Module 1 - General Principles of Pharmacology Flashcards
1
Q
What is the half-life of a drug?
A
- It is the time it takes for 50% of the drug to be eliminated from the body.
- A drug’s half-life can vary greatly from patient to patient (usually associated with impairment of the liver or kidneys but also by genetic variations in metabolizing enzymes).
2
Q
What is the steady state of a drug?
A
Refers to a state that occurs when there is repeated administration of a drug, usually 4-5 doses, that results in a drug’s concentration in the body being equal with its elimination
3
Q
What does Tmax mean?
A
It is a term used to describe the time it takes a drug to reach peak concentrations in plasma
4
Q
What does Cmax mean?
A
Refers to when peak concentrations of a drug are reached in the blood
5
Q
What is creatinine clearance?
A
- It is an indirect measure of renal function
- An age-related decline in creatinine clearance occurs in about 2/3 of the population. Note, this decline may not be reflected in an equivalent rise in serum creatinine because the production of creatinine is reduced as muscle mass declines with age (hence the use of creatinine clearance in the elderly).
6
Q
What are teratogenic drugs?
A
For a drug to be considered teratogenic the drug should:
- Result in a characteristic set of malformations, indicating selectivity for certain target organs
- Exert its effects at a particular stage of fetal development
- Show a dose-dependent incidence.
7
Q
What are some drugs with definite teratogenic potential?
A
alcohol, androgens, antineoplastics, oral anticoagulants, diethylstilbestrol, smoking and thalidomide
8
Q
What are some examples of teratogenic drugs?
A
phenytoin, carbamazepine, valproic acid, lithium, warfarin, retinoids, and danazol
9
Q
Describe the FDA categories for drug safety in pregnancy
A
Pregnancy Category
A. No fetal harm in studies in women
B. No fetal harm in animals; no studies in women
C. Fetal harm in animals; no studies in women
D. Fetal harm in studies in women; Weigh risk vs. benefit
X. Definite fetal harm in studies in women. Contraindicated
10
Q
What is the MOA of theophylline?
A
Theophylline produces bronchodilation by relaxing the smooth muscle of the bronchi by blocking the receptors for adenosine.
11
Q
What is theophylline used for?
A
Asthma:
- Oral theophylline is used for maintenance therapy for chronic stable asthma. With regular use, it can decrease the frequency and severity of asthma attacks
12
Q
What are some drug/food interactions with theophylline?
A
- Taking caffeine with theophylline can cause a competition for drug-metabolizing enzymes for both substances, causing theophylline levels to rise. It can also lead to more intense CNS and heart adverse effects
- Smoking while taking theophylline causes an increased drug clearance of the theophylline leading to lower theophylline levels in the body.
13
Q
What is bioavailability?
A
It is the percentage of the dose of the drug administered by any route that reaches the systemic circulation
14
Q
What is bioequivalence?
A
- Occurs when there is equivalent release of the same drug substance from 2 or more drug products or formulations
- Ex: the generic drug must produce AUC, Cmax and Tmax values that are neither clinically nor statistically different from a brand name drug to be termed bioequivalent
15
Q
What are first-order reactions?
A
- A reaction in which the rate of absorption and elimination is proportional to concentration
- The higher the blood concentration of a drug, the faster it is eliminated from the body
16
Q
What is meant when a drug operates at zero order?
A
- Occurs when the rate of drug absorption is independent of its concentration (sometimes called saturation kinetics, capacity-limited elimination, or Michaelis Menten kinetics).
- Ex: of zero order drugs: Alcohol; aspirin at high concentrations, & phenytoin at therapeutic concentrations are the best known drugs with zero order elimination
17
Q
What is a loading dose?
A
It is a large dose of a medication that may be used to boost the drug’s concentration into the therapeutic range more quickly, especially if the drug has a large volume of distribution, a long half-life, or it is important to reach therapeutic concentration quickly.
18
Q
What are some important physiologic changes seen with aging?
A
The aged subject will likely have:
- decreased gastric acidity
- increased body fat
- decreased body water
- decreased serum albumin,
- decreased cardiac output
- lean body mass
- decreased renal blood flow, splanchnic blood flow, and hepatic blood flow.
19
Q
What are some changes in drug elimination seen with the elderly?
A
- Decreased 1st pass elimination and hepatic function result in increased amount of drug entering the systemic circulation and prolonged half-life.
- Decrease serum albumin may result in increased concentration of unbound drugs and more intense effects.
- An age-related decline in creatinine clearance occurs in about 2/3 of the population.
20
Q
What is an adverse reaction?
A
Any response (to a drug) that is noxious and untended, that occurs within a reasonable time of administration, and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy, excluding failure to accomplish the intended purpose
21
Q
What is the Cytochroe p-450 and what is its importance?
A
- Cytochrome P-450 is a term that describes a group of hepatic enzymes that metabolize drugs.
- Depending on how some drugs interact/affect these hepatic enzymes results in different drug effects for the person:
- Some drugs are P450 substrates (they are metabolized by these hepatic enzymes)
- Some drugs are P450 inducers (they act on the liver to increase drug metabolism, leading to subtherapeutic responses)
- Some drugs are P450 inhibitors (they decrease the rate of drug metabolism, leading to higher blood concentrations of a drug)
22
Q
What is the first pass effect?
A
- Refers to the rapid hepatic inactivation of certain oral drugs on their first pass through the liver.
- To prevent this effect from happening the drug would be given via another route, mostly likely intravenously
23
Q
What are the effects of age on drug metabolism?
A
- The drug-metabolizing capacity of infants is limited because their liver is not fully developed to metabolize drugs until about 1 year of age.
- With older adults, their ability to metabolize drugs is commonly decreased, and dosages should be reduced to avoid toxicity.
24
Q
How are drugs primarily eliminated from the body?
A
- The kidneys are the most important organs for the elimination of drugs and their metabolites.
- Excretion of drugs & metabolites in the urine involves three processes: glomerular filtration, active tubular secretion, and active or passive tubular reabsorption.
- The amount of drug entering the tubular lumen by filtration is dependent on its fractional plasma protein binding, glomerular filtration rate (GFR), and cardiac output.
25
Describe glomerular filtration and its effect on drug elimination
* Involves the process of moving drugs from the blood into the tubular urine.
* Since large molecules (such as proteins) are too big to pass through the capillaries in the glomerulus they cannot be filtered and remain in the blood.
26
What is pharmacology?
It is the total knowledge of drugs including history, chemistry, source, biochemical & physical effects, pharmacodynamics (what the drug does to the body), pharmacokinetics (what the body does to the drug), therapeutics, site of action, interactions, distinctive features, etc.
27
What are orphan drugs?
The Orphan Drug Act of 1983 provides incentives for the development of drugs for treatment of diseases affecting fewer than 200,000 patients in the US, or for research using commonly available (nonpatentable) chemicals for treatment of specific diseases. The incentives (usually tax breaks) are to encourage companies to do research for which they are unlikely to recoup their costs.
28
What is clinical pharmacology?
The study of the effect of drugs in man (as compared to animal or comparative pharmacology). (The emphasis is on the drug and its uses.)
29
What is Pharmacotherapeutics?
Deals with use of drugs in prevention & treatment of disease, usually to alleviate symptoms or, sometimes, to alter the course of the disease. The emphasis is on the disease and the treatment thereof.
30
What is the "therapeutic index" of a drug?
* It is the ratio of the dose capable of killing 50% of animals (LD50) over that required to achieve a beneficial effect in 50% of the animals (ED50).
* In clinical terms, a drug that has a “small therapeutic index” has little difference between the therapeutic dose and the dose that causes toxicity (e.g., digoxin).
31
What is drug tolerance?
* It is hyporeactivity that occurs from chronic exposure to a drug (such as an opioid or alcohol).
* When tolerance develops, usually increasing doses are needed to provide a therapeutic effect.
* This is attributed to neuronal adaptation or cellular tolerance.
32
What is a "side effect" of a drug?
It usually describes any action of the drug other than the desired (therapeutic) effect.
33
What is an "adverse effect" of a drug?
It is any noxious, unintended, and undesired effect that occurs at **normal drug doses**
34
Describe the DEA schedule of drugs
Schedule:
1. Addictive substances with no approved use (e.g., heroin)
2. Highly addictive substances (e.g., morphine; amphetamine). Prescriptions must be written in ink or typed or submitted using electronic prescribing procedures and cannot be refilled.
3. Less addictive; may be prescribed orally and may be refilled up to 5 times in 6 months (e.g., aspirin with codeine C-iii; diazepam C-iv)
4. "same as 3"
5. Low addictive potential. Texas law requires a prescription for C-v drugs so essentially, in Texas, there is no difference in prescribing or how schedules iii, iv & v are handled. See Lehne p. 411 for a more comprehensive description of the various DEA schedules.
35
Describe drug absorption
* It is the transfer of a substance from the site of application to the bloodstream (usually the systemic circulation).
* Intravenous and intrathecal are about the only sites of administration where absorption is not a factor.
36
What effects can low albumin levels have on drugs?
* Malnutrition can cause hypoalbuminemia and may alter the absorption, distribution, metabolism of **protein bound drugs**
* Decreased serum albumin levels may also result in increased concentration of unbound drugs and more cause a more intense effect
37
What does it mean if a drug operates at "zero order"?
* It means that the drugs elimination rate is independent of its concentration
* Tmhe higher the concentration of drug the longer it will take to eliminate the drug
* Ex: Alcohol; aspirin at high concentrations, & phenytoin at therapeutic concentrations are the best known drugs with zero order elimination
* alcohol is eliminated at a rate of 10 cc/hour regardless of the amount of alcohol consumed.
38
What is down regulation?
Occurs when there is a decrease in the number or sensitivity of receptor sites after continued dosing of a drug
39
What is upregulation?
Occurs when the body increases the number of receptors or increase the sensitivity of receptors to a drug
40
What are drug receptors?
They are any functional macromolecules in a cell to which a drug binds to produce its effects. Proteins in cell plasma membranes form the most important class of drug receptors. These proteins can be selective and recognized by selective ligands (e.g., drugs, hormones, neurotransmitters).
41
What are agonists?
An agonist (drug) binds to the receptor and causes a change in cellular activity. It has both affinity and efficacy.
42
What is an antagonist?
An antagonist (drug) binds to the receptor, causes no change in cellular activity, and blocks the ability of endogenous substances or other drugs to bind to the receptor. It lacks efficacy.
43
What is a partial agonist?
A partial agonist (drug) binds to the receptor, causes a low level of change in cellular activity, but blocks endogenous substances or other drugs from binding to the receptor.
44
What is ionization?
* The process of an aciid giving up a proton or a base accepting a proton converts the acid or base into a charged particle (ion).
* The nonionized is usually lipid soluble and able to penetrate the lipid membrane while the ionized cannot
* Exmple: aspirin, acetylsalicylic acid, is a weak acid and is ionized when it gives up a proton
45
What is PH-dependent ionization?
* The extent of which a weak acid or weak base becomes ionized is determined in part by the PH of its environment
* Acids ionize in basic (alkaline) media
* Beses tend to ionize in acidic media
* example: aspirin, a weak acid, are nonionized in the stomachs acidic environment but ionized when they pass down to the alkaline intestine.
*
46
What is Ion-Trapping?
* The process whereby a drug accumulates on the side of the membrane where the pH most favors ionization is referred to as ion trapping or pH partitioning.
Example:
* A weak acid (such as salicylic acid, the active metabolite of aspirin), in an acid medium (such as the stomach or acid urine,) is predominantly in the nonionized state (hence lipid soluble and can be absorbed).
* A weak base (e.g., morphine sulfate) in an acid medium is predominantly in the ionized state; hence gets “trapped” in the more acidic fetus if morphine is given to a woman at term (“ion trapping”)
47
How can acidosis affect the drug action of salicylic acid or aspirin
. Development of acidosis drives the drug to its nonionized form, which can go into tissues (i.e., brain) and cause toxicity. On the other hand, treat salicylate toxicity by alkalinizing the urine to increase the ionized form that cannot be reabsorbed though the kidney tubules. Cases of aspirin toxicity are treated with “forced alkaline diuresis,” i.e. giving sodium bicarbonate IV along with furosemide.
48
How is aspirin at high concentrations eliminated?
Some few drugs operate at **zero order,** where rate is independent of concentration Alcohol; aspirin at high concentrations, & phenytoin at therapeutic concentrations are the best known drugs with zero order elimination. For example, alcohol is eliminated at a rate of 10 cc/hour regardless of the amount of alcohol consumed.
49
What pregnancy class does Aspirin fall under?
* \* Aspirin is listed as Pregnancy Category C or D in different sources. If aspirin is taken within 5 days of delivery, it may affect hemostasis in the neonate or may prolong gestation.
* Avoid aspirin when breastfeeding
50
What are the functions of NSAIDS?
antipyretic, analgesic, and anti-inflammatory
51
What is the mechanism of action of NSAIDS?
MOA: Cyclooxygenase inhibitor
The major mechanism by which the NSAIDs elicit their therapeutic effects is inhibition of prostaglandin (PG) synthesis. Specifically NSAIDs competitively (for the most part) inhibit cyclooxygenases (COXs), the enzymes that catalyze the synthesis of cyclic endoperoxides from arachidonic acid to form prostaglandin
NSAIDS can be subdivided into two groups. First ( inhibit COX-1 and COX 2) and Second generation ( inhibit COX-2).Motrin is a second generation NSAID
52
Why do NSAIDS cause GI bleeding in some?
NSAIDs are metabolized in part by CYP 2C9. A genetic lack of the 2C9\*3 allele increases the risk of acute upper GI bleed, even in patients taking antiulcer drugs.
53
What are adverse effects of NSAIDS?
Teratogenic. NSAIDS affect fetal growth
Nephrotoxicity is a significant side effect of NSAIDS
54
What class of drugs does Lipitor (Atorvastatin) belong to?
Class: HMG-CoA reductase inhibitor (Statins)
55
What are the functions of Lipitor?
Function: Lower LDL, Lower Triglycerides, and increase HDL
56
What is the mechanism of action of astovastastin or lipitor?
MOA: Statins increase the number of LDL receptors on hepatocytes
Statins inhibit cholesterol synthesis by inhibiting hepatic HMG-CoA reductase. For reasons not fully understood, inhibition of cholesterol synthesis causes and increase number of LDL receptors on hepatocytes. Hepatocytes are then better able to remove more LDL more the blood. For statins to be effective the number of LDL receptors must increase.
57
What are drug interactions to consider with Artovastatin/ Lipitor?
* Other lipid lowering drugs- increase incidence of adverse effects (muscle/kidney/liver injury)
* Drugs that inhibit CYP 3A4 - raise levels of lipitor by slowing their innactivation
* **\* Grapefruit** and grapefruit juice- Grapefruit juice inhibits CYP3A4. It decreases intestinal metabolism and increases the absorption of a number of drugs metabolized by CYP3A4. Grapefruit juice may also decrease or delay drug absorption
58
What class of drugs does Ampicillin belong to? and what is it used for?
Class: Penicillin ( broad spectrum)
Function: useful in treating infections caused by Enterococcus Faecalis, Proteus Mirabilis, E.coli, Salmonella, Shigella, and H. influenzae. Penicillins are also useful in the treatment of anthrax poisoning
59
What is the mechanism of action of Ampicillin?
MOA: Disruption of the bacterial cell wall. Penicillins weaken the cell wall by two actions:
1. Inhibition of transpeptidases
2. Disinhibition (activation)
3. of autolysins
60
What are side effects of Ampicillin?
Side Effects: Rash and diarrhea are the most common
(Safe to use in pregnant women)
61
What is Cimetidine and what is the drug class?
Cimetidine is a drug that blocks the production of acid by acid-producing cells in the stomach. It is used for peptic ulcer disease.
Class: H2 antagonist
62
How is Cimetidine a precipitant drug?
A precipitant drug is a drug causing an altered action ( adverse interaction).
**Cimetidine is an Enzyme inhibitor.** It inhibits drug-metabolizing enzymes and can thereby increase levels of other drugs. Drugs of particular concern are warfarin, phenytoin, theophylline, and lidocaine. Dosages of these drugs may require reduction.
63
What are the adverse effects of Cimetidine interactions with Varenicline ( a drug used to help quit smoking).
Cimetidine Increases adverse effects of Varenicline- varenicline has negligible effects on the cytochrome P450 system, however, cimetidine, which decreases renal clearance of varenicline, increased serum concentrations by 29%.
64
What are inducing agents? Example?
Drugs that stimulate the synthesis of CYP isoenzymes thereby stimulating their own metabolism as well as that of other drugs. They usually cause a decreased blood level of the drug.
The classic example of an inducing agent is phenobarbital, a member of the barbiturate family.
65
How do medications need to be adjusted with an inducing agent such as phenobarbital?
When a pt begins taking an inducing agent, dosages of other drugs may need to be increased. When a pt discontinuous an inducing agent, dosages of other drugs may need to be lowered to avoid drug levels going up to high. This is a concern with oral contraceptives and warfarin.
For example, if a woman taking oral contraceptives were to begin taking phenobarbital, induction of drug metabolism by phenobarbital would accelerate the metabolism of the contraceptive, thereby lowering its level. If drug metabolism is increased enough, protection against pregnancy would be lost. To maintain contraceptive efficacy, dosages of the contraceptives should be increased.
66
What is a prodrug?
A prodrug is a compound that is pharmacologically inactive as administered and then undergoes conversion to its active form via metabolism.
ex. All ACE inhibitors are prodrugs except **Lisinopril** which is given in its active form
67
What is the MOA of Ventolin/ Albuterol?
MOA: Albuterol is a relatively selective beta-2 agonist that, by aerosol, has a duration of 4-6 hours. It is given to reduce airway resistance. (Also available as solution for nebulizer, tablets and syrup).
68
What is the indication for albuterol/ ventolin?
Indication: For relief and prevention of reversible bronchospasm associated with asthma, bronchitis, emphysema, and COPD. It is indicated for children as young as 4 y (others indicated for children \> 12 y). Beta-2 agonists are the drugs of choice for rapid treatment of bronchospasm.
69
What are cautions of albuterol and adverse reactions
* Caution: Patients at risk include diabetics, hyperthyroidism, subjects with seizures disorders, and the elderly. Excessive use may cause death, cause unknown but probably cardiac arrest. Oral use may delay preterm labor.
* Adverse reactions: CNS stimulation, palpitation (1-10%), tremors (1-20 %), shakiness (1-20%), hyperactivity (1-20%), headache (2-27%), and nausea & vomiting (2-15%). May cause irritable behavior in infants.
* Epidemiologic studies have suggested a possible connection between the prolonged use of long-acting beta-receptor agonists and death from asthma (**black box warning** for all). Down-regulation of receptors has also been suggested when these products are used.
70
What is the indication for **Salmeterol** [Serevent Diskus]
Salmeterol is a delayed-action, long-lasting preparation (reportedly due to a long side chain that tightly binds to a receptor next to the beta receptor). Salmeterol is given 2 puffs q12h for maintenance of bronchodilation and prevention of symptoms of asthma. It is NOT used for rescue therapy in acute attacks.
71
What is an object drug?
drug whose action or kinetics is altered in a drug to drug interaction
ex- Warfarin
72
What foods alter Warfarin metabolism?
Foods of the brassica family [Brussels sprouts, cabbage] contain an enzyme that stimulates warfarin metabolism. Green leafy vegetables contain vitamin K which interferes with warfarin effect
73
What are the increased adverse effects associated with taking Warfarin and Aspirin together?
they are both anticoagulants so the risk of bleeding is high
74
What is a racemic compound?
* Drugs that have an asymmetric carbon atom (racemic compound) can have two (or more) different configurations (stereoisomerism or enantiomers).
* One of these compounds will fit the receptor site better than the other and thus have a greater effect. (Think of your hands – 4 fingers & 1 thumb – they look the same but are mirror images of each other.)
* Many of our drugs we use today are racemic compounds but most of the action will come from one of the isomers. The other isomer may be less active or inactive, may be more or less toxic, and may be metabolized at a rate different from the active isomer
.
75
How is warfarin a racemic compound?
The S-isomer is 4 times more active than the R form. The S isomer is metabolized by CYP 2C9 while the R isomer is metabolized by CYP 3A4 and at a faster rate than the S isomer.
76
How does smoking affect Warfarin dosing?
Smokers required a 13% increase in warfarin dose (compared with nonsmokers)
77
How does chronic alcoholism affect testosterone levels?
Testosterone levels are lower in chronic alcoholic men.
78
What class of drug is Finasteride and what is it used for?
5-Alpha-reductase inhibitors
Used for BPH or reduction of prostate size
Benefits take months to develop
79
What is the MOA of Finasteride (Proscar)
Acts in reproductive tissue to inhibit 5-alpha-reductase, an enzyme that converts testosterone to dihydrotestosterone (DHT), the active form of testosterone in the prostate. Treatment reduces levels of DHT in the blood by 70%.
By decreasing DHT, it causes the prostate to shrink and reduce the mechanical obstruction of the urethra
80
What pregnancy class is Finasteride?
Finasteride is classified as a Pregnancy Risk Category X because it is teratogenic to the male fetus. It can be absorbed through the skin so pregnant women should not handle tablets.
81
How is methotrexate eliminated?
Elimination is primarily renal, hence in pts with renal impairment, dosage muset be reduced to prevent drug from accumulating at toxic levels.
## Footnote
or drugs excreted \>50% unchanged, rate of elimination is diminished in patients with renal insufficiency. This becomes especially important in drugs with a narrow therapeutic index like methotrexate.
82
What effect does smoking have on diabetics who take insulin?
n, diabetic smokers require more insulin than do nonsmokers. Smoking (nicotine, via vasoconstriction) slows the rate of absorption of insulin from subcutaneous injection sites.
83
How does sympathetic stimulation affect insulin?
Blood glucose increases (glycogen in the liver is broken down into glucose, but insulin is also released)
84
What effect does a adrenergic B2 receptor have?
Beta-2 (predominately non-cardiac) receptors are found on smooth muscle [e.g., bronchi; large blood vessels] causing relaxation. Beta-2 receptors also promote **insulin release** and, in liver & muscle, gluconeogenesis & glycogenolysis as well as lipolysis in fat cells.
85
What effect to catecholamines have on insulin?
Catecholamines have both a stimulating effect on secretion of insulin by the beta cells of the pancreas via beta receptors and an inhibitor effect via alpha-2-receptors
86
What effect does an adrenergic Alpha-2 receptor have?
* Alpha-2 (presynaptic)
* Up- and down-regulation are known to occur in response to decreased or increased activation of receptors. An extreme form of auto-regulation occurs after denervation of some tissues, resulting in “denervation supersensitivity” of the tissue.
* Alpha-2 receptors are also present at extrasynaptic sites in blood vessels and in the CNS.
* Stimulation of central alpha-2 receptors in the brainstem decreases sympathetic outflow. Stimulation of alpha-2 receptors in the pancreas **inhibits insulin release.**
