Pharmacokinetics 1 Flashcards
pharmacokinetics
what the body does to drugs
Study of how the body interacts with an administered substance
Branch of pharmacology concerned with the movement of drugs within the body
Clinical pharmacokinetics
application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient
pharmacodynamics
what the drugs do to the body
pharmacokinetics 5 steps
1) drug administration =
oral, IV, intraperitoneal, subcutaneous, intramuscular, inhalation
2) absorption and distribution =
membranes of oral cavity, GI, peritoneum, skin, muscles, and lungs
3) binding = target site, inactive storage depots
4) inactivation = liver - primary metabolizer
5) excretion = intestines, kidneys, lungs, sweat glands -> feces, urine, water vapor, sweat, saliva
Stages of Pharmacokinetics:
Administration
Absorption
Distribution
Metabolism
Elimination
How the drug is administered does affect the absorption, distribution, metabolism, and elimination =
therapeutic response
Routes of Administration
Alimentary Canal: Enteral
Nonalimentary Canal: Parenteral
Non-Systemic
Alimentary Canal: Enteral
oral
sublingual
rectal (hemorrhoids, constipation)
Nonalimentary Canal: Parenteral
Injection
> Intramcuscular
> Subcutaneous
> Intravenous
Transdermal
Inhalation
Non-Systemic
Topical
Intranasal
Ocular drops
Trade-Off: Enteral vs Parenteral
Enteral routes: fairly simple, easy access but less predictable absorption
Parenteral routes: more difficult, inconvenient but more predictable absorption
Most common enteral administration route is __
oral
Enteral: Oral
Advantages =
easy method: can self administer
relatively safe: control over large spikes in blood plasma concentration
Most are absorbed in the small intestines: large surface area for absorption
Aqueous meds more bioavailable via rapid absorption vs tablet form
Enteral: Oral
Disadvantages =
Drugs must have a relatively high level of lipid solubility to pass through the GI mucosa and into the bloodstream
Large non-lipid soluble molecules pass through the GI and exit via the feces
Encapsulated non-lipid soluble will increase ability to be absorbed
Stomach irritation – pain, discomfort, vomiting
Acidic stomach environment may destroy some compounds before they are absorbed
First pass effect:
the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation
Drug is absorbed by the GI = portal vein = drug metabolized in the liver = target cells
Some of the drug is destroyed during ‘first pass’ in the liver
Dose must be sufficient to pass through liver metabolism, travel to the target cells with concentrations high enough to create a response
First pass effect varies depending on the drug
Amount and rate that drug reaches target cells is less predictable than more direct routes of administration
Many factors affect drug absorption in the GI:
> infection
food
rate of gastric emptying
amount of visceral blood flow
First pass metabolism:
nasal = drug absorbs directly into veins
heart = pumps blood out to entire body - no delay
oral medications = sit in stomach for 30-45 minutes
venous system = transports blood from nose directly to heart - no liver metabolism
liver = 90% of oral medication is metabolized and destroyed by the liver before it gets to heart
portal circulation = all blood from intestines is taken to the liver for detoxification
Sublingual:
drug administered under the tongue, typically a faster route than oral (1-5 min), and more efficient absorption
Example: Nitroglycerin = CAD or previous MI
Buccal:
drug administered between the cheek and gums
Drugs absorbed transmucosally -> venous system -> superior vena cava -> right atria
Sublingual, buccal, nasal, vaginal, urethral
What happens with the first-pass effect in drugs administered via sublingual or buccal routes?
Nitroglycerin can not be taken oral = destroyed by stomach acid
Enteral: Sublingual and Buccal
Advantage:
avoid liver metabolism = first pass
Faster effects than oral
> Sublingual/buccal 1-5 minutes vs oral 20-60 minutes
Used with patients who have difficulty swallowing
Enteral: Sublingual and Buccal
Disadvantage:
Extended-release drugs do not work well via sublingual or buccal
Eating, drinking, and smoking can affect absorption
Enteral: Rectal
Used most often for localized condition
Hemorrhoids = local benefit
Enteral: Rectal
Advantage:
Able to administer to an unconscious patient
Used in children
Avoids First Pass Effect
Used in vomiting
Rapid local effects
Enteral: Rectal
Disadvantage:
Absorption can be highly irregular = limited surface area
Patient adherence
Irritation of rectal mucosa
Parenteral
All routes of administration that do not use the GI are considered parental: injection, inhalation, transdermal
Typically more direct route to the target area
Higher degree of predictability in quantity of drug reaching the target area
Drugs administered via a parenteral route typically not subject to the first-pass effect or stomach acid
Parenteral: Inhalation
Drugs in a gaseous or volatile state in an aerosol form
Example: Bronchodilators, steroid inhalers, general anesthesia
Parenteral: Inhalation
Advantages:
Large pulmonary surface area for distribution into the pulmonary circulation
Rapid uptake into the bloodstream = 1-2 minutes
Used commonly with bronchial and alveolar conditions
Parenteral: Inhalation
Disadvantage:
Irritant to the respiratory tract
Difficult to administer to self = technique
Challenging to predict the amount of a drug that reaches the target tissue
Parenteral: Injections that require absorption
Intramuscular = Rapid Absorption
Subcutaneous = Consistent & reliable, good bioavailability
Intravenous = Instantaneous systemic absorption and effect
Intradermal = Local effect
Parenteral: Injections that require absorption
Advantage:
Good option if oral bioavailability is low
Onset relatively rapid
Parenteral: Injections that require absorption
Disadvantages:
Risk of infection
Difficult to self-administering
Absorption unpredictable if perfusion poor
Injection: Intramuscular (IM)
Administered directly to a muscle
Useful for conditions directly associated with the injected muscle
Example: botulinum toxin to treat cerebral palsy spasticity, vaccines
Injection: Intramuscular (IM)
Advantages:
Relatively steady, prolonged release
Relatively rapid effect
Injection: Intramuscular (IM)
Disadvantages:
Localized pain and prolonged soreness
Limited use for repeat injections
Injection: Subcutaneous (SC)
Direct injection beneath the surface of the skin
Used for a local and systemic response
Example: local anesthesia, heparin, and insulin
Injection: Subcutaneous (SC)
Advantages:
Relatively easy to administer
SC administration allows for a slow release of meds to the systemic circulation
Injection: Subcutaneous (SC)
Disadvantages:
Absorption unpredictable if poor perfusion = impacts absorption and distribution
Painful injection site
Injection: IV
Injection of a known quantity of drug into a peripheral vein
Pump or Drip Infusion
IV ‘push’ or bolus
Example: Heparin = anti-coagulant
Injection: IV
Advantages:
Rapid peak levels in the bloodstream = no absorption phase
Rapid effect on the target tissue
Good choice for emergency situations
Prolonged, steady infusion into the bloodstream for inpatient situations = ease of repeat doses
Injection: IV
Disadvantages:
Potential adverse reactions due to rapid delivery of large dosage = adverse effects are difficult to manage
Parenteral: Transdermal
Administered to the surface of the skin with intent that the drug will be absorbed through the dermal layer
Slow, controlled release of a drug with relatively constant blood plasma levels over an extended period of time
Often delivered via a medicated ‘patch’
Examples: nicotine, motion-sickness meds, estrogen and testosterone
Two basic properties of transdermals:
Must be able to penetrate the skin
Must not be metabolized by enzymes in the skin
Examples of ionized medication: Iontophoresis and phonophoresis
Electric current or ultrasound waves used to push the ionized form of medication through the dermal layer
Physical therapists use ionto and phono to treat inflammation
Example: Dexamethasone
Parenteral: Topical
Administered to the surface of the skin or mucus membranes
Used primarily for skin conditions or site of application
Parenteral: Topical
Advantage:
Application to mucus membranes = Significant amounts of a drug applied can be absorbed
Application to skin = good for localized treatment
Easy, rapid, and convenient way to administer a drug
Parenteral: Topical
Disadvantage:
Poor absorption through the epidermis into the bloodstream
Examples: antibiotics for cutaneous infections, anti-inflammatory steroids for skin inflammation, eye drops, nasal spray
Injection: Intra-Arterial
Direct injection into an artery is difficult and dangerous due to rapid availability
Often used with chemotherapy to deliver a drug to a specific site while minimizing exposure to healthy tissue
Injection: Intrathecal
Administered within a sheath = spinal subarachnoid space
Example: antibiotics to treat meningitis, spinal anesthesia, and pain management
Injection: Intrathecal
Advantages =
drugs acts directly on meninges and CNS
bypass blood-brain barrier and blood-csf barrier
Injection: Intrathecal
Disadvantages =
strict aseptic precautions needed
painful procedure
expertise needed
Bioavailability
The percentage of the medication administered that reaches systemic circulation
100 mg given orally = 50 mg reaches systemic circulation = 50% bioavailable
100 mg given IV = 100 mg in systemic circulation = 100% bioavailable
Many factors determine a drugs bioavailability
Blood barriers, enzymatic action, liver metabolism, cell membranes, and tissue barriers
Administration Route: Drugs traveling from original point of entry to target tissue will be affected by many factors to determine bioavailability
Bioavailability: Membrane Structure and Function
Cell membrane structure determines level of permeability to substances
Cell membrane: composed of phospholipids and proteins
Phospholipids are arranged in a bilayer
Hydrophobic tails toward the membrane’s center
Hydrophilic heads away from the center
Protein interspersed amongst the phospholipid bilayer
Lipid bilayer acts as a water barrier and impermeable to non-lipid soluble substances
Lipid soluble compounds = most drugs are able to pass through the cell membrane by dissolving into the phospholipid bilayer
Channels in the lipid bilayer allow for water and non-lipid soluble compounds to pass through
Drugs can be used to excite these channels to open or close
Distribution: Movement Across Membrane Barriers
Following absorption
Unmetabolized drug to the site of action
Passive diffusion
Passive Diffusion:
passage of a drug from one side of a membrane to another given two essential criteria = occurs without expending any energy
Gradients =
Concentration difference or ‘gradient’: substance moves from an area of high concentration to an area of low concentration
Pressure gradient: substance moves from an area of high pressure to an area of low pressure
Membrane permeable to substance that is diffusing
Drugs with a high degree of lipid solubility will diffuse readily
Non-lipid soluble drugs are dependent upon channels and active transport
Rate of diffusion =
dependent upon size of the gradient, size of the diffusing molecule, distance of diffusion, local blood flow, blood brain barrier, and temperature
Factors Impacting Absorption & Distribution of Drugs
Drugs must first diffuse into the cell via phospholipid bilayer and then out the other side of the cell = tight junctions limit movement around cells
Drugs diffuse across a cell membrane from a region of high concentration (eg, GI fluids) to one of low concentration (eg, blood)
The cell membrane is lipid = lipid-soluble drugs diffuse most rapidly
Small molecules tend to penetrate membranes more rapidly than larger ones
Absorption: Water Soluble
Osmosis
Water movement from an area of high concentration to an area of low concentration
Cell membrane ‘channels’ or semi-permeable membranes will allow small non-lipid soluble drugs to pass through as water moves from high to low concentration
Absorption: Active Transport: Non-Lipid Soluble Substances
Use of membrane proteins to transport a substance across the cell membrane
Drugs can utilize active transport systems if the drug resembles some endogenous substance
Example: drugs that resemble amino acids and small peptides will be absorbed in the GI tract via active transport systems that normally absorb AA
Effect of Ionization on Lipid Diffusion
Drugs diffuse more readily in their natural non-ionized form
Ionization decreases lipid solubility
Most drugs remain in a neutral nonionized form due to neutral fluids in the body
Ionization status of a drug changes when:
it moves from an environment of similar pH to an environment with a different pH
Example: aspirin is a weak acid -> it stays in a nonionized form in the stomach, this is also an acidic environment -> absorbed readily in the stomach -> when aspirin reaches the small intestines, a basic environment -> it ionizes and is poorly absorbed
Ionization =
process by which an atom or a molecule acquires a negative or positive charge by gaining or losing electrons to form ions, often in conjunction with other chemical changes
Factors that affect drug distribution:
Administration Route
Tissue permeability
Blood flow
Binding to Plasma Proteins and Subcellular Components
Blood brain barriers
Fat, muscle
Tissue permeability:
drugs ability to pass through cell membranes
Lipid soluble drugs can reach all cells
A large non-lipid soluble will remain in the area that it is administered
Blood Flow:
Drugs circulating in the bloodstream will gain greater access to tissue
Binding to Plasma Proteins and Subcellular Components:
Some drugs will form a reversible bond to protein in the bloodstream
Some drugs will form bonds within specific cells limiting distribution
Drugs that remain bound will not reach target tissue
Blood brain barriers:
highly lipid soluble drugs may cross BBB
Fat, Muscle:
drug accumulation sites
Drug Storage
Drugs are intended for specific target sites = can be stored temporarily in various tissue and cause adverse effects on storage site tissue
Bone: Storage site for heavy metals (lead) and tetracyclines
Muscle: Drugs enter via passive and active transport, bind with proteins, nucleoproteins, and phospholipids within muscle cells
Organs: Drugs enter via passive and active transport, bind with organ cellular components
Adipose Tissue:
primary site for drug storage
Tend to have a long storage time due to low metabolic rate and poor blood perfusion
Example: Highly lipid soluble anesthetics
Adverse consequences of Drug Storage
High concentrations of drugs, drug metabolites, and toxic compounds stored within tissue can cause local damage to the tissue
Liver and kidneys are prone to local damage due to potential high concentrations of drugs
Adverse consequences of Drug Storage
example)
In a healthy individual, acetaminophen metabolites are inactivated in the liver and excreted by the kidney via the urine
High doses of acetaminophen can cause excessive toxic metabolites that can react with liver proteins = causing liver damage
