Midterm Flashcards
origin of the word pharmacology
greek
pharmakon = remedy
logos = study
what is pharmacology?
the study of drugs
includes how it is delivered, how it works, the therapeutic effects and adverse effects
classification of therapeutics
drugs - traditional drugs i.e. chemical agents
biologics - ie antibodies, hormones
natural health products - i.e. herbals, vitamins, minerals `
Describe the levels of Canadian Drug Legislation
Food and Drugs Act and Regulations
then Health Canada
then Health Canada Products & Food Branch
then
Therapeutic Products Directorate (traditional drugs)
Biologics and Genetic Therapies Directorate (abs, hormones)
Natural Health Products Directorate (vitamins, herbals etc)
3 types of drug names
chemical name
generic name
trade name
chemical name
describes the chemical structure of the molecule
used by chemists
generic name
a unique name that identifies a drug
most often used in pharmacology and should be used by health care professionals
trade name
assigned by a drug company
easy to remember and marketable
many companies make the same drug so there can be many trade names for the same drug
steps of approval of marketed drugs in Canada
preclinical testing clinical trial application phase I clinical trial phase II clinical trial phase III clinical trial new drug submission submitted to health Canada phase IV clinical trial
about 15 years total, up to $800 million
preclinical testing
also called discovery
in cultured cells, living tissue or experimental animals
evaluate biological effects, pharmacokinetics and toxicity
about 6.5 years
clinical trial application
paperwork detailing all pre-clinical data must be submitted to Health Canada before any human studies
they will respond within 30 days of receipt
phase I clinical trial
20-100 HEALTHY volunteers
evaluation of pharmacokinetics and pharmacodynamics
about 1 year
phase II clinical trial
300-500 PATIENTS with the target disorder
therapeutic effectiveness, side effects, and dosing information gathered
about 2 years
phase III clinical trial
500-5000 patients with the target disorder
therapeutic effectiveness verified, long-term side effects assessed
about 4 years
new drug submission (NDS)
NDS submitted to Health Canada
a report that details therapeutic effectiveness and safety
includes results from pre-clinical and clinical studies
about 1.5 years
if a NDS is approved what happens?
Health Canada issus a Notice of Compliance (NOC) and a Drug Information Number (DIN)
both are required to market the drug
phase IV clinical trial
post-marketing surveillance
Health Canada monitors the efficacy and safety of the drug after it has been marketed (can be pulled i.e. vioxx)
what is pharmacokinetics?
study of drug movement in the body
what the body does to a drug
includes absorption, distribution, metabolism and excretion
when an oral drug is absorbed and goes to the liver what are the 2 options it has?
can enter systemic circulation and go to heart, brain, muscle, kidney etc
or
can enter the bile duct and be excreted into the intestine
when a drug is parenteral where does it go?
absorbed right into systemic circulation
physiological barriers to drug transport
intestinal villi
tight junctions between cells
what happens in the SER?
metabolizes drugs, carbs and steroids
what happens in the golgi?
processes and packages proteins and lipids
why is the cell membrane fluid?
phospholipids are flexible and undulate
3 ways drugs pass through cell membranes
direct penetration
ion channels and pores
transporters
what molecules go through ion channels and pores?
MW <200 (i.e. very small compounds)
examples: Na, K, Li
uptake transporters
move drugs from outside cell to inside cell
mediate intestinal absorption, renal excretion and reaching target sites
efflux tranporters
move drugs from inside cell to outside
protect cells
are found in the intestine, placenta, kidney and BBB
polar drugs
uneven distribution of charge but no net charge
ie kanamycin
ion drugs
total # of electrons is not equal to protons
have a net charge
ie Na+, Li+ etc
quaternary ammonium compounds
at least one N atom and always have a positive charge
cannot cross cell membranes bc of this charge
when can weak acids and bases cross cell membranes?
when un-ionized
ie weak acid in acidic environment or weak base in basic environment
how do drugs move out of capillaries?
hydrophilic drugs pass between fenestrations
lipophilic drugs either pass between fenestrations or directly through PM of endothelial cells
except in the BBB where there are no fenestrations, there are tight junction - drugs either need to be lipophilic or have a transporter to get into brain
absorption
movement of drug from site of administration into the blood
rate of it determines how quickly drug effect will occur
and the amount of it determines how intense the effect will be
6 factors affecting drug absorption
rate of dissolution surface area blood flow lipid solubility pH partitioning activity of transport proteins
how does rate of dissolution affect drug absorption?
drugs need to dissolve before they can be absorbed
faster dissolution = faster onset of action
surface area and drug absorption
larger surface area = faster absorption
this is why there is more absorption in the intestine than stomach (villi vs rugae)
blood flow and drug absorption
absorption is fastest in areas with high blood flow
high blood flow maintains a concentration gradient to drive absorption
exercises increases blood flow
heart failure, severe hypotension, hypothermia and circulatory shock decrease blood flow
lipid solubility and drug absorption
high lipid solubility are absorbed more rapidly
pH partitioning and drug absorption
absorption is greater when theres a difference between pH at the site of administration and the blood such that the drug is ionized in the blood
activity of drug transporters and absorption
uptake transporters increase absorption
efflux decrease it
major routes of drug administration
ENTERAL
- oral
- rectal
PARENTERAL
- intravenous
- intramuscular
- subcutaneous
OTHER
- sublingual
- transdermal
- pulmonary
advantages and disadvantages of oral drugs
safety, convenience, economical
incomplete and variable absorption
are weak acids absorbed better in the stomach or intestine?
intestine - stomach has thick layer of mucus and small surface area so even though they’d be unionized aren’t absorbed better here
pharmaceutical phase
what occurs after an oral tablet is taken
includes the disintegration phase into granules and smaller particles and the dissolution phase
gastric emptying and drug absorption
increasing gastric emptying increases drug absorption because it puts drugs into the intestine where more absorption occurs
increasing gastric emptying
taking meds on an empty stomach
taking meds with cold water
lying down on the right side
high osmolality feeding (i.e. feeding tube)
taking a pro kinetic drug (increases GI motility)
decreasing gastric emptying
high fat meal
heavy exercise
lying down on the left side
taking drug that inhibits vagus nerve (i.e. anticholinergics)
enteric coating
special coating that prevents drugs from dissolving in the acidic environment of the stomach
coating will dissolve once in the intestine
bioavailability
fraction of drug that reaches systemic circulation unchanged
influenced by drug formulation, route of administration and degree of metabolism
bioavailability by drug formulation, lowest to highest
time release capsules enteric coated compressed tablets capsules granules chewable (no disintegration) suspension syrup (no disintegration or dissolution) aqueous solution
sublingual drug delivery
put under tongue, dissolves and is absorbed across oral mucosa
venous drainage from oral mucosa is to the superior vena cava to heart
avoid first pass metabolism
need to be lipophilic and uncharged
is especially convenient for drugs that act on the heart
transdermal drug delivery
need to be lipophilic enough to penetrate epidermis
also need to be relatively hydrophilic to dissolve in ECF
<600 Da
usually sprays, ointments, patches etc
provide constant plasma levels (i.e. minimal troughs and peaks)
tolerance may develop unless there is a drug free period (i.e. take patch off for 6-10 hours a day)
what affects transdermal drug absorption
thickness of skin
hydration
number of hair follicles (give a way to bypass the epidermis barrier)
application area
integrity of the barrier (i.e. psoriasis, burned skin etc increases absorption)
rectal drug absorption
useful when unconscious or vomiting
approx 50% bypasses the liver
given as a suppository which dissolves, crosses the rectal mucosa into the blood
disadvantages include incomplete absorption and some drugs may irritate the rectal mucosa
IV drug absorption
directly into peripheral vein, usually back of the hand or median cubital vein at the elbow (any visible can be used though)
IV bolus or drip
if it is a drip, usually diluted in a vehicle i.e. saline
advantages of IV drug absorption
no barriers, 100% bioavailability
precise control of dosage and duration of action
can administer poorly soluble drugs that need to be diluted in a large volume
can inject drugs that are irritants slowly so they are diluted in blood
disadvantages of IV drug absorption
expensive invasive inconvenient drug cannot be removed once injected risk of infection and fluid overload risk of injecting wrong formulation i.e. giving IM by IV
subcutaneous drug absorption
under skin into subcutaneous tissue
only barrier to absorption is the capillary wall
cannot inject irritants - will cause pain and/or tissue sloughing
primary determinants of rate of absorption are blood flow and water solubility (need to be water soluble to dissolve in ECF)
intramuscular drug absorption
injected into muscle tissue
absorption determined by ability of drug to pass through fenestrations in capillary wall
primary determinants of rate of absorption are blood flow and water solubility
advantages of IM
can be used for poorly soluble drugs
can administer depot preparations
disadvantages of IM
pain/discomfort
can cause local tissue and/or nerve damage if not done properly
how does blood flow affect IM drug absorption
deltoid > vastus lateralis > gluteal
exercises increases
heart failure, severe hypotension, hypothermia decrease
pulmonary drug absorption
gaseous and volatile drugs can be inhaled and absorbed through pulmonary epithelium
very rapid absorption bc there is a large surface area
good for pulmonary disease drugs i.e. for asthma bc they are delivered to site of action
often used for general anaesthetics
what drugs distribute to the interstitial space?
low MW, water soluble
what drugs distribute to the plasma?
strongly bound to proteins, high MW
what drugs distribute to adipose tissue?
lipid soluble
where else do some drug distribute?
muscle
bone - absorb onto the crystal surface and eventually get incorporated in, can be a reservoir for slow release of some drugs
what determines drug distribution? how does this affect blood concentration?
blood flow to tissues
ability to move out of capillaries
ability to move into cells
more distributes = less in the blood
blood flow and drug distribution
well perfused i.e. liver, kidney, brain = rapid distribution
lower blood flow i.e. skin, fat, bone = slow
examples of altered blood flow
neonates have limited blood flow
heart failure or shock
solid tumors have low regional blood flow (decreases towards middle)
abscesses have no blood supply (need to drain)
P-glycoprotein
efflux transporter
protective
facilitates drug excretion and protects body from exposure to drugs and other toxins
active (needs ATP), against concentration gradient
in heptocytes on the bile canicular membrane - excrete in bile
in enterocytes on apical side - prevent absorption into blood
in proximal tubule cells on luminal side - excretion
in neuronal cells on blood vessel side - keep drugs away from brain
albumin
high affinity for lipophilic and anionic (weak acids)
malnutrition, trauma, aging, liver and kidney disease decrease plasma albumin
this increases free drug concentration, can cause toxicity
alpha 1 acid glycoprotein
primarily binds cationic (weak bases) and hydrophilic drugs
aging, trauma, and hepatic inflammation (ie hepatitis) increase plasma alpha 1 acid glycoprotein
decreases free drug concentration, can lead to ineffective therapy
Vd for drugs with low, intermediate and high Vds
low = 0.057 L/kg
intermediate -= 0.2 L/kg
high = >0.2 L/kg
volume of distribution
apparent volume that a drug distributes into
Vd = D/C (total amount/plasma concentration)
plasma
4 L
interstitial fluid
10 L
intracellular fluid
28 L
drugs with small Vd
remain in the capillaries
highly protein bound
large molecular weight (can’t get through fenestrations)
can’t leave the plasma
Vd is about 0.057L/kg
drugs with intermediate Vd
low molecular weight (can go through fenestrations) very hydrophilic (can't go through PM) intermediate protein binding
can leave plasma and enter interstitial fluid, but can’t go into cells
Vd is about 0.2 L/kg
drugs with large Vd
low molecular weight
lipophilic
minimal protein binding
can leave vascular space and interstitial fluid and go into fat, bone, muscle etc (i.e. into intracellular fluid)
Vd >0.2 L/kg
what happens if small Vd drug is displaced from proteins
does NOT distribute to tissue, stays in plasma so free drug concentration increases
what happens if large Vd drug is displaced from proteins
distributes into tissues, total plasma drug concentration decreases and apparent Vd increases further
how does body composition affect drug distribution?
elderly ppl have increased fat mass
- > drugs that distribute into fat will have larger Vd in elderly or obese ppl
- > drugs that distribute into muscle will have lower Vd in elderly (less muscle mass)
what is metabolism and where does it occur
enzyme-mediated alteration of a drug’s structure
also called biotransformation
liver- primary site intestine - enterocytes can metabolize drugs stomach - alcohol metabolism kidney intestinal bacteria
5 possible therapeutic consequences of drug metabolism
1) increase water solubility to promote excretion
2) inactivate drugs
3) increase drug effectiveness
4) activate prodrugs
5) increase drug toxicity
first order kinetics
most drugs
concentration of drug is much lower than the metabolic capacity of body (i.e. less drug than enzymes)
drug metabolism is directly proportional to the concentration of free drug
constant fraction metabolized per unit time
zero order kinetics
ie ethanol
plasma drug concentration is much higher than metabolic capacity of the body
drug metabolism is constant over time i.e. constant amount is metabolized per unit time
metabolism is independent of drug concentration
where can drugs taken orally undergo first pass metabolism and what is the result
hepatocytes in liver
enterocytes in intestine
stomach
intestinal bacteria
result is decreased parent drug in the systemic circulation
extraction ratio
depends on how much metabolism occurs on the first pass through the liver
high ER = lots of first pass metabolism
can greatly determine bioavailability
high ER drugs
low oral bioavailability (1-20%
PO doses higher than IV doses to compensate
small changes in hepatic enzyme activity produce large changes in bioavailability
very susceptible to drug-drug interactions
low ER drugs
high oral bioavailability (>80%)
PO doses similar to IV doses
small changes in hepatic enzyme have little effect on bioavailability
not very susceptible to drug-drug interactions
may pass through liver via systemic circulation multiple times before completely metabolized
phase I drug metabolism
lipophilic to more polar by introducing or unmasking polar functional groups (i.e. OH, NH2)
involved oxidation, reduction, hydrolysis
CYP enzymes, esterases and dehydrogenases
metabolites can be more active, less active or equally active as parent drug
occurs in SER
phase II drug metabolism
increase polarity of lipophilic by conjugation of large water soluble molecules to drug
ie glucuronic acid, sulphate, acetate, amino acids
metabolites are less active than the parent drug
** exception - morphine 6-glucuronide is more potent analgesic than morphine**
occurs in cytosol, except glucuronidation which is in SER
CYP enzymes
predominant phase I drug metabolizing enzymes
mostly hepatic, in SER
oxidize drugs by inserting one O atom into the drug molecule, produces water as a byproduct
12 families, 3 does most drug metabolism
(naming goes family, subfamily, isozyme)
malnutrition can decrease CYP activity as they requires dietary protein, iron, folic acid and zinc
CYP3A4 metabolizes 50% of currently marketed drugs
5 types of phase II drug metabolizing enzymes
UGTs SULTs GSTs NATs TPMT
UGTs
UDP-glucuronosyltransferases
only phase II found in SER
catalyze transfer of a glucuronic acid to a drug
once glucuronidated = more polar for easier excretion
SULTs
sulfotransferases phase II cytosolic transfer sulfate to hydroxyl of a drug more polar, easier excretion
GSTs
glutathione S transferases
phase II
cytosolic
transfer glutathione to drug (glutathione is an intracellular anti-oxidant)
putting glutathione onto a reactive drug renders the metabolite less toxic
NATs
N-acetyltransferases phase II cytosolic transfer acetyl from acetyl CoA to drug subject to polymorphisms which causes large variability in drug response
TPMT
thiopurine methyltransferase
phase II
cytosolic
transfer methyl from S-adenosylmethionine to a drug
subject to SNPs, rare but have dramatic effect
4 factors that affect drug metabolism
age
drug interactions i.e. enzyme inducers and inhibitors
disease state
SNPs
age and drug metabolism
infants have almost no CYP activity
1 year until reasonable, 2 until adult levels
elderly also have decreased levels
diseases that decrease CYP activity
liver disease
kidney disease
inflammatory diseases
infection
CYP2C9
metabolizes anticoagulant warfarin
SNPs can decrease activity
patients require lower dose of warfarin , if not get extensive bleeding
CYP2D6
metabolizes codeine to morphine = more potent analgesic SNPs give 4 phenotypes ultra-rapid metabolizer (multiple copies) extensive metabolizer (normal) intermediate metabolizer poor metabolizer (almost no metabolic activity)
UGT1A1
glucuronidates SN-38 (anti-cancer drug, active metabolite of irinotecan)
SNPs decrease its activity
increased risk of diarrhea and dose limiting bone marrow suppression (potentially fatal)
NAT2
acetylates isoniazid (tuberculosis drug), caffeine and various cancer causing chemicals either rapid or slow acetylator
slow are more susceptible to isoniazid toxicity (neuropathy, hepatotoxicity) than rapid acetylators are
also have higher risk of developing some cancers
methotrexate side effects
azotemia infection inflammation of gums anemia (decreased platelets) prone to infections fever loss of appetite
mercaptopurine side effects
vomiting
diarrhea
loss of appetite
easy bruising and bleeding
methotrexate pharmacokinetics
hepatic and intracellular metabolism poorly crosses placenta and BBB bc its ionized ~50% protein bound orally readily absorbed high bioavailability long 1/2 life
mercaptopurine pharmacokinetics
incompletely absorbed when oral metabolized in liver excreted in urine pro-drug - active form is thioguanine nucleotides inactivated by TPMT
what happens if you have a TPMT SNP and take mercaptopurine?
decreased activity of TPMT, get build up of toxic metabolites
how to diagnose TPMT SNPs and what to do to mercaptopurine doses
genotype or phenotype
hetero = 50% reduction in dose
homo = 90% reduction
sites of drug excretion
kidney
bile
lung
breast milk
what happens if your kidneys aren’t functioning properly
get prolonged action and intensity of drug effects
what does the nephron control
water, electrolyte and drug excretion
blood volume, blood pressure, blood pH and solute excretion
factors affecting renal drug excretion
glomerular filtration
tubular secretion
tubular reabsorption
what percentage of renal plasma flow is GFR?
~20%
do lipid solubility and pH affect glomerular filtration of drugs?
no
what drugs are filtered at the glomerulus?
only free (i.e. not protein-bound)
tubular secretion
drugs can be secreted from the blood into the tubule in the proximal tubule
there are 2 systems, one for weak acids, one for weak bases
tubular reabsorption
water is reabsorbed in loop of henle so drugs become more concentrated
in distal tubule drug concentration often exceeds that of the blood surrounding
if uncharged or lipid soluble can be reabsorbed
age and renal function
decreases as we age
characteristics of drugs eliminated in bile
MW > 300 Da
amphipathic (ie lipophilic and polar groups)
glucuronidated
biliary drug excretion
transporters on canalicular membrane of hepatocytes transport drugs and metabolites into the bile
P-gp transports amphipathic ones and MRP2 does glucuronidated metabolites
get released into intestine during digestion then excreted in fees or recycled
enterohepatic recycling
intestinal bacteria can cleave conjugate metabolites leaving the original drug
can then be reabsorbed through the intestine
drugs that do this persist in the body for substantially longer periods
pulmonary drug excretion
gaseous or highly volatile i.e. general anesthetics
not heavily reliant on drug metabolism
affected by: rate of respiration, cardiac output, solubility of drug in blood
i.e. high blood solubility = low pulmonary excretion
drug excretion in breast milk
> 90% of women take a drug in the first week postpartum
low protein binding
low molecular weight
high lipophilicity
transported by breast cancer resistance protein (BCRP)
breast milk has a lower pH and higher lipid content than plasma
so lipophilic will go in
substrates for BCRP will go in
weak base unionized will go in and then become ionized and trapped
name 3 lesser routes of drug excretion
hair - drugs can be excreted into hair follicles, can use to determine how long a person has been exposed (hair grows 1 cm/month)
saliva - usually if excreted in saliva swallowed and then either get intestinal absorption or fecal excretion
sweat - mostly washed away, some dermal reabsorption can occur
clinical pharmacokinetics
want a quantitative relationship between drug dose and effect and a framework to interpret measures of drug concentrations in biological fluids to benefit patient in drug therapy
clearance
efficiency of irreversible drug elimination from the body
ml/min or L/hr
can be by route of elimination or total
can be used to determine the dosage rate required to maintain a certain plasma concentration
dosing rate = plasma concentration * clearance
elimination half life
measure of the rate of removal of the drug from the body
T1/2 = 0.693*Vd/Cl
so larger Vd gives longer half life
why are drugs measured in plasma usually?
relatively non-invasive
most drugs have good correlation between plasma concentration and therapeutic and toxic effects
note: measure total plasma [ ] not just free (still a good measure though)
oral drug concentration time curve
at first absorption is greater than elimination so plasma concentrations increase
there is a peak called Cmax where the absorption and elimination are equal
then elimination rate is greater than absorption so plasma concentrations decrease
MEC
minimum effective concentration ie minimum concentration needed for therapeutic effect
duration
length of time [drug] is above MEC
therapeutic range
above MEC but below toxic
width is an index for the safety of the drug
narrow therapeutic range = therapeutic drug monitoring, usually trough sampling
onset of action
oral drugs usually have a lag period
rate and extent of absorption affect it
onset of action determines how soon a drug’s effect will occur
continuous IV infusion
constant rate of drug entry
no absorption bc it goes directly into systemic circulation
plasma concentration rises until infusion equals elimination then have steady state until infusion is stopped
then plasma concentrations decrease
IV bolus
drug is rapidly injected into the blood, quickly distributes and then is eliminated over time
usually first order kinetics for elimination i.e. rate of elimination is dependent on the blood concentration
repeated dosing
accumulation occurs until a plateau is reached - steady state
want steady state to be within therapeutic range (concentration fluctuates for oral or IV bolus drugs)
steady state
when the peak and trough concentrations are the same between doses
if the same dose is given it takes about 5 half lives to get to steady state
if the dose of the drug is constant the time to reach steady state is independent of the size of the dose
how can you reduce fluctuations in plasma drug concentration?
continuous IV infusion
depot preparations
change the dosing interval i.e. multiple smaller doses
loading dose
drugs with long half life will take a while to get to steady state so can give a large loading dose first and then smaller maintenance doses
loading dose = target [plasma]*Vd
(assuming 100% bioavailability)
declining from steady state
depends on the drug’s half life
time is independent of the dose
5 half lives for most (97%)
9 half lives for every molecule
pharacodynamics
what the drug does to the body i.e. biochemical and physiological effects of drugs
dose response curve
increasing dose increases response
monotonic
not linear, usually use semi-logarithmic plot
phases of semi-logarithmic dose response curve
phase 1 = doses are too low to elicit a clinically relevant response
phase 2 = response is graded and nearly linear
phase 3 = larger doses do not lead to greater response (may cause toxicity) i.e. has plateaued
efficacy
how effective a drug is at a given dose
max efficacy is the top of dose response curve
potency
amount of drug required to elicit a pharmacological response
can’t compare unless the drugs have the same therapeutic effect
ED50 used to assess (the dose required to produce a half-maximal response)
low ED50 = more potent
ED50
dose required to produce a half maximal response
OR
dose that elicits response in 50% of patients
give an example of a drug that doesn’t act on a cellular target
antacids - neutralize stomach acid
what is a receptor and what are the 4 most important types?
a protein that a drug binds to and produces a measurable response
ligand gated channels
g protein coupled receptors
enzyme linked receptors
intracellular receptors
ligand gated channels
ligands control the opening and closing of ion channels
duration of milliseconds
many neurotransmitters bind these channels
ie GABA binds to GABA receptor and causes channel to open allowing Cl- to flow into the cell
benzodiazepene drugs also bind to GABA receptors
activation of this receptor causes sedation and muscle relaxation
GPCRs
norepinephrine, serotonin and histamine all mediate their effects through GPCRs
response lasts from seconds to minutes
enzyme-linked receptors
response are within seconds
ie insulin receptor, get phosphorylation then activation of intracellular effector which then causes translocation of GLUT to cell membrane
get increased cellular glucose uptake and utilization
intracellular receptors
transcription factors
ligands diffused or are transported across membrane, bind and then the complex goes into the nucleus and binds DNA
response is hours to days
ligands are usually highly lipid soluble
drug receptor selectivity
lock and key hypothesis
lock is receptor, drug is key, needs to be the right size and shape
selective drugs will only bind to one receptor and will be less likely to produce side effects
side effects can still occur if only binding to one receptor though because that receptor may be located in multiple tissues even though you only want to target one
simple occupancy theory
intensity of drug’s response is proportional to # of receptors occupied
maximal response occurs when all receptors are occupied
implies that 2 drugs on the same receptor should have the same effect (obviously not true)
modified occupancy theory
intensity of response is proportional to # of receptors occupied
2 drugs occupying the same receptor can have different binding strengths (affinities)
2 drugs occupying the same receptor can have different intrinsic activities
what is the primary determinant of a drug’s potency?
its affinity for the receptor
what helps determine a drugs efficacy?
intrinsic activity
agonists
have both affinity and intrinsic activity
agonists can cause increased or decreased physiological response
some can bind to different receptors depending on the dose
dopamine and dose
low dose = dopamine receptors, causes renal artery vasodilation, increased renal blood flow and urine output
intermediate dose = B1 adrenergic receptors, increased cardiac output
high dose = alpha adrenergic receptors, renal artery vasoconstriction, decreased renal blood flow and urine output
antagonists
have affinity but no intrinsic activity
pharmacological effet is dependent on the presence of an agonist
beta blockers
block binding of endogenous epinephrine to beta 1 receptors in the heart
slows beating of the heart
antihistamines
block histamine binding to H1 histamine receptors in the nasal mucosa
prevents symptoms of allergy
gastric acid reducers
block histamine binding to H2 histamine receptors in the gut
decreases gastric acid secretion
opioid receptor blockers
block opioids binding to opiate receptors
useful for overdose
competitive antagonists
same site as agonist, reversible
if antagonist and agonist have equal affinities, higher concentration wins
irreversible antagonists
same site, irreversible
decreases maximal response the agonist may have
effects last until the receptor is replaced
allosteric antagonists
different site
reversible, but not competitive
decrease maximal response
partial agonist
act as agonists with minimal or partial activity or as antagonists
3 types of drug tolerance
desensitization
metabolic tolerance
tachyphylaxis
desensitization
receptors are internalized or destroyed
decreased receptors on cell surface, decreased effects of drug
metabolic tolerance
induction of drug metabolizing enzymes
can cause decrease in plasma [ ] of drug
tachyphylaxis
rapid decrease in response to a drug
may need drug free periods to prevent (i.e. for transdermal routes especially)
receptor upregulation
continuous exposure to an antagonist has opposite effect to tolerance
cell becomes hypersensitive or supersensitive
synthesizes more receptors and puts them on the surface
increased response
what influences a patients response to medication?
genetics, environment and disease state
what phase of clinical trials establish dose response information over a range of doses?
phase II
can evaluate the number of ppl who experience an endpoint at each dose
ED50 = average effective dose i.e. dose required to produce response in 50% of the population
TD50
average toxic dose
dose in which 50% of animals experience drug toxicity
LD50
average lethal dose
dose in which 50% of animals die
what are LD50 and TD50 expressed in?
mg drug/kg body weight
therapeutic index
indicator of a drug’s safety
is the TD50/ED50 or LD50/ED50
high TI = safe
body weight and composition and intermittent variation in response
adjust dose to body weight of patient to compensate for size differences
also adjust drugs by body surface area bc fat distribution can change drug distribution
normal body surface area for an adult
1.73m^2
known differences in drug metabolism between genders
alcohol metabolism is slower in females
certain opioids are more effective in women
certain drugs for irregular heart beat prolong the QT interval of women
why is the effect of gender on a lot of drugs not known?
because until 1997 health canada and the US FDA didn’t put pressure on drug companies to include women in trials of new drugs
give an example of race known to effect drug metabolism
rosuvastatin a cholesterol lowering drug has 2-3 times higher concentrations in asian patients compared to caucasians
how does kidney disease affect drug metabolism?
drug excretion is decreased, which causes the half life of renally excreted drugs to increase
hepatic and intestinal drug metabolism are also decreased
net effect is increased oral bioavailability and decreased excretion
how does liver disease affect drug metabolism?
decreased hepatic metabolism in diseases such as cirrhosis and hepatitis
drugs that are extensively metabolized can have significantly increased half lives
examples of environmental exposures that affect drug metabolism
cigarette smoke induces some drug metabolizing enzymes
alcohol can exacerbate toxicity of some other drugs (i.e. in liver)
exercise improves the actions of insulin
some pesticides can induce CYPs
adverse drug reactions
unintended and undesired responses from drugs
7.5% of hospital admissions in canada a year
7 types of adverse drug reactions
side effects drug toxicity allergic reaction idiosyncratic reaction carcinogenic effects mutagenic effects teratogenic effects
side effects
are expected
occur at normal therapeutic doses and are unavoidable
often due to poor selectivity
example of side effects
antihistamines block H1 receptors to prevent allergy symptoms, but they also cause drowsiness, dry mouth and urinary retention because they bind OTHER receptors in the brain
drug toxicity and an example
any severe adverse drug event
often due to overdose
often extensions of the therapeutic effect
i.e. take too much insulin, become hypoglycemic
allergic reactions
mediated by immune system and require prior sensitization
mast cells release chemicals such as histamine
can vary from itching and rash to life threatening anaphylaxis (bronchospasm, edam and severe hypotension)
intensity is independent of dosage
10% of ADRs are due to allergic reaction
trunk is most common area, then arms and legs and neck, then feet and hands and face is last
examples of drugs that commonly cause allergic reactions
pencillins
sulfonamides (antibiotic)
NSAIDs
idiosyncratic reactions
occur rarely and unpredictably in the population
SNPs in metabolizing enzymes and transport proteins probably account for most
what are some examples of idiosyncratic reactions that can be tested for
warfarin and 6-mercaptopurine
CYP2C9 and TPMT respectively
OATP1B1 SNP
uptake transporter in the liver
15% of asian and caucasian patients have SNP that decreases function leading to increased plasma drug concentrations
implicated in myopathy (muscle toxicity) in patients taking statins
carcinogenic effects example
cause cancer ie DES (diethylstilbestrol) used to be used to prevent spontaneous abortion but was found to cause vaginal or uterine cancer in female babies later in life
mutagenic effects
change DNA
can be mutagenic but not carcinogenic or teratogenic
tested as mutagens using the Ames test, which evaluates the ability of the compound to cause a mutation in specialized strains of bacteria
teratogenic effects
produce birth defects or impair fertility
can be physical, behavioural or metabolic
less than 1% are caused by drugs
sensitivity to teratogens changes during development
gross malformations are usually during 1st trimester
2nd and 3rd usually affect function
CNS highly sensitive throughout most of pregnancy, most other systems are only highly sensitive during the 1st trimester
when is transfer of drugs across the placenta greatest?
3rd trimester because SA has increased and the placental-fetal barrier is thinner
who classified teratogens?
US FDA
class A pregnancy risk
well controlled human studies have failed to show risk to fetus during 1st trimester
no evidence of harm later in pregnancy
class B pregnancy risk
animal reproduction studies have failed to show harm to the fetus and there are no well controlled studies in humans
OR
animal studies have shown an adverse effect but well controlled studies in humans have fail to show any harm
class C pregnancy risk
animal studies have shown harm to fetus but there are no well-controlled studies in humans
potential benefits outweigh the potential risk
class D pregnancy risk
clear risk to fetus from studies in humans
potential benefits outweigh potential risk
class X pregnancy risk
studies in animals and humans clearly demonstrate risk to the fetus
risk using clearly outweighs the benefits
should never be used in pregnancy women
i.e. known teratogen
where does organ-specific toxicity occur? where is it most common?
kidney, lung, heart, liver, muscle, inner ear
most common are liver and heart
hepatotoxicity
most common reason drugs are removed from the market
some drugs once metabolized in the liver, metabolites can cause liver injury
signs are jaundice, dark urine, light-coloured stool, nausea and vomiting
AST and ALT are increased in the blood when liver is damaged
drugs known to be hepatic should be used with caution in patients at high risk for hepatic disease i.e. alcoholics, ppl with hepatic disease already and ppl taking other medications that cause hepatotoxicity
QT interval prolongation
major risk factor for development of tornadoes de points, a life threatening form of ventricular arrhythmia (ventricles contract and then take a while to relax and fill with blood)
more than 100 drugs known to cause it have been removed from the market
drugs that prolong QT interval should be used with caution in patients that are predisposed to arrhythmias
who is predisposed to QT prolongation
elderly ppl with bradycardia heart failure low potassium congenital QT prolongation women (their normal one is longer)
P wave
atrial depolarization
QRS complex
rapid depolarization of right and left ventricles
U wave
not always seen
T wave
repolarization of the ventricles
QT interval
time required for the ventricles to repolarize
opiate withdrawal
normally used for analgesia
anorexia irritability nausea vomiting weakness muscle spasm
benzodiazepene withdrawal
anxiety med
anxiety insomnia sweating tremors panic delirium paranoia convulsions
beta blocker withdrawal
med for hypertension, decrease heart rate
rebound hypertension
chest pain
MI
arrhythmia
most common cause of adverse drug reactions
medication errors
iatrogenic error
caused by a health care professional
5 categories of medication errors
prescribing - prescribe the wrong drug, dose or route
dispensing - pharmacist screws up
administration - health care professional administers wrong dose, drug or route
patient education - patient doesn’t understand instructions
patient - understands instructions but doesn’t follow i.e. misses a dose
what causes drug naming errors?
poor handwriting, illiteracy, strong accents
~15% of all medication errors
IU abbreviation
means international unit, ppl might think it says IV or 10
say units instead
q.d abbreviation
everyday
q.o.d abbreviation
every other day
trailing 0 after decimal point i.e. 1.0 mg
might think its 10 so write 1 mg
leading zero missing i.e. .5
might think its 5 so write 0.5 mg
MgSO4 abbreviation
magnesium sulfate, might think its morphine sulphate so write the name
MS or MSO4 abbreviations
morphine sulfate, might think its magnesium sulphate so write the whole name
what are the most common drug-drug interactions?
pharmacokinetic ones (ADME)
when drugs interact what are the possible consequences?
increased effects
decreased effects
new effect
4 types of drug interactions
direct physical interaction pharmacokinetic interaction (ADME) pharmacodynamic interaction (receptor binding) combined toxicity (ie toxic to same organ)
direct physical interaction of drugs
most commonly when two or more IV solutions are mixed together and form a precipitate
diazepam (benzodiazepine) should never be mixed with anything else
can occur outside or inside the patient
i.e. if you give sodium bicarbonate and then calcium gluconate a precipitate can form in the blood
how do drug interactions alter absorption?
altered pH chelation/binding altered blood flow gut motility vomiting drugs that kill intestinal bacteria
explain how drugs that alter pH can cause drug interactions that have to do with absorption
antacids increase gastric pH, which increases absorption of weak bases and decreases absorption of weak acids
also can cause enteric coated drugs to dissolve in the stomach - can cause stomach issues or destroy the drug
explain how chelation/bind can affect drug absorption (interaction)
some drugs will bind to each other in the intestine and form insoluble complexes that can’t be absorbed
ie bile acid sequestrates are supposed to bind cholestyramine and this complex will bind the drug digoxin, which decreases its absorption
how do drugs that alter blood flow affect absorption (interaction)
drugs that decrease blood flow decrease absorption of drugs
how do drugs that alter gut motility affect absorption (interaction)
laxatives increase gut motility which decreases drug absorption because the drug is in contact with the microvilli for less time
opiates decrease gut motility which increases drug absorption
how do drugs that induce vomiting affect the absorption of other drugs?
they will decrease the absorption of other drugs
if vomiting occurs 20-30 minutes after taking medication it is likely that absorption is incomplete
need to determine if another dose should be given
if drug has already entered the intestine when vomiting occurs, giving more could cause toxicity
describe how drugs that kill intestinal bacteria affect the absorption of other drugs
intestinal bacteria deconjugate phase II drug metabolites so if they are killed there is less absorption during enterohepatic recycling
results in decreased plasma concentration
an example is oral contraceptives
how do drug interactions alter distribution?
altering pH
protein binding
describe how drugs that alter pH can alter drug distribution (interaction)
a drug that changes extracellular pH can influence ionization of other drugs
sodium bicarbonate increases extracellular pH, ammonium chloride decreases it
i.e. if someone overdoses on aspirin, a weak acid, you can increase the extracellular pH with sodium bicarbonate which will draw aspirin outside the cell and trap it there (can then be excreted in urine)
describe how drugs that alter protein binding can alter drug distribution (interaction)
if 2 drugs bind to the same site of plasma proteins, co-administration will lead to competition
lower affinity drug will become free
can cause increased therapeutic effect, toxicity or excretion
where do most metabolism-involved drug interactions occur?
in the liver or intestine
examples of CYP inducers
cigarette/ marijuana smoke (1 joint = 5-10 cigarettes)
rifampin and St John’s Wart - CYP34A
phenobarbital - many CYPs
barbecued food - CYP1A2
alcohol - CYP2E1 (severe alcoholism causing cirrhosis decreases CYP activity though)
examples of CYP inhibitors
many antibiotics and antifungals, HIV protease, grapefruit juice - CYP3A4
fluvoxamine - CYP1A2
selective serotonin reuptake inhibitors - CYP2D6
how do drug interactions alter excretion?
altered blood flow
altered pH
tubular secretion
how do drugs that alter blood flow alter excretion (interaction)
drugs that decrease renal blood flow, decrease glomerular filtration
this gives decreased renal excretion and increased plasma concentrations
NSAIDs cause renal vasoconstriction (decrease blood flow)
beta blockers decrease CO, which indirectly decreases renal blood flow also
how do drugs that alter pH alter excretion (interaction)
drugs that change the pH of renal tubular filtrate can alter excretion
ie overdose on amphetamines, a weak base, can acidify filtrate with ammonium chloride to trap in tubule and prevent reabsorption (i.e. increase excretion)
how do drugs that alter tubular secretion alter excretion (interaction)
if one drug blocks a transporter that secretes drugs into the tubule lumen then a drug that uses that transporter will have increased plasma concentration (and decreased renal excretion)
ie probenecid (for gout) blocks the transporter that secretes penicillin get increased penicillin in the blood
two main types of pharmacodynamic drug interactions
same receptor
separate sites
drug interactions at the same receptor
usually antagonist blocking agonist
can cause decreased therapeutic action or can decrease toxicity in overdose situations
ie morphine overdose, give naloxone and compete out morphine to reverse symptoms
drug interactions at different receptors
drugs with different mechanisms can produce an interaction if they produce the same physiological response
ie diazepam (anxiolytic drug) and morphine are both CNS depressants, but bind to different receptors (morphine on opiod, diazepam on benzodiazepine) take together, get enhanced CNS depression
combined toxicity
ie acetaminophen and alcohol, both are hepatoxic
same with isoniazid and rifampin, which are used to treat tuberculosis
need to take both though, so have to monitor liver function
examples of food drug interactions
grapefruit juice inhibits CYP3A4
monoamine oxidase inhibitors (depression) inhibit the breakdown of tyramine
tyramine is found in aged cheese, yeast, red wine, sauerkraut and cured meat
need to avoid while taking MAO inhibitors
tyramine causes increased release of NE from peripheral nerves and results in a potentially fatal hypertensive crisis
symptoms of hypertensive crisis
tachycardia sever hypertension headache nausea vomiting
St John’s Wart
treatment for depression
can interact with tacrolimus because it induces CYP3A4 and P-glycoprotein
induces CYP3A4 through pregnant X receptor (transcription factor)
this leads to metabolism of tacrolimus and therefore decreased concentrations of it (no longer effective)
