Week 1-3 Flashcards
What does the Therapeutic Index measure?
Therapeutic Index is a measure of drug safety
How do you calculate the therapeutic index?
LD50 = average lethal dose/dose that is lethal in 50% of subjects treated
ED50 = effective dose in 50% of subjects treated
Therapeutic index = ratio of LD50 to ED 50
True or false, a high therapeutic index means a drug is safe
True. The highest dose needed to produce effects must be significantly lower than the lowest required to produce death for a medication to be safe. High therapeutic index means safety
In terms of drug-drug interactions, there are three general outcomes possible
Potentiative, Inhibitory and creation of a unique response
What occurs in a potentiative drug interaction? Provide an example.
Intensification of Effects (Potentiative)
Increased therapeutic effects: can have beneficial potentiative interactions
Increased adverse effects: negative potentiative interactions
Ex. Warfarin and aspirin cause increased risk of bleeding
What occurs in an inhibitory drug interaction? Provide an example.
Reduction of Effects (Inhibitory)
Reduced therapeutic effects
Reduced adverse effects: can reduce toxicity.
Ex. Naloxone and morphine
What occurs in a drug interaction with creation of a unique response? Provide an example.
Creation of a unique response that does not occur with either drug used alone.
Ex. alcohol and antabuse causing unpleasant responses that do not occur when either is used alone.
There are four general mechanisms of drug-drug interactions:
Direct chemical/physical interactions
Pharmacokinetic interactions
Pharmacodynamic interactions
Combined toxicity
What is the most common cause of direct chemical/physical drug interactions?
Incompatible IV components being mixed. Can also occur when incompatible drugs are given by other routes.
Pharmacokinetic interactions occur when two drugs are taken together that alter the _____, ______, _____, or _____ of the other
Absorption, distribution, metabolism, excretion (ADME)
Can you think of an example of a pharmacokinetic interaction related to altered absorption?
Changing pH in stomach can increase the ability of basic drugs to cross membranes and be absorbed
Laxatives can reduce oral drug absorption by decreasing transit time
Drugs that slow peristalsis (morphine, atropine) can prolong transit time and increase absorption of drugs
Drugs that induce vomiting can decrease oral drug absorption
Oral drugs that are not absorbed can absorb other drugs into them and prevent those drugs from being absorbed in the blood. Ex. Cholestyramine
Drugs that reduce blood flow delay absorption
Can you think of an example of a pharmacokinetic interaction related to altered distribution?
Competition for protein binding: if two drugs bind same site on plasma albumin then binding of one or both drugs will be reduced, resulting in increased free-drug which could increase drug effects, but if liver/renal function is normal, it usually doesn’t matter as the free drug undergoes elimination
Alteration of extracellular pH changes distribution of drugs. Ex. Making extracellular pH more basic draws acidic drugs out of cells – in aspirin toxicity, giving sodium bicarb helps move aspirin out of the cells and minimizes cell injury
Can you think of an example of a pharmacokinetic interaction related to altered metabolism?
One or the most important drug interaction mechanisms
Drugs can increase the metabolism of other drugs by inducing synthesis of hepatic drug-metabolizing enzymes or can decrease metabolism by inhibiting synthesis of these enzymes.
Majority of drug metabolism is catalyzed by cytochrome P450 enzymes – composed of large number of isoenzyme families (CYP1, CYP2, CYP3), further divided into specific forms, 5 of which are responsible for the metabolism of most drugs (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4)
When an inducing agent is taken with another drug, the metabolism of the drug may be increased to the point where drug effect is lost, this would require an increased dose. If the inducing agent is stopped, the dose would then need to be lowered
Inhibition can be harmful or beneficial, can allow achievement of therapeutic drug levels at lower doses, or can lead to toxicity
Can you think of an example of a pharmacokinetic interaction related to altered excretion?
Drugs can alter the renal excretion of other drugs in all phases of renal excretion: filtration, reabsorption and active secretion
Glomerular filtration can be decreased by drugs that decrease cardiac output as this decreases renal perfusion and therefore drug excretion
Altering urinary pH can alter drug passive tubular reabsorption
Competition for active tubular secretion can decrease excretion of both agents
Pharmacodynamic interactions can be interactions at the same receptor sites or from actions at separate sites. True or false: interactions at the same receptor site can be inhibitory or potentiative
False – these interactions are typically inhibitory as an antagonist drug blocks the access of an agonist drug to its receptor.
This can reduce therapeutic effects or can reduce toxicity
Provide an example of a pharmacodynamic interaction with separate receptor sites
Drugs can act at different sites on through difference mechanisms but on the same physiologic processes and thereby alter responses of other drugs. Can be potentiative or inhibitory
Ex. Morphine and diazepam act on different sites but are both CNS depressants, when given together the CNS depressant effects of one reinforces the other
Ex. Two diuretics, spironolactone and hydrochlorothiazide have opposite effects on potassium levels, given together the effects negate each other, resulting in no change to potassium levels
If drug A and B are toxic to the same organ then taking them together will cause more injury than if they were not combined. This is called a _______ _______ interaction.
Combined toxicity
What are some ways in which food can interact with drugs?
Food can cause decreased rate (which just delays the effects) or extent (which decreases the intensity of peak responses) of drug absorption
Food can also increase absorption in some cases
Can you think of any specific food examples that may cause drug interactions?
Grapefruit juice raises drug levels by inhibiting metabolism through the inhibition of cytochrome P450 isoenzymes
Foods containing vitamin K can reduce the efficacy of warfarin
What is P-glycoprotein (PGP)
PGP is a transmembrane protein that transports a wide variety of drugs out of cells. Like P450 isoenzymes, PGP experiences induction and inhibition by drugs. Most drugs that induce or inhibit P450 have the same impact on PGP
PGP induction causes: reduced absorption, reduced fetal drug exposure, reduced brain drug exposure, increased drug elimination – all due to increased drug export from cells.
PGP inhibition causes opposite effects
Metabolism aka?
What is metabolism?
Biotransformation
= the enzymatic alteration of drug structure
WHere does most metabolism of drugs take place?
Liver
The P450 system is a hepatic microsomal enzyme system named after cytochrome P450. What’s the deal with this system and cytochrome 450?
responsible for most metabolism in liver
Cytochrome P450 = a group of 12 closely related enzyme families
Three of the cytochrome P450 (CYP) families—designated CYP1, CYP2, and CYP3— metabolize drugs. The other nine families metabolize endogenous compounds (e.g., steroids, fatty acids).
According to internet: “cytochrome P450 (CYP) enzymes are considered the major enzyme family capable of catalyzing oxidative biotransformation (phase 1 metabolism) of most drugs and other lipophilic xenobiotics”
They contain heme.
There are 6 possible therapeutic consequences of drug metabolism. The first is accelerated renal excretion of drugs. How does this occur?
most important consequence of drug metabolism!
kidneys cannot excrete highly lipid soluble drugs, so converted into hydrophilic forms during metabolism
There are 6 possible therapeutic consequences of drug metabolism. The 2nd is the most common end results of drug metabolism. what is it?
Drug inactivation
There are 6 possible therapeutic consequences of drug metabolism. The 3rd is increased therapeutic action of the drug. What is a common example of this?
ex: codeine becomes morphine (so morphine is actually responsible for pain relief from codeine)
The 4th therapeutic consequence of drug metabolism has to do with pro-drugs. Describe this.
Activation of prodrugs: a compound that is pharmacologically inactive as administered and then undergoes conversion to its active form through metabolism
T/F One function of activation of the pro-drug is that it can allow the drug to more easily pass the BBB
True
The 5th possible consequence of drug metabolism is increased toxicity. What is happening here? Example?
Metabolites of the drug are more toxic than the drug itself.
ex - acetaminophen metabolites are what is responsible for hepatotoxicity, not the drug itself
The 6th consequence of drug metabolism is decreased toxicity… No question because I don’t know how to formulate one :)
See reverse for summary!
Drug metabolism has six possible consequences of therapeutic significance:
* Accelerated renal excretion of drugs
* Drug inactivation
* Increased therapeutic action
* Activation of prodrugs
* Increased toxicity
* Decreased toxicity
The liver doesn’t fully develop in terms of ability to metabolize drugs until what age?
1 year
T/F Older adults typically have the same ability to metabolize drugs as younger adults
False - liver function decreases in old age
Drugs may be P450 substrates, P450 enzyme inducers, and P450 enzyme inhibitors. What is the general effect of drug metabolism of each of these?
If substrate, drug is metabolized by P450
Inducers increase rate of drug metabolism
Inhibitors dec rate of drug metb
T/F A drug can be a P450 substrate AND an inducer
True - can be more than one (inducer, substrate, inhibitor)
Describe how P450 enzyme inducers change rate of drug metabolism. Does this increase or decrease drug levels?
Inducers act on liver to inc enzyme synthesis (induction) –> inc rate of drug metb –> plasma drug levels fall (need to adjust dosage to ensure in therapeutic range)
T/F P450 enzyme inhibitors risk causing toxicity
True.
Inhibition –> dec metb of drugs –> inc risk of adverse effects/toxicity
What is the first pass effect?
How does this affect the drug’s activity?
First Pass Effect: refers to rapid hepatic inactivation of certain oral drugs
Oral meds go GI tract directly to liver via hepatic portal vein before entering system circ
If liver can metabolize all of drug, complete inactivation will occur during first pass & no therapeutic effect will be seen – need to administer these drugs parenterally to bypass first pass effect
How does your nutritional status affect your drug metabolism?
cofactors are required for drug-metabolizing enzymes (which you need to get through nutrition)
If you take 2 drugs that are metabolized by the same pathway, how might this affect the rate of metabolism?
may compete and decrease rate at which one drug is metabolized
What is enterohepatic recirculation? Describe the path of drug movement.
= a repeating cycle in which a drug is transported from the liver into the duodenum (through the bile duct) and then back to the liver (through the portal blood)
Pathway: liver –> excreted in bile into GI tract (duodenum) –> re-absorbed through GI tract –> portal vein back to liver.
Because of enterohepatic recycling, drugs can remain in the body much longer than they otherwise would
Some nitty gritty (probably unnecessary) details:
- process is limited to drugs that have undergone glucuronidation, a process that converts lipid-soluble drugs to water-soluble drugs by binding them to glucuronic acid (then can enter bile)
- In the intestine, some drugs can be hydrolyzed by intestinal β-glucuronidase, an enzyme that breaks the bond between the original drug and the glucuronide moiety, thereby releasing the free drug.
- Because the free drug is more lipid soluble than the glucuronidated form, the free drug can undergo reabsorption across the intestinal wall, followed by transport back to the liver, where the cycle can start again.
What are possible ways that drugs are excreted from the body?
Drugs and their metabolites can exit the body in urine, bile, sweat, saliva, breast milk, and expired air.
Where does the majority of drug excretion take place?
Kidneys
How does renal impairment affect drug response for drugs that are renally excreted?
duration & intensity of drug responses increase
What are the 3 steps in renal drug excretion? (just the names, not description)
1) Glomerular filtration
2) Passive Tubular reabsorption
3) Active tubular secretion
What is occurring in the glomerular filtration part of renal drug excretion?
What is happening to protein-bound drugs?
Moves drug through the glomerular capillaries into tubular urine
Can’t filter proteins so protein-bound drugs stay in blood
Describe what is occurring at the “passive tubular reabsorption” part of renal drug excretion?
How is this different for lipid soluble vs not lipid soluble drugs?
vessels that deliver blood to the glomerulus return to proximity with the renal tubule at a point distal to the glomerulus – at this site, drug concentrations in blood lower than in tubule à concentration gradient drives drugs from lumen back into blood
Because lipid-soluble drugs can readily cross the membranes that compose the tubular and vascular walls, drugs that are lipid soluble undergo passive reabsorption from the tubule back into the blood. In contrast, drugs that are not lipid soluble (ions and polar compounds) remain in the urine to be excreted.
Describe what is happening at the “active tubular secretion” part of renal excretion
Active transport systems in tubules pump drugs from blood to tubular urine
Have relatively high capacity & play significant role in excreting certain compounds
There are 3 major factors that modify renal drug excretion. The first is pH-dependent ionization. What is the deal with this? How is manipulated to alter rates of drug excretion?
Normally, because ions are not lipid soluble, drugs that are ionized at the pH of tubular urine will remain in the tubule and be excreted (not go back to blood via passive tubular reabsorption)
**can be used to accelerate renal excretion of drugs : Can manipulate urinary pH to promote ionization of drug à decreases passive reabsorption back into blood à hastens excretion
This is used to promote excretion of poisons and meds taken at toxic doses
There are 3 major factors that modify renal drug excretion. The 2nd is “Competition for active tubular transport”. What does this mean?
active transport systems of the renal tubules can be envisioned as motor-driven revolving doors that carry drugs from the plasma into the renal tubules. These “revolving doors” can carry only a limited number of drug molecules per unit of time.
Because of competition, if we administer two drugs at the same time and if both drugs use the same transport system, excretion of each will be delayed by the presence of the other.
There are 3 major factors that modify renal drug excretion. The last is age. Describe how young/old age affects kidney fx?
Infants kidneys have limited capacity to excrete until 3 months
Older adults have smaller kidneys & fewer nephrons
Vessel changes via atherosclerosis also alter blood flow
T/F non-renal routes of drug excretion usually have minimal clinical significant but can be important in certain circumstances
True
Breast milk: Some drugs excreted into milk, exposing infant
Bile is important route of excretion for some drugs – if does not undergo enterohepatic recirculation, will be excreted in feces
Saliva & sweat have little significance
Lungs major route for excretion of…?
Lungs major for excretion of volatile anesthetics; EtOh partially excreted this way
Which characteristic of drugs will allow them to move more freely into breast milk?
Same passage as any other membrane, so more with lipid-soluble and less with polar, ionized or protein-bound
T/F When looking at drug levels, we need to measure the amount of drug present at the site of action. Plasma levels are inadequate for knowing how much drug is really present.
False
Most of time, time course of drug action bears direct relationship to centration of drug in the blood
Can’t regulate amount of drug at site of action so monitor at blood
For most drugs, there is a direct correlation between therapeutic and toxic responses and the amount of drug present in plasma…so we can rely on plasma levels for the most part
What is the minimum effective concentration (MEC)?
= the plasma drug level less than which therapeutic effects will not occur
So need the plasma drug level to be above the MEC to have effect
What is the “toxic concentration”?
plasma level at which toxic effects begin
What is the therapeutic range?
Falls between the MEC and the toxic concentration
There is enough drug present to produce therapeutic responses but not so much that toxicity results – goal of dosing is to keep within this range
What is safer: a drug with a wide or narrow therapeutic range?
Wide
Drugs that have a wide therapeutic range can be administered safely with relative ease
The therapeutic range is quantified, or measured, by the ________ (another term for similar measurement)
therapeutic index.
Of A, D, M, and/or E, which of these processe(s) are primarily determinants of how long drug actions will persist?
Because metabolism and excretion are the processes most responsible for causing plasma drug levels to fall, these processes are the primary determinants of how long drug effects will persist
What is a half life?
= the time required for the amount of drug in the body to decrease by 50% (regardless of dose of drug)
Is an index for how rapidly the amount of drug in the body declines
Will determine dosing intervals
Does half life apply to ALL drugs?
does NOT apply to the elimination of all drugs.
A few agents, most notably ethanol (alcohol), leave the body at a constant rate, regardless of how much is present
What is the plateau drug level?
Administering repeated doses will cause a drug to build up in the body until a plateau (steady level) has been achieved.
When the amount of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached
When a drug is administered repeatedly in the same dose, plateau will be reached in approximately _____ half-lives.
4
If you give consistent but larger doses of a drug (say 4 doses of 100mg) instead of 4 smaller doses (25mg), do you reach plateau level faster?
NO
As long as dosage remains constant, the time required to reach plateau is independent of dosage size. Put another way, the time required to reach plateau when giving repeated large doses of a particular drug is identical to the time required to reach plateau when giving repeated small doses of that drug – the HEIGHT of the plateau will be higher with higher doses, but not different in terms of how long it takes to plateau
Highest level of drug between doses is the ______ concentration and lowest level is the ______concentration
Peak
Trough
Acceptable range of peaks and troughs depends on the drugs ___________
therapeutic range
Name 3 techniques for reducing fluctuations in plasma drug levels
1) Administer drugs by continuous infusion
2) administer a depot preparation (releases drug slowly and steadily)
3) reduce both size of each dose and dosing interval (keeping daily dose constant)
WHat technique can be used to achieve a plateau level more quickly?
Administer a larger LOADING DOSE
Then can start smaller doses to maintain the plateau = MAINTENANCE DOSES
** This does not mean reaching the plateau for the large loading dose, but rather reaching the plateau for a smaller maintenance dose faster (because of that initial higher dose). If you wanted a plateau for that loading dose, would still need to admin equal doses for period of 4 half lives
When drug administration is discontinued, most (94%) of the drug in the body will be eliminated over an interval equal to approximately _____ half-lives
4
Define pharmacokinetics
Study of drug movement throughout body
Name the four basic pharmacokinetic processes
Absorption, distribution, metabolism, excretion
What is absroption?
Drug movement from site of adminstration to the blood
What is distribution?
Drugs movement from blood to interstitial space of tissues and from there into cells
What is metabolism?
(Biotransformation). Enzymatically mediated alteration of drug structure
What is excretion?
Movement of drugs and their metabolites out of body
What is elimination?
Combination of metabolism and excretion
The rate of absorption determines….
How soon drug effects will begin
The amount of absorption determines….
How intense the effects will be
What is chemical equivalence
Drugs are chemically equivalent if they contain the same amount of the identical chemical compound (drug)
When are drugs considered equal in bioavailability?
When the drug they contain is absorbed at the same rate and to the same extent
True or false: Two formulations of the same drug can be chemically equivalent, but differ in bioavailability
True
Name some factors that affect drug absorption
Dissolution of drug
Surface area available for absorption (i.e., absorption of orally administered drugs is greater from the small intestine than the stomach bc the intestine has greater SA)
Blood flow (more blood flow= more rapidly absorbed)
Lipid solubility (more lipid soluble is usually absorbed more rapidly)
pH partitioning (faster absorbed if drug has greater tendency to ionize and be absrobed into plasma)
What are the 3 main factors affecting drug distribution
Blood flow to tissues, ability of drug to exit the vascular system, and ability of drug to enter cells
What kinds of drugs can pass the blood brain barrier
Generally, drugs that are lipid soluble or have a transport system
Name the barriers to absorption for IV, IM, SC, and oral routes of administration
IV- none (absorption bypassed)
IM/ SC- capillary wall (easy to pass)
Oral- epithelial lining of GI tract and capillary wall
What drugs easily pass through the placenta?
Lipid soluble, non ionized
Describe how the absorption pattern differs by route of administration
IV> IM > SC> PO = instantaneous > rapid with water soluble drugs (slow with poorly soluble) > slow and variable
Disadvantages of oral route of administration
Variable absorption, inactivation of drugs by gastric acid/ digestive enzymes, possible nausea and vomiting from local irritation, patient must be cooperative
What is the most important protein for drug binding in the plasma?
Albumin
Why do we care about protein binding?
Protein bound drug cannot leave circulation to have effects on target cell (albumin is too large to leave circulation). They also cannot be metabolized or excreted until the drug protein bond is broken and the drug is free to leave circulation.
