General Principles of Pharmacology Flashcards
pharmacology
branch of medicine that deals with interaction of drugs with the systems and processes of living animals
drugs
broadly defined as any chemical agent that affects living processes
- affects mind/body
- used to diagnose, treat, prevent
- used recreationally for effects on CNS
pharmacology derived from Greek word..
pharmakon; a magic charm for tearing disease
-later came to mean a remedy or drug
different drug names
- brand
- generic
- pre market manufacturer code
- chemical
pharmacokinetics
- what the body does to the drug
- process of absorption, distribution, metabolism/biotransformation, and excretion
pharmacodynamics
- what the drug does to the body
- processes of receptor binding, signal transduction, biological effect
Most drugs are supposed to be …. because ….
beneficial; they are prescribed based on known mechanism of action
side effects
secondary effect due to known mechanism; expected
adverse effects
due to interactions of some UNKNOWN mechanisms; unexpected
iatrogenic effect
and adverse effect or complication caused by a physician resulting from medical treatment or device
enteral
through the digestive tracts
-oral, sublingual, rectal
parenteral
a route other than the digestive tract
-intravenous, intramuscular, subcutaneous, intraatrerial, intrathecal, intraperitoneal
intravenous
100% bioavailability
drug absorption
the passage of drug from site of administration into general circulation
better absorbed
non-ionized, small molecules, lipid soluble drugs
two organs where cell layer is interrupted (fenestrations/pores)
- capillary beds in kidney glomerulus (tubular space in nephron, gaps between endothelial cells)
- liver (interstitial space in organ)
sites that act as a barrier created by uninterrupted cell layers
GI tract epithelium, capillary beds
pKa
the pH at which half o the drug is ionized
acid/acidic
- proton donor
- more protons
- protonated form is charged and better absorbed (non ionized)
base/alkaline
- proton acceptors
- less protons
- protonated form is charged and not well absorbed (ionized)
ion trapping
-an acidic drug would accumulate on more basic side of membrane and a basic to the more acidic side
To increase excretion of acidic drugs such as phenobarbital…
intravenous sodium bicarbonate is given
To increase excretion of basic drugs such as amphetamine..
ammonium chloride or ascorbic acid may be given
bioavailability
the fraction of an ORALLY given drug that reaches the circulation (fraction between 0 and 1)
bioavailability =
quantity of drug reaching systemic circulation / quantity of drug administered
Metabolizing enzymes in…
intestinal wall and/or liver
Everything taken orally must go through…
the liver
If taking drugs sublingually, they go straight to..
the heart and bypass metabolism through the liver
cheese-wine rxn
- tyramine in cheese and wine, metabolized by monoamine oxidases
- when patient takes MAO inhibitor, tyramine will be absorbed, reach circulation and nerve terminals and release NE
- NE stimulates adrenergic receptors causing tachycardia and high BP
Most drugs exists as …… or …..
free drug, bound drug (bound to plasma proteins)
factors affecting drug distribution
- ionization
- capillary permeability
- blood flow
- plasma protein binding
drugs in the capillaries of liver and spleen
regardless or whether they are poorly lipid soluble, charged, or polar, drugs leave the capillaries
In the liver and spleen, the capillaries are very…
leaky
capillaries in the brain
-have tight junction, only lipophilic drugs diffuse across unless actively transported
Tissues that receive more …. receive more drug.
blood flow
Drugs reach the majority of tissues via..
the general circulation
Rate at which drugs distribute from bloodstream to tissues depends on..
relative blood flow to various tissues
total body water
2/3 in ICF, 1/3 in ECF (1/3 is intravascular/plasma)
adult blood volume
~5L
Vd
volume of distribution
volume of distribution
a theoretical volume in which the total amount of administered drug should be uniformly distributed throughout the body and to account for its plasma or blood conc.
Vd =
dose administered / plasma concentration
We normally take … of a drug to calculate Vd.
plasma samples
high Vd
indicates that most of the drug is in the extravascular compartment
low Vd
indicates that most of the drug is in the vascular compartment (plasma)
drug metabolism
chemical modification of drugs by enzymes, to make them more polar and therefore readily excretable by the kidneys
drug metabolizing enzymes present in…
- liver
- gastrointestinal wall
- lungs
- kidneys
- skin
- blood
- brain
phase I of biotransformation
making drug more polar thru oxidation, reduction, and hydrolytic reactions
phase II of biotransformation
conjugation to polar groups resulting in most drugs inactivation and rapid excretion
-a chemical group such as glucuronic acid, sulphate, glutathione, amino acids, or acetate is added to the drug
phase I main enzymes
microsomal Cytochrome P450 MonoOxygenase family
Cytochrome P450 MonoOxygenase
- located in the ER
- require O2
- metabolize widest range of drugs
- rxns inactivate a drug
90% of drug oxidation by cytochrome enzymes can be attributed to..
isoforms
- CYP1A2
- CYP2C9
- CYP2C19
- CYP2D6
- CYP2E1
- CYP3A4
CYP3A4
primary enzyme for metabolism of about HALF of ALL drugs
-inhibited or induced by many drugs, which can cause drug-drug interactions
A drug can interact (stimulate or inhibit) with..
drugs, foods, herbals/medicines
Induction or inhibition of phase I enzymes (especially CYT P450) can cause..
drug interactions when two or more drugs that are metabolized by the same enzyme are given
inducers
- cause expression of more enzymes and faster elimination of drugs
- lower than expected drug levels can cause treatment failure
examples of inducers
rifampin, barbiturates, st johns wort
inhibitors
- inhibit activity of enzymes and reduce elimination of substrate drugs
- higher than expected drug levels can cause drug toxicity
examples of inhibitors
- grapefruit juice
- cimetidine
- erythromycin
- intraconazole
one of the most commonly prescribed antibiotics
erythromycin
Most common P450 polymorphism in Caucasians is the lack of…expression
CYP2D6
CYP2D6
metabolizes codeine to morphine for the analgesic effect; for people lacking expression of CYP2D6, codeine is almost ineffective
Enzymes for Phase II rxns are mostly located in..
the cell cytosol
50% of Americans and 60% of Europeans have reduced expression of..
acetylating enzymes N-acetyl transferase which cause slow metabolism of drugs such as isoniazid (antiTB drug), procainamide (anti-arhythmic drug) and caffeine
factors affecting drug metabolism
- lipid solubility
- 1st order or zero order rate of metabolism
- blood flow to liver
- maturation of metabolizing enzymes
- diseases of liver and kidney
prodrugs
inactive precursor with favourable pharmacokinetics, which metabolize into the active drug in the body
-useful for when certain drugs do not reach their site of action because of pharmacokinetic obstacles
omeprazole and lansoprazole
prodrugs used to reduce stomach acid secretion
-proton pump inhibitors
levo-dopa
a prodrug that is converted into the active compound dopamine used for Parkinson’s disease
P-glycoprotein
- an EFFLUX pump that uses ATP to remove compounds for INSIDE to OUTSIDE and protects CNS
- has a broad substrate specificity, located at many site on luminal surfaces (cancer tissue)
- can be induced and inhibited
P-glycoprotein expression is induced by..
St. John’s Wort, rifampin
P-glycoprotein is inhibited by …
verapamil, quinidine, macrolide, antibiotics, antifungals
clinical significance or P-glycoprotein
- plays a role in drug resistance to cancer chemotherapeutic agents
- pumps out anticancer drugs
phenothiazine and cyclosporin A
calcium channel clockers that inhibit P-glycoprotein and may be useful to reverse resistance
enterohepatic recirculation
a phenomenon that prolongs the duration of action (half-life) of a drug and allows recycling of bile salts
95% of bile salts are…
reabsorbed and used in cholesterol systhesis
cycle of estrogen during enter-hepatic recirculation
- conjugation of estrogen to estrogen glucuronide
- excreted as bile
- deconjugation in the intestines by bacterial enzymes
- reabsorption via circulation
affecting factors of excretion
- lipid solubility
- first order or zero order
- blood flow to kidney/GFR
- maturation of metabolizing enzymes
- dises of liver + kidney
- competition for transport systems in renal tubules
- pH of blood and urine
- plasma protein binding
clearance
volume of blood from which a drug is irreversibly removed
Use for knowing clearance values?
useful to calculate maintenance dose (rate of administration) of a drug
rate of administration/ maintenance dose should be equal to..
rate of elimination
filtration
- passive
- only free drug is filtered at glomerulus (not protein-bound drugs)
drugs that are strong acids and strong bases are secreted through… and is an … process
proximal tubule, active
net removal =
filtered + secreted - reabsorbed
most drugs are eliminated according to ..
a first order rate process
first-order rate process
a CONSTANT FRACTION of a drug is eliminated per unit of time
metabolizing enzymes located in..
liver
how much of a drugs metabolized?
1/5th
zero-order rate process
a CONSTANT AMOUNT of a drug is eliminated per unit of time
How does the zero-order process determine the constant amount?
it is the maximum rate of elimination when the pathway for ELIMINATION IS SATURATED
half-life
time required for the blood or plasma conc. of a drug to be reduced by 50%
If a FIXED dose is given repeatedly at fixed intervals, it takes… half-lives for that drug to achieve steady state conc. in the plasma (for about 97% of a drug to be effectively eliminated from the body.
5
finding half-life applies to drugs that are eliminated by …. order rate
first
Time to steady state or elimination is independent of..
dosage
Increased effect from a drug interaction can cause..
toxicity
Decreased effect in a drug interaction can cause…
treatment failure
Drug use is greatesr among…
frail elderly, hospitalized patients, and nursing home residents
drug-drug interaction
between two drugs metabolized by the same CYP isoform
drug-food interaction example
drugs metabolized by CYP enzymes and grapefruit juice
drug-herb interaction example
drugs metabolized by CYP enzymes and St. Johns Wort
pharmacodynamic interaction
two drugs affecting the same system (effect on the organism)
pharmacokinetic interaction
one drug changes the absorption, distribution, metabolism, excretion of another.
absorption DDI example
antacids reduce absorption of tetracycline
-calcium supplements reduce absorption of thyroxine
Distribution DDI example
-competition for plasma protein binding by non-steroidal anti-inflammatory drugs (NSAIDs) and warfarin (anticoagulant)
excretion DDI example
probenecid reduces excretion of penicillin by competition for the kidney tubule transport system
most common reason for DDI?
one drug affecting the metabolism of another drug
liver and kidney affects?
metabolism and excretion and plasma levels of many drugs
When should the possibility of DDIs be considered?
when a patient is taking two or more drugs
When taking a single drug metabolized by the cytochrome P450 enzyme, what should be considered?
interactions with food items or herbal medecines
In cases of drug toxicity or treatment failure, what should be considered?
genetic variation of metabolizing enzymes
