Chapter 1: Pharmacokinetics and Pharmacodynamics Flashcards
Pharmacokinetics vs Pharmacodynamics
Pharmacokinetics- how substances are distributed through the body
Pharmacodynamics- interactions of the substance with a receptor
Pharmacology
the scientific study of actions of drugs and their effects on a living organism
Neuropharmacology
Psychopharmacology
Neuropsychopharmacology
Neuropharmacology- drug induced changes in nervous system function
Psychopharmacology- drug-induced changes in mood, thinking, and behavior
Neuropsychopharmacology- drug- induced changes in the nervous system that influence behavior
Drug Action
- specific molecular change
- drug binds to its target (receptor)
- can be very distant from ultimate effect
- occur at many different target sites
Drug Effect
- more widespread/ systemic change
- eg. in physiology or behavior
- Therapeutic effects
- desirable effects of a drug - Side effects
- undesirable: annoying, distressing, dangerous
Specific Drug Effects vs Nonspecific Drug Effects
Specific Drug Effects
- result from interactions between a drug and it’s target (pharmacodynamics)
Nonspecific Drug Effects
- may affect outcome of drug use
- can't be explained by drug-receptor interactions
- include mood, expectations, perceptions, attitudes
- ex. different moods when drunk, placebo effect
Pharmacokinetics
- what body does to drug
- mechanisms involved in delivering a drug to its target, where it can have a pharmacological effect
- Administration- routes of administration
- Absorption and Distribution- pass through variety of cell membranes and enter blood plasma
- Elimination
- Metabolism- inactivation
- Excretion- liver metabolites are excreted/ unaltered forms are excreted
Bioavailability- […]
depends on several factors:
- (...) into the blood by route of administration
- affected by (...)
- drug (...) to target sites
- (...)
- (...)/ clearance mechanisms
- for a drug to be (...) it must be (...) or (...)
Bioavailability- is the amount of drug in the blood that is free to act on a specific target
depends on several factors:
- absorption into the blood by route of administration
- affected by lipid solubility, ionization, selective barriers
- drug distribution to target sites
- plasma proteins, depot binding (inactive storage site)
- elimination/ clearance mechanisms
- for a drug to be bioactive it must be unchanged (not metabolized) or active metabolite
Pharmacokinetic factors determine bioavailability
- Drug Administration- oral, intravenous, intraperitoneal, subcutaneous, intramuscular, inhalation
- Absorption and Distribution- membranes of oral cavity, gastrointestinal tract, peritoneum, skin, muscles, lungs
- Binding
- Target site: neuron receptor
- inactive storage depots: bone and fat - Inactivation- liver, stomach, intestine, kidney, blood plasma, brain
- Excretion- intestines, kidneys, lungs, sweat glands
Excretion products: feces, urine, water vapor, sweat, saliva
Time Course of Plasma Concentration
*picture on phone
Absorption
movement of the drug from site of administration to the blood circulation
- oral delivery requires absorption through the GI tract
- drugs must survive this "first-pass" metabolism (toxins go through portal vein to liver where they're altered by enzymes before passing through heart for circulation) in active form
- once in the blood, a drug can reach its active site or bind to inactive sites in blood (eg albumin) muscle or fat
4 common routes of administration
Oral injection: tablet, capsule, liquid
Injection: intramuscular, intravenous, subcutaneous
- may not go through first pass metabolism
Inhalation: smoking, inhalers, nebulizers
Through mucous membranes: sublingual, intranasal, rectal suppository, transdermal
Route of administration affects drug half-life and bioavailability
Absorption: lipid solubility
- cell membranes are comprised of phospholipid bilayers
- substances must be lipid-soluble to pass through the membranes by passive diffusion
- movement down a concentration gradient
- higher concentration gradient= faster movement
Membrane lipid bilayer:
- Phosphate head group
- carry ionic charge
- polar, hydrophilic
- 2 fatty acid tails
- do not carry charge
- non-polar, hydrophobic
- impedes ability of substances to cross membrane
Absorption: ionization
- most psychoactive drugs are weak acids or weak bases that are ionized in water
- passive diffusion ceases when drug is 50% ionized and 50% unionized
- highly charged molecules don’t absorb easily in GI tract - ionization depends on pH of solution and pKa of molecule
- example. aspirin
Absorption: transport across membranes
- Blood- Brain Barrier: supplies O2, glucose, AA; gets rid of CO2, and other waste
- reduces diffusion of ionized molecules - Placental Barrier
- acute toxicity
- teratogenic effects (some depend on timing of exposure)
Distribution
once absorbed, a drug is distributed throughout the body via the circulatory system
The amount of drug at a target is a fraction of the total dose administered
Drug depots
- aka silent receptors
- plasma proteins ( eg albumin), muscle and fat
- affects its administration and elimination
- reduces bioavailability
- determines the duration and intensity of the drug effect; including side-effects
- non- selective binding; drug displacement
Depot binding
- binding of drugs to inactive sites
- delays onset, lowers intensity (once a month injection rather than daily dose)
- contributes to drug interactions due to non- selective binding/ drug displacement
- slows metabolism, prolongs duration
- can terminate drug action
- reduces drug concentration at active sites so only free, unbound drugs can pass through membrane
Elimination
process by which the body removes drug
Psychoactive drugs are commonly metabolized […] and excreted by the […]
Psychoactive drugs are commonly metabolized liver and excreted by the kidney
- rates of elimination depend on drug concentration in the blood, and on the blood flow into the metabolizing organ
- First-order kinetics- exponentially cleared from body; unsaturated enzymes
- Half- life (t1/2)- amount of time to clear 50% of drug (most drugs of clearance of 6 half-lifes)
- determines steady state plasma levels- desired blood concentration of drug when absorption/ distribution= metabolism/ excretion - clearance rate is an important factor when considering dosing schedule (time interval between doses)
- Some drugs are cleared on zero-order kinetics- drug cleared at constant rate regardless of concentration; enzyme saturation (ex ethyl alcohol)
Extended Release
lower peak concentration, but much longer duration
The liver […] the drug
The liver inactivates the drug
- The active substance is converted to an inactive substance (metabolite) by
- microsomal liver enzymes (CYP450 family) that chemically modify the drug
2 types of modifications: makes molecules more soluble
- type 1 (nonsynthetic, nonconjugate): oxidation (most common), reduction, hydrolysis
- type 2 (synthetic, conjugate): glucuronide, sulfate, methyl groups
type 2 modifications cause molecules become bulkier
The kidney […] the drug
The kidney excrete the drug
- The kidneys filter the metabolites from blood, to be excreted in urine
- has an easier time getting bulkier, more soluble molecules out
Drug elimination is affected by the amount and activity of liver enzymes
Enzyme Inhibition- some drugs directly inhibit liver enzymes
- metabolism decreases
- drug levels go up
Enzyme Induction- increased enzyme levels following chronic use
- can affect other drugs modified by some enzyme
Drug Competition occurs when drugs share metabolic system
Patient- related factors affecting drug elimination
Genetics
Gender
Age
Liver disease
Pharamcodynamics
interactions between the drug and it’s target (receptor)
- mechanisms of drug action
- Concentration- response relationships
- Receptor affinity
- Drug potency and efficacy
Agonists vs Antagonists
Receptor Agonists- binds to particular receptor protein
- Drugs that mimic the effect of the endogenous transmitter
Receptor Antagonists- block active ligand from binding to receptor
- drugs that block the effect of the endogenous transmitter
Partial Agonists- less efficient than agonist, but better than antagonist
- drugs that cannot produce the full agonist response
- agonist at low concs, but antagonist at high concs
Inverse Agonists- bind to receptor, but have the opposite effect of agonist
Receptor
- protein in neural membrane/ inside neuron
- protein molecules that are initial sites of action
- has at least 1 binding site for substance
- receptor selectively binds endogenous ligand like NT
Function:
- produce longer lasting changes
- when ligand bind the receptor, signal relayed inside neuron
- magnitude of response is determined by receptor occupancy (bound with drug) and rate of unbinding (dissociation)
Ligand- Receptor Interaction
- dynamic and reversible
- in constant state of binding (association) and dissociation (breaking away)
- initiates series of intracellular effects
- follows the law of mass action
Ligand
any molecule that binds to receptor with some selectivity
Dose- response curve
extent of biological/ behavioral effect produced from certain drug concentration
Law of Mass Action
- rate of chemical reaction is proportional to product of masses of reacting substances
- amount of LR* formed depends on how much product of reactants there are
- ligand combines with receptor to form an activated ligand- receptor complex
- at equilibrium, the rate of LR* formation is equal to the rate of L+R dissociation
- the concentration of L determines the biological effect
- magnitude is determined by ligand concentration (and available receptors)
learn the formula
Potency
amount of drug necessary to produce specific effect
Receptor occupancy depends on […] of the receptor for ligand
Receptor occupancy depends on affinity of the receptor for ligand
L-R interaction can be described by affinity or dissociation constants
formulas
- units of Kd are M (mols)
- lower Kd represents higher affinity
Total number of receptors is [Rt]
[Rt]= bound receptors [LR*] + free (unbound) receptors [R]
understand the two formulas
Radioligand
- ligand that has been labeled with radioactive element
- incubated with a tissue preparation that contains the binding sites of interest
- amount of radioligand bound to tissue is measured using scintillation/ gamma counter
- Total binding increases with higher concentration of radioligand [L]
Total Binding
- includes specific and non-specific binding
- Specific: high-affinity, few binding sites
- Non- Specific: low-affinity; many binding sites - want to look at specific binding
- to determine non-specific, an excess (very high concentration) of unlabeled ligand is added
- excess unlabeled (“cold”) ligand outcompetes (“hot”) radioligand for specific binding sites
**Receptor binding is specific, high-affinity, and saturable
Binding Criteria: 1. 2. 3. 4.
- Specificity
- Saturability
- Reversibility and high affinity
- Biological relevance
Autoradiography
can help look at distribution of receptors their affinity in certain brain tissue
[…] are used to determine Bmax
Equilibrium Binding Curve are used to determine Bmax
- specific binding is determined for several concentrations of radioligand [L]
- at very high concentrations of [L], all specific binding sites are occupied with radioligand
** equilibrium binding curves show saturability of specific binding at many [L]
Saturation Curve
can measure total number of binding sites and receptor affinity
looks at Kd and Bmax
Concentration- Response Relationship
- describes ligand- receptor interaction
- depicts the magnitude of drug effects at progressively larger doses - The response can be:
- pharmacological (receptor binding)
- biochemical (receptor activation)
- physiological (neural activity)
- behavioral (whole animal)
Semi- logarithmic saturation curve
x- axis: log [L]
Bmax: same for any particular receptor population
Receptor Affinity
how tightly the receptor holds onto the drug
- lock and key mechanism
Drug Potency
the amount (concentration) of drug necessary to produce a desired level of effect
- high potency is correlated to high affinity
Drug Efficacy
the maximum response produced by a drug
Therapeutic Index
TI= TD50 (toxic effect)/ ED50 (therapeutic effect)
Competitive antagonists
“compete” with the agonist for binding to agonist binding site
- high affinity for the agonist binding site, but no efficacy
- shifts dose- response curve to right
- can eventually outcompete antagonist
Noncompetitive antagonists
bind to site different from agonist binding site
- negative allosteric modulation
- agonists can’t overcome inhibition
Partial agonist
low efficacy
agonist at low concentrations
antagonist at high concentration
Physiological antagonism
Additive effects
Potentiation
look at picture
Potentiation- bigger response than if just added together
Drug Tolerance
diminished response to drug administrations after multiple exposures
Cross Tolerance
tolerance to one drug can diminish effects of second drug
Characteristics of Tolerance
1. 2. 3. 4. 5.
Characteristics of Tolerance
- Reversible
- Dependent on dose, frequency, and environment
- May occur rapidly, after long time, or never
- Not all drug effects have same degree of tolerance
- Different mechanisms show different forms of tolerance
Acute Tolerance
develop during single administration
Metabolic Tolerance
- drug disposition tolerance
- repeated use of drug reduced amount of the drug available at the target tissue
Pharmacodynamic Tolerance
changes in nerve cell function compensate for continued present of the drug
Behavioral Tolerance
- context- specific tolerance
- tolerance is not apparent or is reduced in a novel environment
State- Dependent Learning
- tasks learned in the presence of a psychoactive drug may subsequently be performed better in the drugged than the non-drugged state
- conversely, learning acquired in the non-drugged state may be more available
Sensitization
- reverse tolerance
- enhancement of drug effects after repeated administration of the same dose
- can persist over long periods of abstinence
Therapeutic Drug Monitoring
blood samples taken after drug administration to determine plasma levels of drug
- detects changes in pharmacodynamics
Pharmacogenetics
study of genetic basis of variability in drug response among individuals
