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Chapter 1 Part 2: Pharmacokinetics - Coggle Diagram
Chapter 1 Part 2: Pharmacokinetics
Elimination
Biotransformation (metabolism): process by which drugs are eliminated
most biotransformation occurs in the LIVER
Goal: produce INACTIVE metabolites that are water soluble (ionized)
metabolites formed in the liver are RETURNED to systemic circulation
make drug more IONIZED so it CAN'T CROSS BBB and can be taken up through urine/feces for elimination
2 Major types of biotransformation
Type I (Phase I - CYP450 enzymes)
non-synthetic modification of drug molecule
ex. oxidation
Microsomal enzymes: liver enzymes that metabolize psychoactive drugs
LACK strict specificity
CYP450 family
SIX are responsible for 90% of all activity for OXIDIZING most psychoactive drugs (phase I reactions)
many drugs can be metabolized by the SAME CYP enzyme and if the drugs are taken simultaneously, only ONE will be metabolized and the rest can be TOXIC in the blood
Type II (Phase II - non-CYP enzymes)
synthetic (requires conjugation): requires combination of the drug with some small molecule
ex. glucuronide conjugation
some metabolites are ACTIVE and can only be inactive after biotransformation process
active metabolites can prolong drug's actions
PRODRUG is not an active compound until it's metabolized and the metabolite produces the therapeutic effect
Influences on biotransformation capacity
Enzyme induction: repeated use of a drug INCREASES the number of enzyme molecules and SPEEDS biotransformation
drug tolerance: drug loses effectiveness with repeated use
Enzyme inhibition: drug may INHIBIT an enzyme and REDUCE metabolism of OTHER drugs
causes other drugs to have prolonged effects because it can't be broken down
ex. Monoamine Oxidase inhibitors - Wine and Cheese Syndrome
MAOis inhibit degradation of enzymes and leads to enhanced synaptic levels of monomaines
if you inhibit MAO in the liver, you prevent breakdown of tyramine
leads to increase in blood pressure/heartbeat
Drug competition for an enzyme: elevated levels of one drug REDUCES metabolism of the second drug causing potentially TOXIC levels
ex. alcohol + sedative compete for the same CYP450
Individual differences: age, gender, genetics --> high or low enzyme activity can make patient more/less sensitive to drug
Drug clearance from the blood
zero-order kinetics (linear)
rare because most abusive drugs only need small dose to get effect
molecules are cleared at a CONSTANT RATE regardless of concentration (i.e. 10mg/hr)
rate is CONCENTRATION INDEPENDENT
when drug levels are HIGH and routes of metabolism are SATURATED (degradative enzyme sites are saturated)
more drug molecules are available than sites
first-order kinetics (exponential)
CONSTANT FRACTION of drug eliminated per unit of time (ex. 50%/hour)
rate is CONCENTRATION-DEPENDENT: rate changes when concentration of drug changes
PROPORTIONAL to the drug concentration
most common because it occurs only when a fraction of drug clearance sites are occupied
Examples
Ex. Plasma half-life: amount of time required for removal of 50% of the drug from blood plasma
drugs with LONGER half lives have more potential to be TOXIC
Steady state: absorption/distribution = metabolism/excretion
when we want to take a drug that needs to reach a specific level in the bloodstream to have therapeutic effects
Excretion
urine: most important route for drug elimination
kidneys filter materials from the BLOOD --> URINE (excretion of WATER-SOLUBLE substances)
water, electrolytes, and lipid-soluble molecules are REABSORBED from kidney tubules BACK into blood circulation
ionized molecules CANNOT diffuse back into circulation
reabsorption is pH dependent (urine: pH 4.5-8.0)
Pharmacodynamics: what drugs do to the body
Drug-Receptor Interactions
ligand-receptor binding is temporary (REVERSIBLE)
a neurotransmitter will bind and release MANY TIMES to initiate its effects (reversibility)
Receptors: have SPECIFICITY FOR LIGANDS due to their molecular shapes
receptor agonist: has best chemical "fit" (affinity)
partial agonists: INTERMEDIATE EFFICACY at maximum binding
inverse agonists: action that is OPPOSITE to that produced by an agonist
indirect agonists: enhance release/action of an endogenous NT but has no SPECIFIC AGONIST activity at the NT receptor itself
receptor antagonists: also fit receptors (affinity)
can PREVENT the active ligands from binding, NO EFFICACY
Receptor proteins
Up-regulation: number of receptors INCREASES in response to ABSENCE of ligands or CHRONIC ANTAGONISM
down-regulation: number of receptors is REDUCED because of CHRONIC ACTIVATION
irreversible down-regulation: endocytosis of the actual receptors, degraded completely
reversible down-regulation: receptors are internalized briefly, can be reinserted into the membrane after NT levels drop to normal levels
Dose-Response Curves: S shape
threshold dose: smallest does that produces a measurable effect
Efficacy (Emax): maximum response achieved by a drug (assumes all receptors are occupied - SATURATED)
ED50: 50% effective dose
does that produces half maximal effect
dose at which 50% of the population responds
TD50 (50% toxic dose): dose at which 50% of the population experiences a toxic effect
Therapeutic index (TI) = TD50/ED50
higher is better: high TD50 means a large quantity is required for toxicity
Potency: Absolute amount of drug required to produce a specific effect
Affinity: the tenacity (grip) with which a drug binds to its receptor
rates of dissociation and association are compared to get an estimate of receptor affinity (dissociation constant (Kd)
low Kd: high affinity (slow rate of off, high rate of on)
high Kd: low affinity (fast rate off, slow rate on)
ligands that readily bind and slowly dissociate have the highest affinity
ligand-receptor affinities are influenced by noncovalent, intermolecular actions between 2 molecules
Competitive Binding Assay
Competitive antagonists bind REVERSIBLY to the same receptor site as agonist
RIGHTWARD SHIFT of dose-response curve
if pretreated with competitive antagonist, needs HIGHER dose for same effect
do NOT initiate intracellular effects
Partial agonists: drugs that produce LOWER RESPONSE at full receptor occupancy than full agonists
Non-competitive antagonists: prevent agnoist from ever reaching Emax
Allosteric vs. orthosteric site binding
allosteric site binding: on a receptor, not native NT site - physically different site
orthosteric: IRREVERSIBLE competitive antagonism: binds to the active site and DOES NOT come off
Biobehavioral interaction between drugs
Physiological antagonism: 2 drugs interact and produce OPPOSITE effects --> reduce each other's effectiveness
Addictive effects: combined drug effect = sum of each drug alone
Potentiation: when combo of 2 drugs produces effects greater than sum of their individual effects
Biobehavioral effects of chronic drug use
Tolerance
DIMINISHED response to drug after REPEATED drug exposure
cross tolerance: tolerance to one drug can DIMINISH effectiveness of a 2nd drug in the SAME CLASS
metabolic tolerance: repeated use of a drug REDUCED amount of the drug available at target tissue
acute tolerance: a DECREASE IN RESPONSE to alcohol within a single exposure to the drug
occurs independently of changes in BAC
develops during a single administration
effects of alcohol during increase are MORE SEVERE than during elimination although the BAC was the same
pharmacodynamic tolerance: changes in nerve cell function COMPENSATE for continued presence or absence of the drug (upregulation vs. downregulation)
Behavioral tolerance: tolerance is seen in same environment but is REDUCED in a novel environment
Classical conditioning
"Needle freak": addicts conditioned to feel cortical arousal and euphoria just from the sight of drug tools
Operant conditioning
repeated exposure and REINFORCEMENT, a person can learn to COMPENSATE for drug-induced changes in behavior
ex. the functional alcoholic, responds by drinking, reinforcer: not being caught
State-dependent learning: tasks learned in the presence of a drug may subsequently be performed BETTER in the drugged than non-drugged state
Sensitization (reverse tolerance): ENHANCEMENT of drug effects after repeated administration of the same dose (needs less amount of drug to get same effect)
Pharmacogenetics: study of genetic basis for variability in drug response among individuals
Genetic variation in drug-metabolizing enzymes - drug dosage could be adjusted if an individual's genetic makeup is known
