Pharm Quiz 1 learning objectives

absorption

the movement of a drug from its site of administration to the bloodstream

distribution

the movement of the drug between the bloodstream and tissues/body compartments

metabolism

enzymatic chemical modification of a drug, primarily by the liver

excretion

removal of drug or its metabolites from the body, most commonly through the kidneys into urine

CYP enzymes

particularly P450 enzymes in the liver, metabolize many drugs

CYP inhibition

decrease enzyme activity —> decrease metabolism of susceptible drugs —> often increase drug concentration

CYP induction

increase enzyme expression/activity —> increase metabolism —> often decrease drug concentration

metabolism

which process is impacted by liver failure?

excretion

which process is impacted by renal failure

distribution

if a patient is malnourished with low albumin, which process will be most influenced.

decreased albumin —> increased unbound drug fraction —> potentially greater tissue ______ and altered apparent volume of ______.

factors that affect the distribution of drugs

• blood flow/perfusion to tissues

• plasma-protein binding, especially albumin

• lipid solubility and ability to cross cell membranes

• tissue binding/barriers, including BBB

• molecular size, ionization pH, and body composition

bioavailability

the fraction of administered dose that reaches the systemic circulation unchanged

first-pass effect

metabolism of an absorbed drug, especially by the intestinal wall and liver, before it reaches the systemic circulation. it lowers oral bioavailability.

enterohepatic cycling

drug/metabolite is secreted by the liver into the bile —> enters intestine —> is reabsorbed —> returns through the portal circulation to the liver/systemic circulation

• this recycling can prolong a drug’s prescence and efects

IV (FIV=100%)

What route has higher bioavailability: intravenous or PO?

IV

What route has higher bioavailability: IV or IM?

polymorphism

a relatively common variation in DNA sequencing among individuals

• can alter drug-metabolizing enzymes, transporters, or receptors, and therefore change a person’s response to a drug

Cmax

maximum plasma concentration achieved after drug administration

Tmax

time required to reach Cmax

AUC

area under the plasma concentration vs time curve

• represents total systemic drug exposure

MEC

minimum effective concentration

• the plasma concentration below which the desired therapeutic effect generally does not occur

Duration of action

length of time that drug concentrations remain high enough to produce the therapeutic effect, often conceptualized as time ABOVE the MEC

AUCoral/AUC IV

formula for bioavailability

volume of distribution

the apparent volume into which a drug distributes based on the amount of drug in the body relative to its plasma concentration

• Vd = amount of drug in body/plasma drug concentration

• tells you how much a drug appears to leave the bloodstream and distribute into tissues

low Vd

if a drug extensively enters/binds to tissues: increase concentration in the plasma, means _____

high Vd

decreased concentration in the plasma -→ _______

First order elimination

constant fraction per unit time

First order elimination rate

proportional to concentration

first order half-life

constant

First order concentration vs time

exponential decline

first order typical situation

most drugs

first order examples

most therapeutic drugs

zero order elimination

constant amount per unit time

zero order elimination rate

independent of concentration

zero order half-life

not constant

zero order concentration vs time

approximately linear decline

zero order typical situation

saturated elimination pathway

zero order examples

ethanol at common intoxicating concentrations

steady state concentration

rate of drug administration = rate of drug elimination

• generally considered effectively reached after 4-5 half-lives

steady state concentration

dosing rate/clearance rate

tripling the steady-state concentration

Tripling the dose of a drug affects steady state drug concentration by …

increases

Tripling the half-life of a drug (as a result from reduced elimination), means steady state concentration ______

decreasing the steady state by half

Cutting the dose in half affects steady state drug concentration by …

competitive inhibitor

competes with the agonist for the same receptor binding site

• its effect can generally be overcome by increasing the concentration of the agonist

• it shifts the agonist dose-response curve to the right, increasing EC50 but not decreasing Emax

non-competitive inhibitor

reduces receptor activity in a way that cannot be overcome simply by adding more agonist

by binding irreversibly or binding at an allosteric site

generally decreases the maximal response (Emax)

Nuclear receptor

receptor is inside the cell and causes the cell to initiate transcription and create new proteins

drug —> intracellular receptor —> DNA transcription —> new proteins

ligand-gated ion channel

binding causes alteration fo the conductance of ions, resulting in signaling changes

GPCR

binding on the cell membrane causes a cascade of changes inside the cell

steroid hormones MOA

steroid hormones are lipid soluble, allowing them to diffuse through the cell membrane and bind to intracellular receptors in the cytoplasm or nucleus

• because transcription and synthesis take time, many steroid effects have a relatively slow onset, but prolong duration

affinity

how strongly a drug binds to its receptor

efficacy

the ability of the bound drug to activate the receptor and produce a response

antagonist

a drug that has high affinity but zero efficacy

• binds well but does not activate the receptor

agonist

binds to a receptor and activates it, producing a biological response

• possesses both affinity and efficacy

antagonist

binds to a receptor but does not activate

• prevents an agonist from activating the receptor

• possesses affinity but essentially no efficacy

partial agonist

• activates the receptor but has lower efficacy

• even when all available receptors are occupied, it cannot produce the same maximum response as the full agonist

desensitization

a decreased response to an agonist following prolonged or repeated agonist exposure

• mechanisms can include receptor phosphorylation, receptor internalization, uncoupling from signaling pathways, and downregulation of receptor number

supersensitivity

increased response, commonly following prolonged reduction in receptor stimulation or chronic antagonist exposure

• one mechanism is upregulation of receptors

same

A 65-year-old patient with chronic pain reports needing more oxycodone to control his pain.   

He has been on the same dose for 3 months and is requesting an increase. Compared with when he started opioid therapy: 

binding affinity for oxycodone at receptor site is the _____

decreased

A 65-year-old patient with chronic pain reports needing more oxycodone to control his pain.  

He has been on the same dose for 3 months and is requesting an increase. Compared with when he started opioid therapy: 

the number of opioid receptors on the cell membrane is _______

downregulation

long-term adaptation to an increase in agonist is ______ of receptors

upregulation

a long-term adaptation to antagonist is _____ of receptors

pharmacodynamic tolerance

the target tissue becomes less responsive to the same concentration of drug because of adaptiations such as receptor desensitization/downregulation and downstream signaling changes.

ED50

the dose that produces the specified therapeutic effect in 50% of the population

therapeutic index

ED50/TD50

• larger = larger margin of safety

certain safety factor

TD1/ED99

autonomic nervous system

smooth muscle, gland, cardiac tissue

somatic nervous system

skeletal muscle

parasympathetic

The _____ nerves have long preganglionic fibers, and short postganglionic fibers

sympathetic

The ______ nerves have short preganglionic fibers and long postganglionic fibers

sympathetic

The _____ nerves release Ach which activates the adrenal medulla to release E and NE

acetylcholine

neurotransmitter released based on the following: Autonomic ganglia (both parasympathetic neuromuscular junction and somatic neuromuscular junction)

norepinephrine

neurotransmitter released based on the following: sympathetic NMJ

acetylcholine

neurotransmitter released based on the following: enteric nervous system