Week 1 Flashcards
controlled substance
- regulated by DEA
- have potential for abuse (stimulants, narcotics, depressants)
What are the steps new drugs go through before they can get on the market?
- Preclinical testing on animals (1-5 years)
- Apply to FDA as Investigational New Drug (get 20 yr patent)
- Clinical testing - (takes 10-15 years)
- phase 1 - healthy volunteers
- phase 2 - patients to see if effective
- phase 3 - bigger sample size to see safety and effectiveness
- New Drug Application - approved by FDA allows marketing
- phase 4 - postmarketing surveillance
Generic drugs
- lower case
- chemical or official name
- indicates “drug group”
Trade name
- name used to market drug
- invented by pharmaceutical co.
Six Rights of Drug Administration
Right
- medication
- dose
- delivery/route
- time
- patient
- rationale
Pharmacokinetics
- What the BODY does to the DRUGS
- Movements of drugs throughout the body to reach target site (cells)
- Processes
- absorption
- distribution
- metabolism
- excretion/elimination
absorption
- movement of drug from administration site into blood
- how drug is administered will determine how soon effects will take place
Enteral absorption
PO - by mouth into blood
SL (sublingual) - from mucous membrane into blood
parenteral absorption
IV - intravenous
IM - intramuscular
SC (subQ) - subcutaneous
topical absorption
from skin into blood
Bioavailability (F): absorption
fraction of the dose that gets into systemic blood circulation & is available to act on cells
- IV route: 100%
- other routes:
first pass effect (biotransformation)
- only applied to PO drugs
- drugs are partially metabolized by liver before they can get into systemic circulation
- drugs with large first pass effect require much higher PO doses compared to IV
Factors affecting absorption
- route of administration
- preparation for oral administration
Tablets
- enteric-coated preps
- sustained-release (extended-release)
- capsules
Liquid elixirs
Distribution
“Spreading” of the drug throughout the body
Factors affecting Distribution
- blood flow to tissue (cardiac output/CO)
- plasma protein (albumin) binding
- blood brain barrier (BBB)
- pregnancy & lactation
Factors affecting Distribution: blood flow to tissue
- areas that receive large amounts of blood get drug rapidly (liver, kidney, heart)
- low blood flow areas are difficult to treat (bones, abscess has 0 internal blood vessels; must drain before treating)
Factors affecting Distribution: plasma protein binding
- most drugs are bound to proteins (albumins) in the blood
- makes them inactive
- stored & released slowly / longer duration of drug action
- unbound/free drug molecules = pharmacologically active, so reach target cells
e. g. Warfarin (coumadin) - 99% are protein-bound; duration of action is 3-5 days
if malnourished, there is reduced plasma in blood so higher risk of toxicity (not enough protein to attach to)
Factors affecting Distribution: BBB
- drug distribution in CNS is limited
- tight junctions between cells & capillaries
- allow only selected (lipid soluble) drugs (e.g. anti-anxiety and seizure meds)
- prevent movement of drug molecules into brain
Newborn babies - BBB not fully developed = heightened sensitivity to drugs that act on brain; especially vulnerable to CNS toxicity
Factors affecting Distribution: pregnancy & lactation
- most drugs cross placenta & enter fetal circulation (may affect fetus)
- no prescription or OTC drugs should be taken (except prenatal vitamins
- many drugs enter breast milk (may affect nursing infants)
Metabolism (biotransformation)
most drugs are chemically changed by hepatic microsomal enzyme system (in liver)
- Cytochrome P450 system (CYP)
- changed into inactive form (destruction)
- changed into active form (activation ) - prodrug
metabolic processes are used to destroy drugs (it’s a natural protective mechanism against poisons)
CYP
a group of 12 closely related enzyme families that affect drug metabolism
Consequences of drug metabolism
increase or decrease therapeutic action
OR
increase or decrease toxicity
Factors affecting Metabolism
- Liver Function - liver diseases can decrease metabolism –> increases toxicity
- Age - infants can decrease metabolism –> increases toxicity
- Oral drugs – first pass effect – decreases metabolism
Drug therapy in hepatic impairment
- drugs stay in body longer
- incr. risk for drug toxicity (avoid hepatoxic drugs, like Tylenol & alcohol; decrease dosage)
- monitor liver function (liver function test - LFT)
- CYP
Decreased liver function will show:
⇡ Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT)
⇡ alkaline phosphate
⇡ bilirubin
↓ albumin (protein in blood)
↓ prothrombin time (PT) and partial prothrombin time (PTT) - tell you about clotting time & factors
Excretion / Elimination of drugs
- in urine (most common)
- in stool, saliva, sweat
Major organ involved - kidney
Factors affecting Elimination
- Renal disease: ↑ risk for drug accumulation and toxicity
- adjust drug selection (non-nephrotoxic) and dosage
- monitor renal status (RFT = renal function test, BUN = blood urea nitrogen test, creatine test) - Age
- Urine pH: manipulating urine pH = ↑ drug elimination in urine
plasma drug level
- subtherapeutic concentration: plasma drug level is MEC, so drug is effective, but not toxid
- toxic concentration: plasma drug level at excessive level
therapeutic range (TR)
- enough drug to produce therapeutic effect, but not enough to be toxic
Narrow TR - therapeutic doses are very close to toxic doses / narrow margin of safety / need frequent checks / e.g. coumadin, lithium, digoxin
Wide therapeutic range - safe
MEC -
- minimum effective concentration
- lowest drug concentration at which the drug action occurs
Peak
Highest plasma level of drug
Duration
Length of drug action
Time during which plasma drug level is > MEC
Drug half Life (t1/2)
- time required for plasma concentration of a drug to decrease by 50%
- E.g after 5 t1//2 - approx 97% of drug eliminated
t1/2 determines dosing frequency
Shorter half life - need more frequent dosing
Longer half life - can be dosed less frequently
steady state concentration
Plateau - building up the level of drug w/repeated admin of drug = therapeutic level
- Will be reached in 5 half lives.
loading vs maintenance doses
bolus = loading dose - given when 1/2 lives are long to help reach plateau
maintenance dose given at lower levels, but more frequent
trough level
- the lowest level of drug in blood plasma
- measure right before give dose
peak level
- highest level of drug
- measure approx 30 min after dose
pharmacodynamics
- what the drug does to the body
- how a drug changes the body
Mechanism of drug action & effect in body:
RECEPTOR drug action
most drugs work by binding to receptors at cell membrane
Mechanism of drug action & effect in body:
NON-RECEPTOR drug action
e.g. upset stomach - take medicine to change pH of stomach
dose-response curve
bigger does are unable to elicit a further increase in response == all receptors are full - any more drug could be toxic
drug - receptor interactions
- many drugs work by binding to proteins
- drugs cannot give cells new function
agonists
activate receptors by mimicking the action of endogenous molecules (“turn on”)
antagonists
prevent activation of receptors by inhibiting action of endogenous molecules (“turn off”)
competitive antagonist
competes w/agonist for receptor sites
noncompetitive antagonist
blocks agonists’ access to receptor site
therapeutic index (TI)
- a measure of drug safety
- ratio of drug’s LD50 (lethal dose that kills 50% of mice) to ED50 (effective dose in 50% of people)
- higher it is = safer the drug
- narrow RI = not as safe; more dangerous
E.g. ED50 is 10 & LD50 is 100 = wide range
ED50 is 20 & LD50 is 30 = narrow range
pharmacogenetics
only since 1950’s
varies from patient to patient due to their genetic variation of CYP (a liver enzyme)
- if overactive = ⇡drug metabolism
- if underactive = ↓ drug metabolism
INR
international normalized ration = between 2-3
3.0 = risk of bleeding
Warfarin (coumadin) - narrow therapeutic range
- FDA recommends genetic testing
personalized medicine
= right medication in the right dose for the right patient = fewer side effects
drug- drug interaction:
- additive
1 + 1 = 2
sum of drugs A & B
drug- drug interaction:
- synergistic
or potentative = 1 + 1 = 3
Interaction between two or more drugs or agents resulting in a pharmacologic response greater than the sum of individual responses to each drug or agent.
drug- drug interaction:
- antidote
or antidote = 1 + 1 = 0
cancel each other out
drug- drug interaction:
- new response
- combination may produce a new response
- e.g. alcohol & disulfiram (Antabuse - used to try to stop drinking): unpleasant & dangerous response
drug- drug interaction: absorption
when 2 drugs taken together, one may alter the absorption of the other
e.g. antacid will prevent absorption of digoxin
drug- drug interaction: altered metabolism
inducer: induction of CYP isoenzymes
- if drug A is inducer; causes ⇡metabolism of drug B; dosage of drug B needs to be ⇡ as drug level will ↓
drug- drug interaction: altered metabolism
inhibitor: inhibition of CYP isoenzyme
- if drug A is inhibitor, causes ↓ metabolism of drug B; causes ⇡ drug B in plasma. Risk of toxicity of drug B
clinical significance of drug-drug interactions
- can ⇡↓ therapeutic effects or ⇡↓ toxicity
- ⇡risk of serious drug interaction ⇡ # of drugs a patient takes
- special attn to drugs w/narrow TI
Impact of food on drug metabolism:
grapefruit
CYP inhibitor
↓ metabolism of many drugs –> ⇡ plasma drug levels –> ⇡ risk of toxicity
- all drugs, but mainly anti-coagulants (w/narrow TI)
Impact of food on drug metabolism:
foods w/tyramine (aged cheese, red wine)
can cause hypertensive reaction in pt. taking MAOI (for depression)
Impact of food on drug metabolism:
foods w/ Vit K
can oppose anticoagulant effect of warfarin (coumadin) - which work by inhibiting synthesis of Vit K dependent clotting factors (II,VII, IX, X)
drugs + herbs
- need to be included in medical history
- Warfarin - St. John’s wort, ginseng = CYP inducer
- Fish oil, Vit E = CYP inhibitor - cardiovascular meds & herbs
- Digoxin + licorice (CYP inhibitor)
- Ephedra = sympathomimetic
- Statins + St. John’s wort (CYP inducer)
idiosyncratic vs iatroentic effect
idiosyncratic = uncommon drug response resulting from a genetic predisposition (e.g. benadryl - hyperactivity in children) - unique to person
iatrogenic = drug caused disease (e.g. Cushing’s syndrome due to long-term steroid therapy)
cross tolerance
- tolerance to pharmacologically related drugs
- e.g. alcoholics many need > usual dose of sedative to calm down
ways to minimize ADR
- monitor rights to ↓ med errors
- Pt & family education @ signs of what to report to HCP
- monitor function of target organs
Treatment of Drug OD / poisoning
- supportive care
- ID cause of OD/poison
- responses
Treatment of Drug OD / poisoning - activated charcoal
- prevents further absorption
- effects w/in 30 min
- can absorb 90% of drug
- eliminated in stool
Treatment of Drug OD / poisoning - gastric lavage & aspiration
- flushes stomach w/fluid & aspirated back out
Treatment of Drug OD / poisoning - antidotes
- Naloxone (Narcan) - opioid/narcotics OD
- Flumazenil (Romazicon) - benzodiazepine OD
- Digoxin Fab (Digibind): - digoxin OD
- Vitamin K: warfarin (if bleeding; will ⇡ INR
- Protamine sulfate: Heparin OD
- Acetylcysteine (Mucomyst): acetaminophen OD
