Lecture 2 Flashcards
Bioavailability
amount of drug in the bloodstream that is free to bind at target receptors.
Pharmacokinetic (PK) components of drug action
- Route of administration.
- Absorption and Distribution.
- Binding.
- Inactivation.
- Excretion.
Route of Administration
How and where a drug is administered determines how quickly and how completely the drug is absorbed into the blood.
Absorption and Distribution
movement of drug from site of administration to blood circulation.
Binding
drug molecules move to tissues to bind to active target sites (receptors).
Inactivation/biotransformation
occurs primarily as a result of metabolic processes.
Excretion
- The liver metabolites are eliminated from the body with the urine, feces or kidney.
Depot binding
Binding to sites that are not the target site.
Why is depot binding important
- slows down the rate of accumulation of the drug at its site of action.
- diminishes the concentration of the drug at its site of action.
- delays the onset of the drug.
- prolongs the action of the drug.
Enteral adminstration
- use the gastrointestinal (GI) tract.
- agents administered are slow in onset and produce highly variable blood levels of drug.
Phospholipid bilayer
Cell membranes are primarily composed of molecules called phospholipids, which have a negatively charged region and two uncharged tails, arranged in a bilayer.
Passive diffusion
a movement of ions across cell membranes without need of energy input.
Lipid solubility
refers to the capability of a substance to dissolve in lipids, fats, or oils.
Ionization
depends on the pH of the solution and the pKa of a drug,
What do proteins do in the phospholipid bilayer?
they serve as receptors or channels or transporters.
Types of Routes Of Administration
- oral
- topical
- transdermal
- injection
Oral (PO)
- drug must dissolve in stomach fluids and pass through the stomach wall to reach blood capillaries.
- first-pass metabolism
First-pass metabolism
All drugs (and food) given PO enter the liver where they may be chemically altered.
Topical
application to body surfaces such as the skin or mucous membranes
Transdermal
through the skin, administration with skin patches.
Injection
shot, or a dose of medicine given by way of a syringe and a needle.
Subcutaneous (SC)
Drug is injected just below the skin.
Intravenous (IV)
Agent is placed directly into the blood.
Intramuscular (IM)
injected into muscle tissue.
Intraperitoneal (IP)
Drug is injected through abdominal wall.
Intra-arterial
injected straight into the artery.
Intrathecal (epidural)
Through spinal fluid
Intracranial
Drug injection into brain tissue.
Intracerebroventricular
Drug injected into csf filled chambers.
Infusion pump
Implanted under the skin of the scalp.
Inhalation
Drug is absorbed from the lungs.
Gene Therapy
Can be used to increase or block expression of gene product to correct a clinical condition.
Pros & Cons of Oral administration
Advantage
- safe
- self- administered
- economical
- no needles- related complications.
Disadvantage
- slow and highly variable absorption
- subject to first- pass metabolism
- less- predictable blood levels.
Pros & Cons of Intravenous Administration
Advantage:
- most rapid
- most accurate blood concentration.
Disadvantages:
- overdose danger
- cannot be readily reversed
- requires sterile needles and medical technique.
Pros & Cons of Intramuscular Administration
Advantages:
- Slow and even absorption.
Disadvantages:
- localized irritation at the site of injection
- needs sterile equipment.
Pros & Cons of Subcutaneous Administration
Advantages
- slow and prolonged absorption.
Disadvantages:
- variable absorption depending on blood flow.
Pros & Cons of Inhalation Administration
Advantages:
- large absorption surface
- very rapid onset
- no injection equipment needed.
Disadvantages:
- irritation of nasal passages
- inhaled small particles may damage lungs.
Pros & Cons of Topical Administration
Advantages:
- localized action and effects
- easy to self- administer.
Disadvantages:
- may be absorbed into general circulation.
Pros & Cons of Transdermal Administration
Advantage:
- controlled and prolonged absorption.
Disadvantage:
- local Irritation
- useful only for lipid- soluble drugs.
Pros & Cons of Epidural Administration
Advantage:
- bypasses blood- brain barrier
- very rapid effect on CNS.
Disadvantage:
- not reversible
- needs trained anesthesiologist
- possible nerve damage.
Pros & Cons of Intranasal Administration
Advantage
- ease of use
- local effects
- very rapid
- no first pass metabolism
- bypasses blood-brain barrier.
Disadvantage:
- not all drugs can be atomized
- potential irritation of nasal mucosa.
Diet
Absorption is slower when you take it with food because it competes with food to get into intestines first.
Capillaries
really small blood vessels with large pores through which drugs can leave the blood even if the drugs are not lipid-soluble.
Brain Capillaries
have no intercellular clefts; only very tight junctions.
Placental Barrier
Placenta forms a barrier between the maternal blood circulation and the fetus.
teratogenic effects
development abnormalities that outlast exposure postpartum
ex: fetal alcohol syndrome
How are Drugs metabolized & excreted?
Drugs are eliminated via bio-transformation and metabolites are excreted.
- vie urine or bile.
Metabolites
make chemical into a different form so it can be excreted more easily.
Cytochrome P450 (CYP450)
enzyme family responsible for metabolizing most psychoactive drugs.
Co-metabolism
When enzyme is breaking down two different drugs, it binds them together in some way and creates a different/new drug.
Factors that modify biotransformation capacity?
- Enzyme induction
- Enzyme inhibition
- Drug competition
- Individual differences in age, gender, & genetics.
Enzyme induction
Repeated use of a drug increases the number of enzyme molecules and speeds up biotransformation.
Enzyme inhibition
A drug may inhibit an enzyme, also reducing metabolism of other drugs.
Drug competition
Elevated levels of one drug reduces metabolism of the second, resulting in potentially toxic levels.
Half Life
- Amount of time required for removal of 50% of the drug.
- Based on first order kinetics.
First Order Kinetics
drug clearance from the blood is usually exponential.
Zero-order kinetics
Molecules are cleared at a constant rate regardless of concentration.
Pharmacodynamics
Study of the physiological and biochemical interaction of drug molecules with cell receptors.
Receptors
Proteins on cell surfaces or within cells to which drugs & neurotransmitters bind.
Ligand
Molecule that binds to a receptor with some selectivity.
Intracellular receptors
Found in cytoplasm or nucleus & alter gene expression.
Receptor Agonist
Attaches readily to the receptor and produces significant biological effect.
- affinity and efficacy
Affinity
strength of attachment.
Efficacy
the ability to activate the receptor.
Receptor Antagonist
- Fit receptors but produce no cellular effect.
- Affinity but zero efficacy.
Dose
amount/concentration administered.
Dosage
amount of drug taken over time.
Response
magnitude of effect within individuals & number of people showing the effect.
Dose-Response Curve
Describes the extent of biological or behavioral effect of a drug.
Threshold Dose
smallest dose that produces a measurable effect.
Potency
Absolute amount of drug necessary to produce a specific effect.
ED50
dose that produces half the maximal effect.
ED 100
dose that produces the maximum effect.
Why can’t Aspirin be directly compared to other opiods?
It has a difference in efficacy so it can’t be directly compared.
List the Potency of hydromorphone, morphine and codeine from lowest to highest.
- Codeine
- Morphine
- Hydromorphone
Therapeutic
index
- (TI) = TD50/ED50.
- Measurement of drug safety.
Therapeutic Window
the range of drug dosages which can treat disease effectively without having toxic effects.
Agonist + receptor
drug action/effect
Antagonist + receptor
NO drug action/effect
Agonist Types
Full: high affinity & efficacy.
Partial: low efficacy.
Mixed agonist/antagonist: varying activity depending on the receptor & the dose.
Inverse: produces opposite effects.
Competitive antagonist
drugs that directly compete with agonists/neurotransmitter for binding site on receptors.
Non-competitive antagonist
bind with very high affinity or bind elsewhere to decrease activation of receptor.
Physiological antagonism
two drugs produce opposite effects, reducing the effectiveness of both.
Additive effects
outcome equals the sum of two individual effects.
Potentiation
the combination of two drugs produces effects greater than the sum of their individual effects.
Types of Drug Interactions
- ) Physiological antagonism
- ) Additive
- ) Potentiation
Downregulation
decrease in receptor numbers with prolonged/repeated drug use.
Up-regulation
increase in receptor numbers with prolonged/repeated drug use.
Tolerance
Decreased response after repeated/chronic use.
Cross Tolerance
tolerance to one drug can diminish the effectiveness of a second drug that works through the same receptor.
Acute Tolerance
Develops during a single administration.
What are the significant characteristics of Tolerance?
- Reversible when drug use stops.
- Dependent on dose and frequency of drug use and drug taking environment.
- Not all effects of drug show the same degree of tolerance.
- Several different mechanisms explain multiple forms of tolerance.
Types of Tolerances
Metabolic
Pharmacodynamic
Behavioural
Metabolic tolerance
increased enzyme production leads to lower drug levels.
Pharmacodynamic (PD) tolerance
changes in nerve cell function compensate for continued presence of the drug.
Behavioral tolerance
Many psychoactive drugs elicit reflexive effects such as cortical arousal, elevated blood pressure, or euphoria, and these can act as unconditioned stimuli that elicit the drug’s effect more easily.
Sensitization
Enhancement of drug effects after repeated administration of the same dose.
Pharmacogenetics
study of the genetic basis for variability in drug response among individuals.
