Wk 1 Principles Flashcards
Three phases of drug action
- Pharmaceutic
- Pharmacokinetic
- Pharmacodynamic
Pharmaceutic phase
dissolution of the drug occurs, the drug begins to dissolve so it can be used and absorbed
ONLY ORAL DRUGS
Pharmacokinetic phase
- drug moving through the body and what the body does to the drug
- absorption
- distribution
- metabolism/biotransformation
- excretion
Absorption
moves to small intestines to be ABSORBED INTO THE BLOOD
- small intestines
Distribution
once absorbed into blood, leaving the blood and passing through the cell membrane to the site of action where it needs to exert its effect
- blood
Metabolism
once it has exerted its effect, its broken down/metabolized by the LIVER
Excretion
from lipid soluble metabolite to water soluble metabolite to send to kidneys to excrete it
Pharmacodynamic phase
what the drug does to the body
- the action of the drug/mechanism of action (MOA)
- the intended effect of the drug
- the therapeutic action
Absorption - Crossing the cell membranes - the phospholipid bilayer
cell membranes are composed of layers of cells close together, drugs must pass through to get to blood and site of action
Absorption - Phospholipid bilayer
- semipermeable
- hydrophilic head group
- hydrophobic fatty acids
- drugs must be lipid soluble to pass membrane
- water soluble drugs require passage through channels or pores
First Pass Effect affecting absorption
- the metabolism of drug by the liver before its systemic availability/circulation
- alters the amount of drug absorbed
- % of drug broken down in liver
- PO drugs
- must pass through the liver
- if a large portion of the drug is chemically changed to inactive form by the liver, only a small amount of the drug will be available to exert effects
Bioavailability + absorption
the amount of drug left after first pass
- bioavailability of PO varies
- bioavailability of IV is 100%
Three routes of absorption
- enteral
- parenteral
- topical (transdermal)
Enteral absorption
by way of the GI tract (oral/gastric mucosa, small intestine, rectum)
- PO drugs breakdown starts in stomach, still first pass effect
- EC (enteric coated) intended to break down in small intestine, NOT stomach, still first pass effect
SL, Buccal, Rectal (part of enteral)
highly vascularized tissue
No first pass effect, by-passes liver
Parenteral absorption
- SQ, IM, IV, intrathecal (into spinal canal), epidural (the space around the spinal cord)
- IV is the fastest (no barriers to absorption, often irreversible)
- fastest, does not go through first-pass effect
Topical (transdermal) absorption
application of meds to body surfaces such as eyes, skin, ears, nose, lungs
- onset is slower and more prolonged
- not concerned with first pass effect
Distribution
- second part of pharmacokinetic phase
- the movement of the drug through the body
- process by which the drug molecules leave the bloodstream and arrive at the site of action
- depends largely on adequacy of blood circulation
Disruptions in distribution
decreased blood flow = decreased distribution
- peripheral vascular disease
- abscesses - decreased blood flow because of the swelling and exudate
- tumors
Blood Brain Barrier
effects distribution
- cells in the capillary wall in the brain with very tight junctions that prevent drug passages
- only drugs that have a transport system or are VERY lipid-soluble can cross the BBB
BBB
- alcohol can cross BBB
- glucose can also cross BBB
- BBB in infants is not fully developed
Distribution: Protein-Binding Effect
Temporary storage of drug molecule that allows drug to be available for a longer period of time
- drug ratio of bound to unbound (free) molecules varies
- binding is reversible (a rapid process)
- want normal/consistent amount of bound to unbound ratio to keep steady state
Goal of protein-binding effect
maintain a steady free drug concentration aka Steady State
- remember ONLY unbound drug is active and free to exert effects
What effects protein-binding
- amount of protein in person’s blood
- albumin is the primary plasma protein in blood
- drugs bind to protein (albumin)
- if drug is highly protein bound, looking for protein always
Problem with protein-binding
problem with pts with hypoalbuminemia (ie, malnutrition or liver disease)
- more free drug is available for distribution to tissue site
- possibility of overdose or toxicity
Example of protein-binding - warfarin/Coumadin
- drug used to decrease coagulation (blood thinner)
- very highly protein bound (97-99%), leaves 1-3% free to exert effect
- a client with low albumin = less bound Coumadin (inactive) and more free Coumadin (active)
- more free Coumadin can exert effect
- increased risk of toxicity + increased bleeding
Pharmacokinetic Phase: Metabolism
aka - biotransformation
- method by which drugs are inactivated or biotransformed
- new broken down/inactivated structure is called a metabolite
Liver + Metabolism
major site for drug metabolism
- converts lipid-soluble drugs into water-soluble metabolites so kidneys can excrete
- main way that liver does this is through cytochrome P-450 enzyme
If liver doesn’t work properly for metabolism
can have drug toxicity
Cytochrome P-450 Enzyme (CYP450)
CYP
- group of isoenzymes that metabolize drugs
- about 1/2 of all drugs are metabolized by this system
- drug-drug interactions can occur when drugs metabolized by the same isoenzymes are taken concurrently
Clinical significance of CYP450
- substrate
- inducer
- inhibitor
Substrate
if a drug uses the CYP450 system for metabolism, at beginning of metabolism
- pro-drug is a substrate that uses the CYP450 system to convert to an active form
Inducer
drug/item that increases/speeds up metabolism of the CYP450 system
- reduces the amount of drug in the body
- reduces therapeutic effect
Inhibitor
drug/item that slows down metabolism of the CYP450 system
- increases the amount of drug in the body
- increases risk of toxicity
CYP450 Inhibitor Example
Grapefruit juice
- taking grapefruit juice with another drug that uses this system increases the amount of that drug in the body
- can lead to toxicity
- avoid for 2-4 hours after taking medication
Pharmacokinetic Phase: Excretion
Elimination of drug from the body
- generally only hydrophilic drugs can be excreted effectively
Kidney is
major site of excretion
- through glomerular filtration
- tubular secretion
- tubular reabsorption
Reabsorption and Secretion
some of the drug is secreted, some of the drug is reabsorbed
- important in maintaining a steady state
- penicillin G is 90% excreted, so drug would need to be given more frequently
Kidney disease + excretion
- kidney disease or dysfunction = decreased excretion = drug build up and cause toxicity
Renal labs + excretion
blood urea nitrogen (BUN) and creatinine
Glomerular filtration rate (GFR)
best measure of kidney function
- calculated from the creatinine level, age, body size, and gender
- GFR of drugs is related to free drug concentration in plasma
Elimination + Half-Life
Serum half-life (T 1/2) is time required for the serum concentration of a drug to decrease by 50%
5 half-lives
97% of the drug to be eliminated
T 1/2
varies from drug to drug
- can be minutes, hours, days, weeks, or more
- helps dictate how far apart dosing intervals
Steady state + half life
takes about 4-5 half-lives for “steady state” to occur
- goal is steady state
Steady state is
when intake of the drug is equal to the amount metabolized/excreted
- want to keep enough of drug to help BP, enough abx in system to kill bacteria
Around the Clock Dosing (ATC)
- goal is to maintain 50% concentration in body
- ex = Morphine with T 1/2 3 hours would be given every 3 hours ATC, after about 4 doses there would be a steady state of 5 mg at all times
- used to treat chronic pain and then PRN for “breakthrough” pain
Onset
time it takes for the drug to elicit therapeutic response (latent period)
Peak
time it takes for drug to reach its maximum therapeutic effect
- how long does it take to feel the full effect of 10mg of morphine
Duration
time drug concentration is sufficient to elicit a therapeutic response
- how long does it take for us to get that 5mgs going
Pharmacodynamic phase = phase 3
what the drug does to the body
- drugs may increase, decrease, inhibit, destroy, protect, or irritate to create a response
- Drugs can exert multiple rather than single effects on the body, some are desired and some are not
Multiple effects Example
Metaproterenol
MOA = bronchodilator
Uses = acute asthma attack or COPD
Adverse effects = tachycardia and/or palpitations
Multiple effects:
– desired: dilates bronchial passage
– not desired: tachycardia or palpitations
Pharmacodynamics: Receptors
proteins located on cell surfaces (such as hormones or neurotransmitters) that sit on these cells and look for drugs to bind with
- chemicals in the body interact with drugs to produce effects such as hormones and neurotransmitters
- these chemicals BIND with the drug = drug-receptor complex
Drug-receptor complex
initiates a physiochemical reaction
- agonist = stimulates/activates
- antagonist = inhibits/blocks
Receptor Theory of Drug Action: Agonist
a drug that has the ability to INITIATE a desired therapeutic effect by BINDING to a receptor
ex: isoproterenol = beta1 adrenergic agonist
- binds to beta receptors and causes vasodilation lowering peripheral vascular resistance
Receptor Theory of Drug Action: Antagonist
A drug that produces its action not by stimulating receptors but PREVENTING or BLOCKING or INHIBITING other natural substances (ligands) from binding and causing a response
Antagonist examples
ranitidine/Zantac = an H2 ANTAGONIST, blocks release of gastric acid
diphenhydramine/Benadryl = an H1 ANTAGONIST that blocks action of histamine
propranolol/Inderal = a beta 1 adrenergic ANTAGONIST that blocks action of epinephrine
Agonist
drugs that occupy a receptor and activate or stimulate
Antagonist
drugs that occupy a receptor and block other chemicals from activating the receptor
Receptor-Less Activation
- not all drug responses involve receptors
- some drugs act through simple physical or chemical interaction with small molecules
Receptor-less activation example
- antacids = neutralize gastric acidity through direct chemical interaction
- magnesium sulfate works as a powerful laxative by retaining water in the intestinal lumen through osmotic effect
Therapeutic Index
the measure of relative safety of drug
- ratio of drug’s toxic level to the level where it provides therapeutic index
Narrow Therapeutic Index (NTI)
have a ratio of lowest concentration at which clinical toxicity commonly occurs
NTI monitoring
drug that has NTI, we check therapeutic levels by taking blood to ensure the medication is dosed effectively by avoid toxicity
- theophylline, digoxin, lithium
Black Box Warning
required by FDA for drugs that are especially dangerous
- strongest safety warning a drug can have and still remain on the market
- must be on package insert, product label, on any magazine or other advertising
Medication Errors + Adverse Drug Reactions
- major cause of morbidity and mortality
High Alert Medications
most likely to cause serious harm or death
- insulin (antidiabetic)
- heparin (anticoagulant)
- opioids (pain mgt)
- chemo
- neuromuscular blocking agents
- injectable potassium chloride (IV KCL)
Drug-Drug Interactions
- may be intended, most are unintended
- increased risk with polypharmacy (multiple drugs)
- especially concerning with NTI drugs
Drug interactions that INCREASE therapeutic effects
- additive effects
- synergism/potentiation
- activation
- displacement
Additive effects
2 drugs taken with similar MOA
- ex: 2 abx given to treat complicated infection
Synergism/Potentiation
2 drugs with DIFFERENT MOA but result in a combined drug effect greater than that of either drug alone
- ex: Coumadin and Aspirin
Activation
of drug-metabolizing enzymes in the liver -> decreases metabolism rate of the drug (CYP450 system)
- purposefully slowing down or stimulating CYP450
Displacement
displacement of one drug from plasma protein-binding sites by a second drug -> increases effect of displaced drug
Drugs that DECREASE therapeutic effects
- antidote
- decrease intestinal absorption
- activation
Antidote
drug given to ANTAGONIZE the toxic effects of another drug
- naloxone antidote for opioid overdose
Decreased intestinal absorption
applied to PO medications
Activation
of drug-metabolizing enzymes in the liver -> enzyme inducers
- increased metabolism rate of the drug, quicker out of their system
- CYP450 system
Older Adults + Pharmacokinetic Consequences
- hepatic changes
- cardiac and circulatory changes
- gastrointestinal changes
- renal changes
Hepatic changes
drugs metabolized more slowly
Cardiac and circulatory changes
impaired circulation = decrease distribution of drugs
Gastrointestinal changes
decreased absorption of oral drugs
Renal changes
drugs excreted less completely
Decreased production of CYP 450 enzymes
in older adults
- increased risk for drug interactions
- can decrease up to 30% in elderly
