Intro Flashcards
Pharmacology
science of drugs including their origin, composition, pharmacokinetics, therapeutic use, and toxicology
Pharmacokinetics
what the body does to a drug as it goes through absorption, distribution, metabolism, and elimination
Pharmacodynamics
what the drug does to the body
Pharmacokinetic properties determine
the onset
the intensity
the duration of drug action
How can pharmacokinetic properties optimize drug regimens?
route of administration
dose
frequency
duration of treatment
Absorption
process of a drug entering the systemic circulation
distribution
process of a drug leaving the systemic circulation and entering the interstitium (ECF) and the tissues
metabolism
process of a drug converting from its original chemical structure into other forms to facilitate elimination from the body
elimination
process of removal of a drug from the body
bioavailability
extent of administered drug that reaches systemic circulation
high >70%
low < 10%
What affects bioavailability?
first pass metabolism in intestine/liver
solubility of drugs
chemical instability
nature of drug formation
Hydrophilic drugs are poorly absorbed due to their inability to cross?
lipid-rich cell membranes
enteral
admin by mouth
includes enteric coated, extended release, sublingual, and buccal
Parenteral
admin directly into systemic circulation
includes IV, IM, SC
Enteral Absorption is
variable
Advantages of Oral admin
safe and common
convenient
economical
disadvantages of oral admin
limited absorption of some drugs due to physical characteristics
1st pass metabolism
drug absorption affected in presence of food/other drugs
low patient compliance
What is 1st pass metabolism?
Destruction of drugs by digestive enzymes or low gastric pH before reaching systemic absorption
Enteric coated preparations
chemically envelope drugs
prevent a drug from causing gastric irritation
prevent a drug from dissolving in stomach acid, helps it to reach the site of action in the ileum and colon
Extended Release preparations
decrease the rate of dissolution to provide slow uniform absorption > 8 hr or longer
Advantages of Extended released preparations
decr frequency of dosing, incr patient compliance
maintain therapeutic effect overnight
decr incidence of adverse effects
decr non therapeutic blood levels of the drug that often occur after admin of IR dosage forms
Sublingual admin
under the tongue
buccal admin
between cheek and gum
Absorption pattern of sublingual and buccal admin
rapid
direct systemic absorption
Advantages of Sublingual/ buccal admin
easy admin
rapid absorption
bypass 1st pass metabolism
Disadvantages of sublingual and buccal admin
limited application to certain types of drugs
only drugs with small doses
must be nonirritating
Parenteral Admin advantages
rapid onset of action
bypass 1st pass metabolism
useful for drugs that are poorly absorbed/ unstable in GI tract
highest bioavailability
deliver to unconscious patients
Disadvantages of Parenteral admin
irreversible admin not good if ADR occurs
pain, necrosis
infections at site of injection
IV admin
into venous blood stream directly
absorption not required
IV admin advantages
immediate effect
ideal for drugs with large volumes
suitable for irritating substances and complex mixes
dose titration
ideal for protein and peptide drugs
IV admin disadvantages
unsuitable for oily substances
irreversible admin not good in case ADR occurs
precipitation of blood constituents, hemolysis
requires slow injection
IM admin
into the muscle
IM admin absorption
depends on drug diluent
in aq solns prompt
in depot preparations slow and sustained
IM admin advantages
moderated drug volume
suitable for oily vehicles and some irritating substances
IM admin disadvantages
painful
potential IM hemorrhage
SC admin
beneath the skin
SC admin absorption
depends on drug diluents
in aq solns prompt
in depot preparations slow and sustained
SC admin advantages
suitable for slow-release drugs
suitable for some poorly soluble suspensions
SC admin disadvantages
pain/necrosis if irritating drugs
unsuitable for large volumes of drugs
Inhalation absorption
systemic
Inhalation admin advantages
rapid absorption
access to blood due to large lung surface area
ideal for gases/volatile substances
dose titration
localized effect to target lungs
fewer systemic side effects
Inhalation admin disadvantages
most addictive route
difficulty in regulating dose
difficulty using inhalers
Topical admin
local admin for local effects
mucous membranes
conjunctiva
nasopharyngeal
oropharynx
vagina
colon
urethra
urinate bladder
In mucous membranes absorption is generally ?
excellent
What are some examples of topical eye admin?
Drug loaded contact lenses
ocular inserts
Transdermal admin
admin to skin
Transdermal admin absorption
slow and sustained
dependent on surface area and lipid solubility of drugs
Transdermal admin advantages
convenient
painless
bypass 1st pass effect
Transdermal admin disadvantages
irritation
only highly lipophilic drugs
delayed drug delivery to site of action
only drugs with small daily doses
rectal admin
drug absorbed via rectal mucosa
rectal admin absorption
erratic and variable
Rectal admin advantages
partially bypass 1st pass metabolism
ideal for drugs that cause gastric irritation, nausea and vomiting
ideal for patients that are comatose
Rectal admin disadvantages
irritation to rectal mucosa
lack of patient acceptability
intra-arterial admin
delivers drug to a particular tissue, or as a diagnostic agent
accidental admin here cause serious complications
Intrathecal admin
injection directly into the cerebrospinal fluid
bypass blood-brain barrier
used for treatment of brain tumors and for spinal anesthesia
What affects drug absorption?
pH
blood flow to the absorption site
total surface area available for absorption
contact time at the absorption surface
expression of a transmembrane transporter protein
Can charged drugs (A^- or BH^+) diffuse through biological membranes?
no
For drugs to cross biological membranes what do they need?
to be lipid soluble/ have a specific transporter
What affects drug distribution?
blood flow
capillary permeability
binding of drugs to plasma proteins and tissue proteins
lipophilicity of the drug
volume of distribution
Which organs receive most of the administered drug?
liver
kidney
brain
other well-perfused organs (lungs)
Which organs have slow drug distribution?
muscle
visceral organs
skin
fat tissues
Does plasma protein binding increase or decrease the amount of drug that can enter tissues from the blood?
decrease
Albumin
binds to acidic drugs
alpha1-acid glycoprotein
binds basic drugs
Fat tissue reservoirs
where lipid soluble drugs accumulate
prolongs half-life of drug and duration of action
Bone tissue reservoir
mostly seen with divalent metal-ion chelating agents and heavy metals accumulate into bone crystal lattice
slow release of toxic agents
What do the tight junction in brain capillary endothelial cells prevent?
The diffusion of hydrophilic drugs from the blood into the CNS
What do the membrane transporters in brain capillary endothelial cells of the blood brain barrier do?
remove drugs from the CNS
decr effectiveness of protease inhibitors for treating HIV in the CNS
What do pericapillary glial cells in the blood brain barrier do?
Form and maintain the blood-brain barrier
establish a diffusion barrier
Placental barrier
placenta has a [high] of metabolic enzymes and export transporters to decrease the [drugs] that enter fetal circulation
to some degree the fetus is exposed to all drugs taken by the mother
Can uncharged drugs diffuse through biological membranes?
yes, so HA will diffuse through acidic environments, and bases will diffuse through basic environments
Distribution of the drug between ionized and non-ionized forms is dependent on?
pH and pKa of the drug
When pH = pKa what is the behavior of acids and bases?
[HA] = [A^-]
[BH^+] = [B]
When pH<pKa what is the behavior of acids and bases?
[HA] > [A^-]
[BH^+] > [B]
protonation is favored
When pH>pKa what is the behavior of acids and bases?
[HA] < [A^-]
[BH^+] < [B]
deprotonation is favored
What is the henderson - hasselbalch equation
ratio of nonionized to ionized drug at given pH
log (protonated form/unprotonated form) = pKa - pH
What percentage of drugs are eliminated unchanged in the urine?
25-30%
What are the primary organs of metabolism?
liver
GI tract
kidneys
lungs
Biotransformation
process by which lipophilic, xenobiotic, or endobiotic chemicals are converted in body by enzymatic reactions to products that are more hydrophilic.
Metabolism Phase 1 reaction
oxidation, reduction, hydrolysis
drug may be activated, unchanged, or often inactivated
done by cytochrome P450
converts lipophilic drugs in to polar molecules
result: loss of pharmacologic activity, can sometimes prolong/enhance it
Metabolism phase 2 reaction
conjugation
conjugated drug is usually inactive
drugs are bound covalently to polar water soluble molecules which are then removed in urine or feces
Prodrugs
drugs that are inactive in the original structure but activated by phase 1 metabolism
What reactions are included in phase 2 metabolism?
glutathione conjugation
sulfation
acetylation
glucuronidation
Which is eliminated more rapidly, water soluble polar molecules or lipid soluble drugs?
water soluble polar molecules
What is the general process of drug clearance by the kidney?
- Glomerular filtration
- Active Tubular secretion
- passive tubular secretion
What is glomerular filtration
Free drug passes through the capillary into the bowman space
What is the glomerular filtration rate?
125 mL/min
If renal disease is present what decreases?
GFR
Does lipid solubility of drug and the pH of the medium affect the glomerular filtration process?
no
Does GFR and drug-protein binding affect glomerular filtration process?
yes
Proximal Tubular secretion
for drugs not transferred into glomerular filtrate
drugs leave glomeruli through efferent arteries
secretion of organic cationic drugs and organic bases primarily happens by energy-requiring active transport systems
Distal tubular reabsorption
as a drug moves towards this its concentration incr
uncharged drugs diffuse out the nephric lumen and go back into systemic circulation n
can manipulate urine pH to minimize this
To minimize distal tubular reabsorption what should be done for an acidic drug? A basic drug?
for acidic drugs alkaline the urine
for basic drugs acidify the urine
When drug concentration in the filtrate is greater than in the tubular lumen…
hydrophobic drugs diffuse out
Are polar/ionized conjugate able to diffuse out of the kidney lumen?
no
Biliary Excretion
transporters in liver cells transport amphipathic lipid soluble drugs into the bile which is then eliminated in feces
Enterohepatic Recycling
some drugs that are secreted into the bile can be reabsorbed by the intestinal tract and renter the circulation
passive diffusion
concentration gradient across a membrane
[high] the gut lumen -> [low] the blood
no energy/carrier
not saturable
majority of drugs absorbed this way
water soluble drugs: aqueous channels/pores
lipid-soluble drugs: dissolve in lipid bilateral membranes and cross the biological membranes
facilitated diffusion
concentration gradient across a membrane
does not require energy
[high] -> [low]
requires carriers
- conformational changes
- can be saturated
- could be inhibited by compounds competing for the carrier
Active transport
against a concentration gradient across a membrane
[low] -> [high]
requires energy
requires carriers
- can be saturated
- selective
- may be inhibited by co-transported substances competing for the carrier
endocytosis
large drug molecules engulfed by the cell membrane and transported into the cell through a vesicle
P-glycoprotein
transmembrane transporter protein
transports drugs from tissues to blood by pumping drugs out of cell
if highly expressed it reduces drug absorption
associated with multidrug resistance
