Lesson 5-8 Flashcards
Several membranes within the body can affect drug distribution (4):
- Cellular membranes
- Capillary walls
- BBB
- Placental barrier
Cellular membrane and drug distribution (5)
Steps + movement via
- Stomach and intestine to blood stream
- Extracellular fluid to interior of cells
- intracellular fluid to exterior
- Kidneys back into blood stream
- Movement via passive diffusion (higher concentration = faster movement) across the membrane, follows a concentration gradient
Heroin vs Morphine
Heroin has 2 acetyl groups making it more lipid soluble this reaching the brain faster. Both are opoids
Capillaries and drug distribution (3)
What +rate
- Small cylindrical blood vessels
- Cells with fenestra (pores) allow passage of drugs out of the blood stream (independent of lipid solubility)
- Rate at which drug enter body tissue depends on: rate of blood flow through the tissue, ease with which drug passes through capillary membrane.
Blood Brain Barrier and drug distribution (3)
What + rate + easiest molecules are
- To get to the brain, a drug must pass through the walls of the capillary (tight junction) and the end foot membrane of the astrocytes
- Rate of passage is dependent on size of the drug and lipid solubility
- Small, fat-soluble go through easiest (psycoactive drugs)
Capillary walls in the brain have —–
no pores
Peniciliin
Canot cross BBB
Physostigmine and Neostigmine (2)
What they do + difference
- Inhibit acetylcholinesterase (breaks down acetylcholine), found in the synpase of choligenric neurons and helps prolong the activity of acetylcholine in the body
- Physotigmine is lipid soluble ( and Neostigmine is not lipid soluble. Thus, Physotigmine is used to treat Alzheimers and Neostigmine is used to treat non brain related (Myathenia gravis- muscles).
Placental Barrier and drug distribution (3)
What + drug passage + examples
- Seperation of blood supply between mother and fetus but there can be passage of oxygen and nutrients
- Drug cross placental membrane by diffusion, fetus gets exposed to all drugs that are lipid soluble (psycoactive drugs)
- Opiates (heroin), gaseous anesthetics (loss of feeling or awareness), alcohol, cocaine, CO (smoking) can reach fetus
Most drugs are eliminated according to ——
First order kinectics
First-order kinectics (3)
fraction + amount + half life
- A constant fraction of the free drug is removed each time interval (exponential)/a constant percentage of the drug is lost per unit time.
- A varying amount of drug is metabolized with each life
- Fewer molecules are metabolized per half life
Half Life (3)
What + 4 half-lives + 6 half-lives
- Time required to remove 50% of drug from the blood
- 4 half-lives remove 94% of drug from system
- 6 half-lives remove 99% of drug from system
Drug will persist in the body for at least —– half-lives
6
Zero-order Kinectics (3)
rate + amount + low levels
- Drug is cleared at a constant rate regardless of concentration
- A constant amount of alcohol is metabolized per hour
- Very low levels (enzyme not saturated) maybe lose linearity
The goal of drug therapy is to ——
maintain a steady state concentration within the therapeautic window
Steady state
rate of drug adminstration is equal to rate of excretion
Termination of drug action (4):
- Drugs are eliminated via biotransformation and metabolites are excreted: Kidneys, lungs (gas), bile, skin (sweat)
- Breath (breathalyzer): excretion of metabolites in breath
- Breast milk: fluoxetine (increases the activity of serotonin in the brain)
- Most commonly, drugs are eliminated via urine, after the liver has biodegraded them
By breaking drugs down to metabolites the goal is to make —–
lipids soluble drugs less lipid soluble for excretion
Metabolism (AKA: biotransformation) (2)
What + process
- Chemical changes that usually reduce the effect of drugs and increase their excretion
- Drugs are transformed by liver enzyme to make less fat soluble so it cannot be reabsorbed by kidneys.
- Kidneys filter waste from blood, collect it in bladder. Lipid soluble drugs are hard for kidney’s to hold onto; after collection the molecules cross back into the circulation are picked up by liver cells (hepatocytes) and biotransformed into metabolites (less-lipid soluble) and goes into kidney.
In metabolism, metabolites are —- lipid soluble drug is —-
- excreted
- reabsorbed
In First order elimination, rate of drug elimination is —— to drug concentration
proportional
In zero order elimination, rate of drug elimination is —— of drug plasma concentration
independent
In first order, half life is independent of ——
+ depends on
initial concentration
- This means that regardless of how much reactant is present at the start, the time it takes for half of it to decay remains constant.
- Notice that the half-life depends only on the rate constant k, not on the initial concentration of the reactant. This is why the half-life remains constant throughout the reaction, regardless of how much reactant is present at any given time.
In first order reaction, length of the half-life is —–
Constant
For zero order reaction, half life depends on —– and decreases as ——–
- initial concentration
- concentration decreases
For zero order elimination, ——- of drug is eliminated per unit time
- constant amount of drug
Factors affecting biotransformation (2):
+ two examples for the second point
- Genectic variability (3 genes that make cytochrome). Too much translation/transcription to make the 3 liver enzyme can cause fast metabolism.
- Drug interactions may increase or decrease metabolism.
- For example, increased in smoking (nicotine) causes tolerance to antidepressents. Nicotine induces the activity of specific liver enzymes, particularly those in the cytochrome P450 system (such as CYP1A2). These enzymes are responsible for metabolizing various drugs, including some antidepressants. When the activity of these enzymes increases due to nicotine, antidepressants may be broken down more quickly in the body, leading to lower drug concentrations and reduced therapeutic efficacy.
- Compound in grapefruit juice inhibit cytochrome enzyme causing decreased CYP450 3A4 leading to increased psychoactive drug level
Down regulation (2)
What + can be…
Type of pharmacodynamic tolerance btw
- Given amount of drug has fewer or less sensitive receptors to act on
- Can be decrease in number of receptor but also in sensitivity
Operant Conditioning (3)
What + type of learning + learn to…
- Learning procedure in which the concequences of a particular behaviour increases or decreases the probability of the behaviour occuring again
- State-dependent learning
- Learn to operate in the environment to maximize reward and decrease punishment. Through operant conditioning, behavior that is rewarded is likely to be repeated, while behavior that is punished is prone to happen less
voluntary behaviour and concequence
Pavlovian conditioning
- learning procedure whereby a neutral stimulus comes to elicit a response because of its repeated pairing with some event
Involuntary response abd a stimulus
Receptor antagonists
- dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist
Dose-response curve (DRC) (6)
used to + axis + shape/math + 3 componets
- used to qauntify the interaction of a drug at a receptor
- function of drug dose versus the magnitide of its effect
- S-curve log scale
- Threshold: Amount needed to see effect
- ED50: Dose that produce half the max effect of drug
- ED100: Max response, all recpetors are occupied
Dose-response curve (DRC) Potency
- Potency decreases as graph shift right
There are 2 primary categories of antagonists:
talk about mechanism + overcome? + example + graph
- Competitive antagonists:
- Reversible, compete with agonists for binding.
- Effects can be overcome by increasing an agonist.
- Antagonists make agonist seem less potent
- Ex: Naloxone kit block opoids and competes for opoid receptor sites preventing overdose. - Irreversible/Noncompetitive antagonists
- Different binding site than the agonist, cannot be displaced
- Changes shape of the receptor
- Ex: Recreational “Fairy Dust” blocks the pre, ion cannot pass through and even if glutamate is bound on NMDA receptor nothing will happen.
Allosteric action
- Binding to nearby site to facilitate transmitter binding. Can increase/decrease neurotransmitter function.
Inverse agonist (ex) vs Partial agonist vs Agonist
Agonist illicit max response at certain dose, partial agonist cannot reach 100%, it still binds and activates but has lower efficacy than a full agonist. An inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. Ex, inverse agonist works on GABA by induciing anxiety instead of relaxing.
Therapeutic Index (3)
want + Equation + variables
- We want this number to be as high as possible
- TI - TD50/ED50
- ED50 = Dose of drug that produces the desired effect in 50% of the population
- TD50 = Dose of a drug that results in a toxic effect in 50% of the population
The GABAa receptor
- Type of ion (ionotropic) receptor
- Barbiturate and benzodiazepine faciliate with GABA to open channel (increase duration to open together)
- Cl- can go in after it opens to hyperpolarize neurons (less likely to fire)
G-Protein Coupled (Metatropic) receptors (3)
What happens + what it does + action is….compared to ionotropic
- Activation induces release of a metatropic G protein
- In turn controls intracellular enzymatic functions such as opening/closing ions
- Action is not as fast as ionotropic receptors
