorption

enteral, parenteral

enteral

through the GI tract, taken by mouth

parenteral

outside the GI tract

-inhalational - respiratory tract

-subcutaneous

-intramuscular

-transdermal

-intravenous

what are some advantages to enteral administration

safe, convenient, economical

what are some disadvantages to enteral administration

gastric irritation, destruction of drugs in GI tract, irregularities in absorption, requires patient cooperation, FIRST-PASS EFFECT

first-pass effect

drug absorbed from the small intestine is absorbed into hepato-portal circulation and arrives at the liver first (the primary center of metabolism in the body), this means it is possible for a drug to potentially be metabolized in the liver before entering systemic circulation

mouth

small surface area; pH - 6

stomach

pH - 1-2; ion trapping

small intestine

large surface area; pH - 5-8

large intestine

50% of blood supply bypasses liver

more acidic drugs (weak acids) will be absorbed in the ...

stomach

more alkaline drugs (weak bases) will be absorbed in the ...

small intestine

what are some advantages of intravenous administration

no absorption required, can attain desired drug concentration more rapidly, can adjust dosage more readily, can administer irritating solution, bypasses first-pass effect

what are some disadvantages of intravenous administration

no absorption required, risk of infection, pain/difficulties in self-medication, cannot administer drugs that precipitate in blood, and cannot mix drugs in oily vehicles

intramuscular

bigger muscles (buttocks, thigh, calf) absorption by filtration, bypasses first-pass effect, absorption rate can be altered, different absorption rates from different muscle groups

different drugs can ...

slow or increase the rate of absorption

subcutaneous

absorption by filtration, bypasses first-pass effect, slow constant absorption, rate can be altered

-aqueous solution

-suspension in oil

-implanted solid drug

inhalational administration

can be site of administration of both local and systemic effects, diffusion into blood through alveoli, absorption characteristics of lung

-large surface of blood flow

-high amount of blood flow

-leads to almost instantaneous absorption

bypasses first pass effect

what are some disadvantages to inhalational administration

cumberstome administration, difficulty in dosage regulation

transdermal administration

can be used for local and systemic administration, absorption by passive diffusion, limited by degree of hydration

what are some factors that modify absorption

drug concentration at absorption site (high concentration = faster absorption, low concentration = slower absorption)

blood flow at absorption site (high blood flow = rapid absorption, low blood flow = slow absorption)

area of absorbing surface

route of administration

food and gastric emptying

intestinal motility

metabolism/destruction in GI tract

distribution

transfer of drug from systemic circulation to tissues

what are some factors that influence distribution

regional blood flow (different parts of the body have different blood flow going to them, heart/brain = high blood flow.....fatty tissue = low blood flow)

capillary permeability

rate of transfer to tissues

binding to plasma proteins

accumulation into tissues (trapping weak acids and weak bases)

plasma protein binding

drug bound to a plasma protein cannot distribute to tissues or be eliminated; the bound drug is pharmacologically inactive. only the free, unbound, form of the drug is available for distribution to sites of action and for elimination. one drug can displace another from binding site

what are different types of plasma proteins

albumin: bind acidic drugs

lipoproteins: bind lipid-soluble drugs

a1-acid glycoprotein: bind basic drugs; induced by trauma, injury, or stress

example test question:

patient is on a drug that binds to plasma albumin, they are about to be administered another drug, it also binds to plasma albumin, what should you do?

reduce the dose of drug x

what are the 3 barriers to drug distribution

blood brain barrier, placental transfer, blood testicular (sertoli cell) barrier

blood brain barrier

formed by capillary endothelial and glial cells, can be altered by inflammation

placental transfer

doesnt prevent transport (600-1000Da), lipid soluble drugs pass freely, problems for fetus

blood testicular (sertoli cell) barrier

prevents drugs from contacting spermatocytes and mature spermatids, inhibit penetration of chemotherapeutic drugs

metabolism

biotransformation of drug into different (more water soluble) form, primarily occurs in the liver but enzymes are all over the body performing metabolic functions

metabolism (biotransformation)

conversion of drug to a different chemical structure, mainly occurs in the liver via a family (system) of liver enzymes - the cytochrome p450 (cyp) system. these enzymes are responsible for phase 1 and 2 reactions

phase 1 reaction

oxidation/reduction reactions by oxygenases and reductases, can occur first but dont have to, simpler transformations - oxidation reduction reactions

phase 2 reaction

formation of conjugates by transferases; drugs are conjugated with a sugar, an amino acid or sulfate,

conjugation reactions

example of metabolism, explain

a drug starts as the first compound, once it goes through a phase 1 reaction a hydroxyl group is added, after it undergoes a phase 2 reaction, from the hydroxyl group, a large glucuronide is added, resulting in the drug becoming soluble, larger, easier to trap, and easily removed in the urine (renal excretion)

what are some consequences of metabolism? metabolites can become:

more water soluble - increased renal excretion

more active (increased therapeutic effect)

--completely active from an inactive drug (called prodrugs)

less active

completely inactive

more or less toxic

---example of drug with toxic metabolite that is clinically relevant: acetaminophen

some drugs are administered pharmacologically inactive and need to be activated via metabolism. these are referred to as ...

prodrugs

why do prodrugs have complications

due to reduced effectiveness if metabolic enzyme is inhibited (drug drug interactions)

examples: clopidogrel (anti-platelet); carbamazepine (anti-epileptic); tamoxifen (hormone chemotherapeutic)

what are some factors affecting drug metabolism

genetics and aging

why can aging affect drug metabolism

very young patients have lower drug metabolism

teens-60 years have a higher drug metabolism

elderly have lower drug clearance

---decreased absorption

---altered distribution

---decreased metabolism

---decreased excretion

excretion

removal of drug from the body, primary route: gi tract and kidney

what are other potential routes for elimination

GI tract (secretion via liver into bile)

kidney (urine)

sweat glands

respiratory tract (exhaled air)

saliva

tear duct

hair

mammary glands (milk production)

hepatic/gastrointestinal elimination

secretion into bile and small intestine

enterohepatic cycling

drug conjugate secreted into the bile and reconverted to parent compound by intestinal bacteria can be reabsorbed from the small intestine - recycling

consequence of hepatic/GI elimination:

alteration of the intestinal flora can affect the ....

action of some drugs

what is the consequence of enterohepatic cycling

it increases drug duration of action, drug half life

renal elimination

glomerular filtration - hydrostatic pressure

active secretion to proximal tubule

passive reabsorption from distal tubule back into systemic circulation

drugs can passively diffuse from urine into tubular cells and back into blood stream - recycling

---ph of urine and pKa of drug are important

what influence does urinary ph have on renal elimination

can affect excretion of weak acids and weak bases

more alkaline urine will result in greater excretion of weak acids/reabsorption of weak bases

-forced alkalinize diuresis

more acidic urine will result in greater excretion of weak bases/reabsorption of weak acids

-forced acidification diuresis

forced alkalinize diuresis

administer bicarbonate or use of diuretic such as acetazolamide will increase bicarbonate in urine and make it more alkaline

forced acidification diuresis

administer ammonium chloride

explain this image

drug goes into the body, circulates through, and then is eliminated

explain this image

you have time for a given drug and time, time is 0 bc drug was just administered, overtime it gradually is absorbed into systemic circulation into plasma, and it gradually increases until it plateaus, more is being eliminated than absorbed, concentration decreases over time until it gets back down to 0. if you ask the patient when they feel the drug you can mark onset of the drug (15 minutes) so plasma concentration is about 35, so anything above this point, they are feeling the drug. drug duration is 7 hours

first order elimination

rate of elimination proportional to concentration of drug remaining in body

constant percentage of drug eliminated per unit time (ex: 50%/4 hr)

plasma half life (t1/2)

time necessary to reduce plasma levels by one half

what is the consequence of first order elimination

drug fully eliminated from body in set amount of time regardless of starting dose (time based on drug half life)

explain this image

if you administer a drug intravenously it will look like this. this drug has a half life of 4 hours, so every 4 hours half of it is eliminated, regardless of the starting dose, after the certain amount of time they will all reach a point and is eliminated at the same time

first order elimination multiple dosing

impact of dosing frequency and dose

both example dosing regimens give the same average plasma concentration over time

however the blue curve has much more variability in hour to hour plasma concentration

explain this image

both lines represent a drug with the same half life

the blue line: drug being administered less frequently with a larger dose

the red line: drug being administered more frequently with a lower dose

zero order elimination

also referred to as rate limited elimination

constant rate of elimination irrespective of plasma concentration

constant amount of drug eliminated per unit time (ex: 50mg/4hr)

most notable example is ethanol

what is the consequence of zero order elimination

time to fully eliminate depends upon initial dose (no half life)

explain this image

the time to eliminate depends on the amount taken. double dose, double time to eliminate. same drug in the image just different dose