Flashcards in Kinetics, Dynamics, and G-Receptors Deck (79)
Pharmacokinetics involves these four processes
Absorption, distribution, metabolism, and exretion
What are pharmacodynamics
What the drug does to the body. nvolves mechanism of effect, sensitivity, and responsiveness
How do the two compartments interact?
Drug enters first central, distributes to peripheral compartment, and returns to central for clearance
The central compartment is made of ______
Highly perfused tissues, such as the kidney, liver, brain, heart, and lungs.
The central compartment receives _____% of the cardiac output despite only representing _____% of the bodymass
75% of CO
10% of bodymass
Peripheral compartmnet is composed of _____
Fat, musce, hair, bones, nails, etc.
Parts of the body with less blood supply.
Rate of compartment transfer decreases with _____
Aging and diminished cardiac function
Formula for calculating Vd
Vd = (Dose of IV drug) / (plasma concentration before elimination)
What does Vd tell you?
If the drug stays in plasma, follows TBW, or if it concentrates in the body tissues
What drug characteristics will affect Vd?
Lipid solubility (highly lipid soluble will directly enter the peripheral compartment)
Protein binding (more binding results in lower Vd. If protein bound - less able to cross membranes)
Molecular size (larger molecules less able to cross membranes)
Define elimination half-time
Time necessary for plasma concentration of a drug to decrease by 50% during the elimination phase
Elimination half-time is (dependent / independent) of the dose administered
Define elimination half-life
Time necessary for 50% of the drug to be eliminated from the body
How do most drugs cross cell membranes?
A high oil to water partition coefficient means the drug is
Highly lipid soluble
Can charged particles cross membranes by simple diffusion?
Weakly acidic drugs are best absorbed where?
Weakly basic drugs are best absorbed where?
Benefits of sublingual / transmucosal medications
Bypass the first pass effect and avoids destruction by gastric enzymes
The rate limiting step of transdermal absorption involves crossing this layer of the epidermis
Stratum corneum - this is the outermost layer of the skin, consisting of dead skin cells that act as a barrier to infection, dehydration, chemicals and mechanical stress
Good location for medication patches
Chest - the skin is thin here
Why is rectal administration of drugs unpredictable?
Depending on how far the medication goes up dat butt, it may enter the portal system and undergo the first pass effect.
Effect of lungs on uptake and distribution
The lung uptakes lipophilic drugs (lidocaine, fentanyl, demerol), and acts as a reservoir to release the drug back into systemic circulation. Lots of the fentanyl we give will go to the lungs because it is vessel rich. This results in the double peak in plasma concentrations. This is also called the lung first pass effect.
How can the BBB be overcome?
Large drug doses, head injury, and hypoxia. Our drugs pass the BBB because they are lipophilic.
During neurosurgery, it is assumed that the _____ has been compromised
Why do many anesthetic agents have short onset and short duration of action?
The drugs we give are highly lipophilic. The brain has a high proportion of lipid and receives 15% of the CO! The duration is short because the drugs quickly exit to enter the body fat (where the drugs are more soluble)
When are acidic drugs highly ionized?
In basic environments. This is why acidic drugs are best absorbed in acidic environments.
What is ion trapping?
When a membranes divides two separate pH levels. The only practical scenario of this would be the placenta. The fetus is slightly more acidotic. For this reason, we decrease epidural dosing for parturients.
Most common plasma proteins involved in protein binding of drugs
Alpha 1 Glycoproteins (bases)
Examples of drugs that are highly protein bound
Warfarin, propanolol, phenytoin, and diazepam
What patients would have decreased serum proteins?
Describe first order kinetics
Drugs administered in the therapeutic dose range are cleared at a rate proportional to the amount in the plasma.
Basically, clearance rate is proportional to the amount of drug given.
Describe zero order kinetics
Occurs when drug levels exceed metabolic or excretory capacity even at therapeutic doses. In this situation, drugs are cleared at a constant rate independent of dose.
Examples of drugs that undergo Zero Order kinetics
ASA, dilantin, and ETOH
Chronic drinkers will need (more/less) medication
Drunk patients will need ______
Acutely drunk alcoholics will need ____
Chronics need more
Drunks need less
Acutely drunk alcoholics need less
Asians metabolize drugs (faster/slower) than average
Germans metabolize drugs (faster/slower) than average
What is the extraction ratio?
An organ's ability to remove a drug from the systemic circulation over a single pass through the organ. This may be influenced by blood flower, protein binding, or intrinsic ability of the organ to eliminate the drug.
For drugs with a high extraction ratio (>.7), drug clearance depends highly on
Blood flow. This also means that low BP will result in slower metabolism of the drug.
This is "perfusion dependent elimination"!
For drugs with a low extraction ratio (<.3), drug clearance depends highly on
Protein binding. A decrease in protein binding or an increase in enzyme activity will result in an increase in hepatic clearance. Changes in blood flow won't really affect clearance.
This is "Capacity-Dependent Elimination"!
The extraction ratio for most drugs is between
.3-.7 meaning that most drugs rely on both capacity and perfusion dependent means
Most important organ for elimination
What happens to highly lipid soluble drugs in the kidney?
They are reabsorbed such that little or no unchanged drug is excreted in the urine. The liver has to metabolize the drug into a water soluble form before it can be excreted by the kidneys.
Main site of drug metabolism and biotransformation
Other, less important, sites of dug metabolism include the lung, kidney, skin, and epithelial cells. Some reactions can also occur in the blood from plasma esterases and pseudocholinesterases.
Once a drug is metabolized, does that mean it is inactive?
Not always. Some drugs can have active metabolites. These metabolites tend not to be as strong as the parent drug. This can extend the life of the drug.
Examples of drugs with active metabolites
Morphine, versed, and ketamine
Phase I Metabolism
Oxidation, reduction, and hydrolysis through the Cytochrome P-450 System.
Phase II Metabolism
Conjugation. Large polar compounds are added to the molecule being metabolized, greatly increasing it's water solubility for renal or biliary excretion.
Cytochrome P-450 System
A family of more than 50 enzymes located on the smooth ER that are responsible for metabolizing certain drugs. Of these, only 6 are responsible for 90% of drug metabolism.
What is induction?
Increasing the ACTIVITY of CP-450 enzymes. This can be caused by ETOH and smoking. Induction will result in a reduced elimination half-life.
How is a person's P-450 system determined?
Genetics. We all have the 6 enzymes the contribute 90% of drug metabolism, but we may have them in different proportions.
Hydrolize drugs that contain ester bonds (esmolol and succhs). Metabolize drugs mostly by conjugation and hydrolysis and are located mostly in the liver, but also in the blood and GI tract. These enzymes are also determined genetically.
Do non-microsomal enzyme undergo indution?
Most common way that drugs exert their effects on the body
By binding to receptors
Receptor Activation Theory
Drugs convert non-activated receptors to their active form
Receptor Occupancy Theory
More receptors occupied by the drug results in more effect of the drug
Example of a drug that does not work by interacting with receptors
Chemical structure of a drug has major implications in
Affinity and intrinsic activity
Define being "hyper-reactive"
An unusually low dose of a drug causes it's expected pharmacologic effect. Similarly, a normal dose can have en exaggerated effect.
Define being "hypersensitive"
It is possible to have a delayed allergy, in that, the body made antibodies to the drug the first time they received it. Therefore, the next time they receive the drug, they may have an allergic reaction.
Example of medications with a synergistic effect
Benzos and narcotics have a synergistic effect on the respiratory system
Examples of cys-loop receptors
Nicotinic AChRs, GABAa receptors, glycine receptors
Examples of Ionotropic glutamate receptors
AMPA, NMDA, and kainate receptors
Examples of drugs that bind to Cys Loop receptors
Nicotine, varenicline (Chantix), muscle relaxants (Succ), barbiturates & diazepam (GABAa)
Drugs that work of ionotropic glutamate receptors
Aniracetam, "smart drugs," ketamine
Number of subunits that cys loop receptors have
5, each with 4 domains. There are also 5 different types of subunits that exist, but the receptor must have AT LEAST 2 alpha subunits.
# of subunits that glutamate receptors have
4, each with 4 domains
Ions that nAChRs pass
Mostly Na & K, but a little Ca
Glycine and GABAa receptors conduct this ion
Cl- (these are both hyperpolarizing/inhibitory receptors
Most synaptic transmission is mediated by these receptors
3 Classes of G-coupled protein receptors
Class A: Adrenergic, and muscarinic ACh
Class B: PTH receptor
Class C: Metabotropic glutamate receptors, GABAb receptors
How do NMDA receptors result in memory formation?
Mg+ is blocking NMDA receptors, but this is voltage dependent. When the neuron is depolarized, the Mg+ gets kicked out, allowing Ca++ to enter the cell, activating CaMKII, which results in the formation of more AMPA receptors. AMPA receptors are the main receptor in signal transduction. More AMPA receptors means the signal can now be passed more easily, resulting in a learned connection. The more the system is depolarized, the more Mg+ will be kicked out and eventually more AMPA receptors will be made.
Number of transmembrane domains that GPCRs have
Examples of drugs that work on GPCRs
Beta blockers, beta agonists, opioids (Mu receptors)
GPCRs. How da fuck do those things work?
When an agonist binds to the GPCR, a conformational change takes place that kicks out the beta-gamma subunit. The alpha subunit is now no-longer inhibited and can bind with GTP. Binding with GTP causes the alpha subunit to activate, and it goes off to do it's thang, activating other proteins n' shit. The alpha subunit eventually breaks down GTP into GDP, it inactivates, and the system resets.
How many types of G-alpha subunits are there?
G-alpha-s, G-alpha-i, G-alpha-q
What does the G-alpha-s subunit do?
Activates adenylyl cyclase, which causes an increase in cAMP, which activates protein kinase A, which then phosphorylates downstream proteins and transcription factors
What does the G-alpha-i subunit do?
Inhibits adenylyl cyclase (meaning that the increase in cAMP and proteins and transcription factors will not happen)