Pharmacodynamics
the study of the mechanisms of drug actions and effects - what drugs do to the body
Pharmacokinetics
he study of the factors that determine bioavailability = what the body does to the drug
time course
timing of the onset, duration, and termination of a drug's effect
bioavailability
how much of the drug actually reaches the target
dose
pharmacokinetics are relative to the dose, (how much was consumed/administered)
RADME
Route of administration - how we take it. main contributor to absorption, speed and intensity of drug effects, reinforcement, abuse potential
Absorption - how it gets into blood stream
Distribution - how it gets around the body and into brain
Metabolism -
Route of Administration types
Oral administration
Inhalation
Mucus membranes/skin
Injection (IV, IP, IM, SC) -fastest to achieve psychoactive drug effect
Oral administration
pros: safe and tasty
cons: slow and complicated, unpredictable
must dissolve in stomach fluid
must survive stomach acid
potential enzymatic degredation
could be delayed by fatty foods
'first pass' at liver
Inhalation
pros: fastest and direct
lung capillaries --> left heart--> brain
cons: drug type
irritation in lungs
dosing can be difficult to control
rapid offset
Mucus membrane
Skin, sublingual, intranasal (snorting or nasal spray), vaginal, rectal
pros:rapid bloodstream absorption
cons: dosing
local effects on membrane (coke)
absorption can vary by molecule
Injection
IV: pros: rapid, accurate dosing
strong/fast effects
cons: most dangerous for same reason
blood vessels collapse after repeated use
infections from needles (hepatitis/HIV)
Absorption depends on
Route of administration
� Dose
� Dosage form (pill/powder/liquid)
� Drug lipid solubility
- Passive diffusion across lipid membranes- More lipid soluble more rapid absoption - Concentration gradient!!
Distribution affected by:
The body's membranes:
� Stomach lining
� Capillary walls
� Cell membranes
� Placental barrier
� Depot binding
� Brain distribution: Blood Brain Barrier
Depot Binding
Depot = temporary inert binding site within body, like circulating proteins/fat/muscle
-reduces concentration in blood
-delays onset/peak
Released when drug concentration is lower/other drugs compete
-delay metabolism/elimination
-cause drug interaction
-
Blood Brain Barrier
Internal barrier between blood and brain. Regular capillaries have porous walls, but brain capillaries don't. tight junctions and covered by astrocyte glial cells.
Transmembrane diffusion
drugs, to get past BBB, must pass through capillary wall and glial sheath. Rate of passage determined by
-size of drug molecule
-lipid solubility
Metabolism
Some drugs get excreted as is in breath/sweat (think breathalyzer)
Most drugs too lipid-soluble to be excreted naturally in urine. So drugs undergo enzyme-catalyzed chemical changes/breakdown
- "Biotransformation"
- Stop drug action
Phase 1 metabolism
Typically in liver.
o Phase 1: drug meets enzyme, which beaks it into metabolites, which are typically inactive (sometimes active), less lipid soluble components. Ex of active: caffeine to theobromine. Codeine to morphine
Phase 2 metabolism
other compounds bind, typically make inactive.
Factors influencing metabolism
Individual differences (eg age).
Genetic variation
Drug/enzyme competition:
Enzyme inhibition
Enzymatic induction
Metabolic cross-tolerance
Complex effects - alcohol and Tylenol both metabolized by CYP 2E1 so both have more lasting effects if taken at the
What's an example of drug/enzyme competition?
Alcohol and valium (CYP2E1)
What's enzymatic inhibition and what's an example?
one drug has psychoactive effect on brain, and also has inhibitive effect on certain enzymes. Ex MAOI (MAO, P450). MAOI -> inhibit MAO -> Tyramine not metabolized -> toxicity
What's enzymatic induction and what's an example?
- process by which a particular drug might lead to an increase in the enzyme which breaks it down. "metabolic tolerance"
� Ex: cigarettes (CYP-1A2)
� Ex: alcohol (CYP-2E1, ADH)
Examples of metabolic cross-tolerance?
� cigarettes and coffee
� Cigarettes and birth control
� Cigarretts ans SSRIs (anti-depressants)
Cytochrome P450
The general name for a large class of enzymes that play a significant role in drug metabolism and drug interactions. (90-95%)
Grapefruit effect
grapefruit juice can
break down enzymes in the GI tract
? leads to less metabolism, more drug absorbed
Half life
The amount of time required for removal of 50% of the drug from the blood stream
constant RATE.
Examples of half lives
� Coke - 0.5 to 1.5 hours
� THC - 20-30 hours
� Nicotine - 2 hours
� Morphine - 0.5-1.5 hours
full" elimination occurs after
6 lives rule" = 98.4%
drug effects
The physiologic reactions of the body to a drug
Specific drug effects
resulting from its biochemical interaction with tissue
-acute vs chronic
-primary vs secondary
-therpeutic/intended vs side effects
Primary effects , example?
Direct NT system of drug action
Ex: Alcohol-> GABA system
Secondary effects
high, craving, abuse potential
Non-specific drug effects
not based on chemical action, but rather on unique characteristics of a particular person (previous drug experience, present mood, environment, expectations, attitudes)
Placebo effect
pharmacologically inert compound leads to physiological/psychological changes
belief, or expectation of help leads to actual help
Double Blind Experiment
Two groups, identity unknown to anyone- Compare relative difference between "drug" and "placebo"
�Placebo effect = non specific drug effect
�Drug effect-Placebo = specific drug effect
Drug Action
specific, acute, primary drug effects
Drugs modulate NT systems that are already there: No unique effects
1. Increase/Decrease effect of NT
2. Increase/Decrease effect at a receptor
Agonist
relative to NT - increases effect of NT
relative to receptor - binds and activates like NT
antagonist
relative to NT - decreases effect of NT
relative to receptor - binds and blocks/decreases effect at receptor
Selective, example
specific to single receptor.
Alcohol is a selective GABAa agonist
Ketamine is selective NMDA antagonist
Affinity
Affinity: Ease/strength of fit of a ligand to a receptor
- NTs have high affinity to their own receptors - Selective drugs have SELECTIVE AFFINITY
- High affinity is associated with stronger drug effects per dose (potency)
Competitive, example?
refers to the location on the receptor. Competitive = same as NT, non-competitive = different location.
Alcohol doesn't bind at same spot as GABA on GABAa receptor, so is non-competitive
Ketamine binds at different spot than Glu on NMDA receptor, so is no
efficacy, example?
ability to initiate action at receptor.
ex: NT's = 100% efficacy
antagonists = 0% efficacy
so ketamine = high affinity, 0 efficacy bc antagonist
Full/partial agonist, example?
refers to efficacy
full agonist = fully activates the receptor = fully mimics NT action at receptor = maximal efficacy
� Partial = only partly effective� EXAMPLE: LSD is an (almost) full receptor agonist
full/partial antagonist
degree of blockade
how would you describe NTs at their own receptors?
full non-selective agonist with high affinity
Dose-response curve
describes relationship between doses of a drug and effect on an individual or population
S-shaped
Max response
is maximum drug effect on individual/population. top of y axis
threshold
concentration that must be surpassed before any effect is seen
lethal dose
min dose that causes death
Effective dose
ED50 = dose that generates effect in 50% of population
Therapeutic index
TD50/ED50
Margin of safety
LD1/ED99, >1 safe for humans
Efficacy
y axis of dose-response curve
potency
x axis of dose-response curve
Receptor downregulation
Decrease in number. Process?
Agonists-> more NT action or more receptor activation -> receptors are internalized
Receptor upregulation
Increase in number. Process?
Antagonist --> Reduce NT action
-->More receptors are added
Receptor desensitization
Decrease in efficiency. Process?
Agonist-->more NT action or receptor activation-->
reduced receptor response
Receptor sensitization
Increase in efficiency. Process?
- Increased NT/agonist-> enhanced response
Drug sensitization
An increase in a specific response to a dose drug following administration
� Need lower doses to get original effect
Ex: teeth chattering in methamphetamine
pushes dose-response curve left
Drug tolerance
A decrease in specific response to a dose of drug following administration.
� Need higher doses for the original effect
3 kinds of drug tolerance?
metabolic tolerance - increase enzymes
behavioral tolerance - increased learned behavior (alcohol)
pharmacodynamic tolerance - decrease in specific response from receptor desensitization/downregulation
Hebb's Law
neurons that fire together wire together
neural basis of change, "synaptic plasticity
LTP
Long term changes in synaptic sensitivity/excitability ("wiring") following stimulation ("firing")
LTP Mechansim
glu released, binds to AMPA which enables influx of Na+ which depolarizes postsynaptic membrane. after enough, the Mg+ moves out of NMDA receptor allowing Ca+ to come in. Early --> AMPA sensitization
Late--> AMPA upregulation-->increased A/N ratio -->more
coincidence detector
NMDA in LTP
Drug Induced LTP
Light before banana...LTP on DA producing neuron makes A/N ratio increase so more firing automatically when exposed to light
Craving
thus cue-->DA-->craving and drug seeking
more DA in Ventral Striatum = more seeking