Pharmacokinetic Basis of Therapeutics and Pharmacodynamic Principles

Generic vs. Brand Name

generic name: cheaper

brand/trade name: specific brand/name
specific brand/manufacturer
10-15 year patent (only specific brand/manufacturer is allowed to make the mx)→other manufacturers can make after with generic name

Medication Prescription Essential Parts

demographics:
date
name
address
DOB

prescriber:
name
address
phone number
signature

mx name

dosage/amount of medication

route/manner of administration

frequency/time of administration

Steps of Prescribing Process

1. thorough history and physical examination

2. formulate a diagnosis

3. establish tx plan
   a. pharmacologic
   b. nonpharmacologic

MX:
select mx:
therapeutic valve vs. risks
mechanisms of action
side effects
interactions (CI)
convenience
storage needs
route of administration
efficacy
cost

ethical and practical issues:
on or off label
pt expectations (pt. wants specific tx)

pt. education:
intended therapeutic effect
potential side effects
how to deal with adverse drug reactions
warning (black box warnings)

Substitutions for Brand Name Mx

if generic version available→it will be dispensed

unless written:

DISPENSE AS WRITTEN
or
DO NOT SUBSTITUTE

Factors Influencing Patient Adherence to Mx

complex tx regimen

prescriber not approachable/motivating

pts take more/other mx

high out of pocket cost

dosage route isn’t best

pt feel like mx works→stop taking it

pt experiencing side effects

ABCDX Pregnancy Categories

old method→not used/phasing out

A: pregnant female controlled study→no risk of fetal abnormalities→safe for pregnant use

B: animal controlled study→safe in animals+no human studies

C: no studies→benefits may outweigh risk
“middle ground”

D: studies demonstrated risk→only for life threatening situations
“emergencies only”

X: studies showed positive evidence of fetal abnormalities→DO NOT USE

PLLR Pregnancy Categories

New method after June 30, 2015

pregnancy and lactation labeling rule

OTC drugs do not change

Pharmacokinetics vs. Pharmacodynamics

Pharmacokinetics: how the body affects the drug
how much of an administered dose will get to its site of action
-reason for giving mx certain dose/route/time

Pharmacodynamics: how the drug affects the body
what effects of a drug will do to the site of action
-how the drug affects the body

Pharmacodynamics Affecting Factors:
-drug-receptor interaction (binding of the drug to it’s receptor/protein to produce an effect)
-characteristics of drugs (lipophilicity/hydrophilicity/size of molecules/etc.)
-pt’s functional state→influences pharmacodynamic processes

4 Pharmacokinetic Principles+Body Locations

ADME:

absorption:
stomach
mouth
small intestine

distribution:
circulatory system
capillaries

metabolism:
liver

excretion/elimination:
kidneys
lungs

Absorption+Factors

the movement of a drug from its site of administration into the blood

rate of absorption: how soon the effects of the drug will begin
ex: depot injections (released slowly over time)

amount of absorption: how intense the effects will be
more absorbed→more intense

impacting factors:

pH of drug+stomach:
ex: aspiring absorbed better than alkaline drugs

lipid/fat solubility:
soluble→more easily absorbed through stomach
insoluble→stays in gut (fiber)

GI motility:
slower transit→more contact time between substance+gut walls

presence/absence of food:
is mx better absorbed with or without food?

surface area available for absorption:
more surface area→faster absorption

blood flow to an area:
more blood flow→more absorption
ex: heat+massage→increased blood flow

Distribution+Factors

the movement of drugs throughout the body

drugs carried by the blood to the tissues/organs of the body

exit bloodstream through capillary beds:
mx pass between capillary cells through little holes
uptake depends on tissue’s capacity to accept the drug

factors enhance mx uptake:
increased lipid solubility
unbound protein fraction of the drug
bound to protein→unable to get out of bloodstream→inactive

Metabolism+Types

converts substances into water-soluble forms for excretion

converts mx into pharmacologically active/inactive forms (biotransformation)

mainly takes place in liver

metabolism types:
active→less active/inactive metabolites
active→active metabolites
prodrug: inactive mx→active mx

Excretion+Factors

removal of drugs from the body

mx+metabolites can exit through:
urine (kidneys)
sweat (skin)
saliva
stool (lower GI tract)
breast milk (mammary glands)
expired air (lungs)

renal excretion factors:
mainly through liver
eliminate unchanged/unbound drugs/metabolites/molecules

glomerular filtration:
low molecular weight
unbound drugs
low volume of distribution

tubular secretion:
occurs in proximal convoluted tubule (PCT)
drug passes from systemic circulation→tubular lumen via transporter (ionized drugs/Penicillin G)

tubular reabsorption:
distal convoluted tubule (DCT)
non-ionized/lipid-soluble molecules reabsorbed into systemic circulation

Affinity vs. Intrinsic Activity

affinity:
the ability of a mx to bind at the receptor site
-determines the potency of mx (how much of a mx is needed to elicit a response)
-”does the mx want to bind to the receptor”

intrinsic activity:
the ability of the drug-receptor complex to initiate a pharmacologic effect
-determines the efficacy of the drug

Bioavailability+Factors

how much of a drug that reaches systemic circulation after dissolving

fraction (F):
measuring factor for bioavailability
percentage of drug that reached systemic circulation
IV mx→100% bioavailability=1
low bioavailability→high first-pass effect

bioavailability factors:
route of administration
ionization
protein binding
metabolism
ability of drug to pass through membranes

Bioavailability Decreasing Factors

physicochemical properties of drug
-water/lipid solubility
-molecular size

presence of food/other drugs in gastric intestinal tract

gastric emptying times

pH of gastric intestinal tract

characteristics of specific mx formula

first pass metabolism

Biliary Excretion+Enterohepatic Recirculation

most metabolites of mx produced in liver→excreted in bile→into the GI tract

enterohepatic recirculation

circulation of metabolites produced in liver (reabsorbed from GI tract)

liver→bile→GI tract→reabsorbed back to the liver

daily→1L bile excreted

First-Pass Effect

metabolization of mx through the liver→reduced strength of mx

Half Life+Steady State

half life: the time required for the amount of mx in the body to decrease by half/50%

steady state: rate of mx administration= rate of mx elimination

-amount of time for the 1st half life to be repeated

-5 half lives→steady state achieved

Clearance+Factors

amount of drug cleared from plasma per unit

depending factors:
renal excretion
metabolism in the liver
metabolism by other organs
combination of events

altering factors:
body weight
body surface area (BSA)
hepatic extraction ratio (first-pass metabolism)
degree of enterohepatic recirculation
renal function
hepatic function
decreased cardiac output

Hydrophilic

mx that has an affinity for water

dissolves easily in water

Hydrophobic

aka: lipophilic

mx that repels water

doesn’t dissolve well in water→dissolves well in lipids

Prodrug

mx that turns pharmacologically active after metabolization

Receptor

a molecule inside/on the surface of a cell that binds to a specific substance and causes a specific effect in the cell

Therapeutic Window+Low Therapeutic Window Mx

Ratio between the median lethal dose (LD50) and the medial effective dose (ED50)

smaller the window→more potential for harm

low therapeutic window mx:
carbamazepine
cyclosporine
phenytoin
tacrolimus
theophylline
warfarin
digoxin
lithium

Volume of Distribution (Vd)

theoretical parameter:
assuming the volume that would accommodate the total mx in the body if the concentration was the same as in plasma

assuming the body behaves as a single compartment→mx is evenly distributed

Vd (in L)= total amount of mx in body (in mg)/plasma drug concentration (in mg/L)

if mx is extensively distributed→blood concentration lower→larger volume of distribution

-lower amount of plasma drug concentration→increased Vd (blood leaves bloodstream→more mx distributed)

-higher amount of plasma drug concentration (mg/L)→lower Vd (blood stays in bloodstream→less mx distributed)

Volume of Distribution (Vd) Factors

lipid solubility (high lipid solubility→high Vd)

affinity for different tissues

blood flow (brain vs. fat)

disease states

plasma protein binding

Minimum vs. Maximum Dose

minimum dose: minimum amount of mx before insufficient usage

maximum dose: maximum amount of mx before a toxic response

Therapeutic vs. Toxic vs. Lethal Dose

therapeutic dose: the amount of dosage that causes the desired response in 50% of patients

toxic dose: amount of dose that causes toxicity

lethal dose: amount of dose that causes death in 50% of population

Agonist vs. Partial Agonist vs. Antagonist

agonist: mx that activates a receptor by binding to it
intrinsic activity

partial agonist: mx that activates a receptor by binding to it→doesn’t elicit the maximum possible response

antagonist: mx that binds to a receptor without activating the receptor+prevents agonist from exerting effect
competitive vs non-competitive

Gated Ion Channels (Na+ Channel Receptor)

1. agonist binds to receptor→activation

2. Na released into cell

3. conductance/action potential activation (depolarization)

Transmembranous Receptors (Tyrosine-Kinase Receptor)

1. phosphorylation of tyrosines on key signaling molecules

2. activation of cell signaling

G Protein-Coupled Receptors

1. agonist binds to receptor→activation

2. g-protein activated

3. second messenger created

4. activation of cell signaling

Intracellular Receptors

1. agonists passes through phospholipid bilayer→inside cell→activation

2. activation of transcription+translation

Efficacy vs. Potency

efficacy: the ability of mx to produce the desired beneficial effect under ideal conditions
-determined by affinity

potency: the concentration or dose of mx required to produce a specific effect
-determined by intrinsic activity

Routes of Administration: Enteral

“the gut”
lips to anus

PO/per oral (mouth)
SL/sublingual (under tongue)
buccal (cheek)
PR/per rectum (rectal)

advantages:
lower cost
more convenient
easier consumption
efficiency

disadvantages:
NPO
unconscious pt.
limitations to dosage
mx formation

Parenteral

“not into the gut”

IV (intravenous)
SC/SQ (subcutaneous)
IM (intramuscular)
INH (inhalation)
TD (transdermal)
Top (topical)

advantages:
fast absorption
continuous dosage
easier administration

disadvantages:
infection risk
difficulty in access
more expensive
painful
varied absorption results
can’t retrieve dosage

Protein Binding

mx can form reversible bonds with various proteins
ex: albumin/alpha-1 acid glycoprotein/lipoproteins

most abundant/important→plasma albumin
-large molecule→always remains in the bloodstream
-impacts drug distribution

only free/unbound fraction of drug is pharmalogically active
-increase in available proteins→increase in protein binding+less available active drug

drug protein complex maintained by a weak bond
-changes in binding are important for drugs that are highly protein bound
ex: warfarin/phenytoin/propanolol/diazepam

Cytochrome P-450 Enzyme System (CYP450)

mixed-function oxidase system
-involves both oxidation and reduction

responsible for metabolism of most mx

lipid solubility (non-ionization) of mx favors passage across cell membranes

individual differences in microsomal enzyme systems→genetically determined

Active vs. Inactive Metabolites

active metabolite: metabolic product with pharmalogical activity
-produces therapeutic/toxic effects

ex: codeine→morphine (active)
diazepam → desmethyldiazepam → oxazepam (active)
prednisone → prednisolone (active)

inactive metabolite: metabolic product without pharmalogical activity
-no therapeutic effect→excreted

ex: Morphine → Morphine-3-glucuronide (inactive)

Lidocaine → Monoethylglycinexylidide → Glycinexylidide (inactive)
Propranolol → various oxidized forms (inactive)

Creatinine Clearance+Renal Drug Excretion

renal function: quantitated by creatinine clearance
measure on lab by serum creatinine

degree of renal function factors:
age
weight
SCr

Cockroft-Gault equation:
Estimated CrCl= (140-age) x (weight in kg) x 0.85 (for F)/72 x SCr

Pharmacist/PharmD

4 years of pharmacy school→graduation: doctor of pharmacy→1-2 year residency/fellowship (optional)

coursework:
-immunology
-microbiology
-anatomy
-physiology
-pathophysiology
-chemistry (organic/bio/molecular)
-healthcare policy+law
-evidence-based medicine
-pharmacology
-pharmacotherapeutics

Prescription vs Nonprescription Drugs

prescription

must have a prescription

over the counter (OTC)

available without a prescription

ex:

• acetaminophen (tylenol)

• ibuprofen (advil)

• famotidine (pepcid)

• etc

behind the counter (BTC)

no prescription needed→must interact with the pharmacist

ex:

• pseudoephedrine (sudafed)

• emergency contraceptives (plan B)

• insulin→some states

• PO contraceptives→some states

supplements+herbal mx

not regulated by FDA→considered a “food”

Enzyme Activitity Alterations

may be responsible for variations in mx responses in specific pts

• smoking
  hydrocarbons induce hepatic oxidases→increased dose requirements
  -theophylline
  -tricyclic antidepressants

• acute alcohol ingestion
  may inhibit mx metabolism

• chronic alcohol ingestion
  induces microsomal enzymes→metabolize mx→accelerated metabolism of mx

Drug-Drug Interactions during Metabolism (Inhibition vs Induction)

inhibition

• competition for CYP binding sites
  -last a short time

• complexation of metabolite with enzyme system
  -lasts longer

induction

• mx→stimulates synthesis of more CYP enzymes

• time course→unpredictable

Drug Metabolizing Enzymes

CYP1A2

substrate

• theophylline

inhibitors

• erythromycin

inducers

• omeprazole

• phenobarbital

CYP2B6

inducers

• phenobarbital

CYP2C9/2C10

substrate

• s-warfarin

• phenytoin

inhibitors

• amiodarone

• fluconazole

inducers

• phenobarbital

Age-Specific Differences in Metabolism

neonates

• decreased metabolizing enzyme activity

• poorly developed BBB

• immature mechanisms for mx excretion
  -by puberty→develops into adult metabolism

Pulmonary Excretion

occurs by simple diffusion across the alveolar-capillary membrane

rate of loss→not constant

a function of

• respiratory rate

• solubility of mx

First-Order Kinetics

followed by most mx

constant fraction/percentage of the mx is removed from body over a finite period of time

rate constant (Ke)→fraction removed

Patient-Specific Factors/Variables

physiologic variables

• age

• gender

• weight

• nutrition

pathologic variables

• diminished fxn of kidneys

• diminished fxn of liver

genetic variables

• can alter mx metabolism→predispose pt to unique interactions

mx interactions

• can alter mx metabolism