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MS1 Fall > FDN Exam 4 > Flashcards

FDN Exam 4 Flashcards

1
Q

Define pharmacogenetics

A

New area; understanding the underlying genetic component that gives variance in drug response from person to person

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2
Q

Define toxicants

A

Toxic subtances produced by human activities (man-made)

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3
Q

What is phase II metabolism?

A

Usually involves biotransformation into a more polar form which is more readily excreted in the urine, feces or bile

More info via Google: glucuronidation, acetylation, and sulfation reactions: “conjugation reactions” that increase water solubility of drug with a polar moiety

phase II reactions convert a parent drug to more polar (water soluble) inactive metabolites by conjugation of subgroups to -OH, -SH, -NH2 functional groups on drug

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4
Q

In first-order metabolism, is the half-life dependent or independent of the concentration of the drug?

A

Independent

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5
Q

What are environmental sources of individuality?

A

Diet, habits like smoking and drinking, and physical things like sunlight

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6
Q

What is a prodrug?

A

a biologically inactive compound that can be metabolized in the body to produce a drug

Example: Acetanilide

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7
Q

What factors determine the extent of drug absorption?

A

Drug factors, biological factors, and formulation factors

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8
Q

Smaller or larger molecular weight improves the rate of drug absorption?

A

Smaller

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9
Q

What is an orphan drug?

A

Drugs intended to treat rare diseases

US government had to find a way to incentivize drug companies to create these since the ability to recoup R&D money would be nearly impossible.

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10
Q

What type of adrenergic receptor causes iris contraction?

A

a1

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11
Q

What is the difference in patient populations from Phase II/III and Phase IV trials?

A

Phase II/III are small, homogenous populations whereas Phase IV is the entire population and is heterogeneous

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12
Q

What factors affect drug distribution?

A

Blood flow, drug binding to plasma proteins, and the activity of P-glycoprotein

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13
Q

What has a predominant parasympathetic tone?

A

Heart, iris, ciliary muscle, GI, urinary bladder, salivary glands

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14
Q

What is potency?

A

Based on the interaction of a drug with a receptor. The concentration or dose that produces 50% of the maximal response

The higher the potency, the lower the concentration of the drug to achieve the same level of receptor occupancy

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15
Q

Which components of the Michaelis-Menten equation are constants?

A

Km and kcat

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16
Q

What is occupation theory?

A

In order for an agonist to activate a receptor, it must occupy the receptor

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17
Q

What is first order elimination? Provide a definition and the equation.

A

The rate of drug elimination is proportional to the drug concentration

First-order elimination rate = -kel[drug]

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18
Q

Most drug-receptor interactions are what kind of bonds?

A

Ionic and hydrogen (very few are covalent)

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19
Q

What is the primary neurotransmitter at the somatic (voluntary) skeletal muscle neuromuscular junction?

A

Acetylcholine

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20
Q

What are the average volumes (in a 70kg adult) of plasma? extracelluar space? intracellular space? Total body water?

A

Plasma = 3L

Extracellular = 9L

Intracellular = 29L

Total body water = 41L

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21
Q

How are ionized comounds and their metabolites excreted in the liver?

A

Via active transport systems

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22
Q

What considerations should you keep in mind when prescribing to a pregnant woman?

A

Increased renal blood flow (pharmacokinetic!)

Placental transfer

And then infant toxicity if/when mother breast feeds

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23
Q

Can drugs excreted in bile re-enter systemic circulation?

A

Yes, via the hepatic portal system these drugs and metabolites can re-enter system circulation where they can undergo phase I and phase II metabolism again

(same mechanism used for bile salt recycling!)

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24
Q

What is ED50?

A

The dose of drug for 50% response

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25
Q

List the steps in the biosynthesis of epinepherine including enzymes

A
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26
Q

What type of adrenergic receptor is present on the liver? What does it do?

A

B2

Increases glycogenolysis and gluconeogensis

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27
Q

Which nicotinic ganglionic blocker can penetrate the CNS and which one cannot?

A

Hexamethonium can’t penetrate the CNS

Mecamylamine can enter the CNS

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28
Q

Is zero-order elimination saturating or non-saturating?

A

Saturating

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29
Q

What effect do Amphetamine and Tyramine have one norepinephrine in the synapse?

A

They facilitate reuptake and re-packaging into vesicles

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30
Q

Phase II enzymes are all what type of enzyme class?

A

Transferase

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31
Q

What are the three endogenous catecholamines?

A
  1. Norepinepherine - principal transmitter of most postganglionic fibers
  2. Dopamine - found in extrapyramidal system & mesolimbic nd mesocortical pathways
  3. Epinepherine - major hormone of the adrenal medulla
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32
Q

What are three ways that individuals vary in their ability to metabolize and excrete drugs?

A
  1. Age
  2. Diet
  3. Genetic differences (ex: rapid acetylators vs. slow acetylators)
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33
Q

Why do some patients have an allergic reaction to a drug but others don’t?

A

The drug could get paired with a larger molecule, and the body may see the larger molecule as an allergen - this mounts IgE response

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34
Q

What is the passive filtration rate in the nephron?

A

125 mL/minute

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35
Q

What phase of metabolism is used in the design of inactive prodrugs?

A

Phase I

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36
Q

What type of adrenergic receptor is responsible for brochial muscle dilation?

A

B2

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37
Q

Where are a1 receptors found?

A

Effector tissues: smooth muscle, glands

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38
Q

What are the major classes of nicotinic receptors?

A
  1. Neuromuscular
  2. Neuronal/ganglionic
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39
Q

Why is thiopental a good rapid anethestic but not a good long-term one?

A

Because it immediately goes to the brain, but shortly thereafter it is sequestered in fat reducing its activity in the brain

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40
Q

What is the two-compartment model?

A

We have a central compartment (i.e. plasma) into which drug is added and removed, but then we also have a peripheral compartment (i.e. brain, lipid) into which the drug is sequestered

This is obviously more complicated than single-compartment elimination

A drug can also enter and exit these peripheral compartments at different rates, further complicating the elimination

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41
Q

What is kcat equivalent to?

A

Vmax

It’s the maximum rate an enzyme can metabolize a drug

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42
Q

If a drug is actively excreted into the proximal tubule, what can the clearance rate go up to?

A

600 mL/minute

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43
Q

True or False: doubling the dose of a first-order drug will double the duration time?

A

False

Doubling the dose increases the duration time by approximately one half life

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44
Q

Define half life and give the equation

A

The time it takes for the drug concentration to fall by 50%

t1/2 = 0.693 / kel

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45
Q

Which cholinergic receptor is a G-protein?

A

Muscarinic

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46
Q

What type of reaction is important for the removal of toxic metabolites?

A

Glutathionation

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47
Q

What effect do Cocaine and Imipramine have on norepinepherine in the synapse?

A

The antagonize the dopamine receptor and leave norepinephrine out in the synapse longer than it should be

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48
Q

Codeine is a prodrug of what?

A

Morphine

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49
Q

What is an antagonist?

A

A drug that binds to the receptor but produces no response

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50
Q

How do most drugs enter the blood?

A

Via simple diffusion

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51
Q

What are nicotinic receptors? Where are they specifically located?

A

They are located on Na+/K+ ion channels and respond to acetylcholine and nicotine by opening the ion channel. They are located post-synapse in somatic pathways (neuromuscular is the major class!!)

Located in the ganglia and in the skeletal muscle end plates

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52
Q

When do acidic drugs have a charge? Low pH or high pH?

A

High

They are neutral at low pHs

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53
Q

What two feedback loops control blood pressure?

A
  1. Autonomic
  2. Hormonal
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54
Q

What is a schedule 1 drug? What is its abuse/dependence rating?

A

Cannot be prescribed and no accepted medical use

High abuse/dependence potential

Examples: LSD, heroin, etc

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55
Q

What does a quantal dose response graph show us?

A

How many people are responding to the treatment at specific doses

The graph is cumulative; we add patients in until 100% of individual responses (the y-axis) are accounted for

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56
Q

What type of adrenergic receptor(s) increase SA and VA node activity + ventricle activity?

A

B1 (and some B2)

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57
Q

What is assessed during phase III clinical testing? Who are the subjects in this phase?

A

Additional information is gathered about safety and efficacy. Often compares new therapy to current standard of care

Subjects: Patients (> 300). Double blind, placebo controlled

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58
Q

What body compartment(s) have a pH generally higher than plasma pH?

A

Small intestine lumen

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59
Q

What is supersensitivity?

A

The rebound effect

If you take a drug like the beta blocker propranolol your body will up-regulate the receptors in an attempt to compensate for the inhibited action

When you remove yourself/the patient from the beta-blocker there will be an up-regulated amount of receptors and a supersensitive response. Gradual tapering is recommended to avoid this.

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60
Q

Is a high or low lipid:water (or oil:water, lipophilic/hydrophboic nature) more important for absorption?

A

High

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61
Q

Which line is more potent? The one on the left or right?

A

The left. You need less of that drug to elicit the same response

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62
Q

Will drugs targeting nicotinic ganglionic receptors affect any other components of the nervous system?

A

Yes, they will affect the entire autonomic nervous system. There is no selectivity for sympathetic or parasympathetic systems

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63
Q

How many half-lives until we’ve reach nearly 100% concetration in the plasma/tissue?

A

5t1/2 = 96.9%

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64
Q

In what state are nicotinic receptors most stable?

A

Desensitized (with ACh still bound)

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65
Q
A
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66
Q

What are two outcomes after rare adverse events are observed?

A
  1. Label warnings are developed (black box). Example: antidepressants tested in adults but then once prescribed to teens we see instances of suicide
  2. Market withdrawal (Vioxx/seldane example - cox 2 inhibitor that caused heart failure in patients)
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67
Q

What are the three main mechanisms by which antidotes work?

A
  1. Binding to the toxicant and inactivating it
  2. Blocking critical receptors
  3. Changing the toxicant metabolism
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68
Q

Define toxins

A

Toxic substances produced by biological systems such as plants and animals (ex: rattlesnake venom)

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69
Q

What is first pass metabolism?

A

a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation.

It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall

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70
Q

How are majority of drugs eliminated: first or zero order?

A

First

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71
Q

What continuously maintains the concentration gradient necessary for passive diffusion to occur?

A

Local blood flow

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72
Q

For first-order elimination, the time to plateau (steady state) is determine solely by what?

A

kel

And if there is a shift in the plateau, the time to reach the new one is determinely solely by kel again

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73
Q

Where are muscarinic receptors present even though there is no parasympathetic innervation?

A

Arterioles

(Explanation from class: “Vagus nerve dumps a bunch of ACh into the blood stream and it causes arteriole dilation”)

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74
Q

In zero-order elimination, if you double the initial dose what happens to the elimination time?

A

It nearly doubles

This is an important distinction from first-order elimination where doubling the initial dose does NOT double the elimination time

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75
Q

Activated G proteins can act on what effectors?

A

Adenylyl cyclase, phospholipases C and A2, cGMP phosphodiesterase, potassium channels, and calcium channels

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76
Q

When does liver toxicity peak in acetaminophen toxicity?

A

72 to 96 hours after the dose

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77
Q

What does Leuprolide do?

A

It is an agonist for gonadotropin-releasing hormone (GnRH) used to treat prostate cancer

GnRH stimulates the release of lutenizing hormone (LH) which in turn stimulates testosterone synthesis

Leuprolide ultimately causes a decrease in testosterone due to desensitization of the pathway

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78
Q

What type of adrenergic receptor is responsible for constriction of blood vessels in skeletal muscle? For dilation of blood vessels in skeletal muscle?

A

Constriction: a1 (due to high levels of epinepherine)

Dilation: B2 (due to low levels of epinepherine)

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79
Q

What form of drugs readily diffuses across the plasma membrane?

A

The unionized form

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80
Q

What is the Single Compartment Model of drug distribution?

A

It assumes that a drug distributes evenly throughout a single homoegenous space in the body

It allows us to predict the general pharmacokinetic properties of the drug sufficiently well enough for clinical use

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81
Q

When does a steady state concentration of a drug in plasma/tissue occur?

A

Rate of drug infusion = rate of drug elimination

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82
Q

What foods induce P450?

A

Charcoal broiled foods and broccoli/sprouts

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83
Q

______ is the primary transmitter in all autonomic ganglia and the stanpses between parasympathetic postganglionic neurons and their effector cells

A

Acetylcholine

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84
Q

What are G-protein coupled receptors also known as?

A

7TMR (seven transmembrane spanning receptors)

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85
Q

What foods inhibit P450?

A

grapefruit juice and tropical fruits

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86
Q

Where are B2 receptors found?

A

Smooth muscle, liver, heart

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87
Q

Can the apparent volume of distribution (Vd) be greater than total body water?

A

Yes. This would indicate that the drug is highly distributed in the tissues

Ex: Digoxin has a Vd of 280 L

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88
Q

Define cholinergic

A

A nerve ending that released acetylcholine; also, a synpase in which the primary transmitter is acetylcholine

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89
Q

What are three symptoms/symptoms of Aresnic poisoning/toxicity?

A
  1. Blackfoot disease (gangrenous feet)
  2. Mee’s lines (white lines on finger nails)
  3. Rice water stools (due to sloughing of GI mucosa)
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90
Q

When considering individuality in drug response, what items fall under “condition or state of being”?

A

Physiological set-point, disease-induced alterations in PK and PD, age, reproduction (i.e. pregnancy), allergic reactions

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91
Q

What is a muscarinic receptor? What kind of protein is it?

A

These receptors respond to muscarine and acetylcholine & are located post-synapse in the parasympathetic pathway and the eccrine sweat sympathetic pathway

Located primarily on autonomic effector cells (including heart, vascular endothelium, smooth muscl, presynaptic nerve terminals, and exocrine glands)

They are G-protein-coupled receptors

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92
Q

What are the muscarinic cholinergic actions?

A

Salivation

Lacrimation

Urination

Defecation

“SLUD”

Also: decreased heart rate, vasodilation, bronchoconstriction, constricted pupils, increased GI motility. This all makes sense because muscarinic receptors are part of the parasympathetic system!

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93
Q

If you plot the logarithm of the drug concetration versus time for a first-order process, what type of graph/line do you expect to see?

A

A straight line

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94
Q

What are the four targets of ANS drugs?

A
  1. CNS
  2. Ganglions
  3. Neurons
  4. Effector Organ Receptors
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95
Q

What are nicotinic ganglionic receptor antagonists called?

A

Ganglionic blockers

Examples: hexamethonium and mecamylamine

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96
Q

What effect does Warfarin have on P450 metabolism?

A

Reduces it

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97
Q

What is EC50?

A

The concentration of drug for 50% response

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98
Q

Can a drug bound to a plasma protein leave systemic circulation?

A

No. Only unbound drugs can leave systemic circulation

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99
Q

What type of adrenergic receptor constrictrs blood vessels in skin, mucosa, arterioles and veins?

A

a1

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100
Q

What is the important exception to norepinepherine being the postganglionic transmitter in sympathetic neurons?

A

Eccrine sweat glands

They use acetylcholine

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101
Q

How many liters of fluid are in plasma, extracellular, and intracellular space?

A

Plasma: 3L

Extracellular: 9L

Intracellular: 29L

102
Q

What are examples of sympatholytics? What step in the catecholamine biosynthesis does each block?

A

Metyrosine blocks tyrosine hyroxylase (stops L-DOPA formation)

a-methyl DOPA blocks the conversion of L-DOPA to dopamine

Guanethidine has a two prong approach: competes with NE for space in vesicles & then lack of NE in vesicles stop their fusion with the plasma membrane & release into the synapse

103
Q

What are three methods of enteral drug administration?

A
  1. Oral - Non-invasive and good for chronic administration
  2. Sublingual - rapid entry of permeable drugs
  3. Rectal - useful when oral administration is impractical
104
Q

Do the nicotinic receptors of autonomic ganglia and neuromuscular junctions have the same specificities for agonists and antagonists?

A

No, they have different specificities. This allows for drugs targeting just the neuromuscular nicotinic receptors, for example, to be used

105
Q

Does carrier-mediated faciltated transport of drugs occur?

A

Sometimes

106
Q

What are examples of ion channel receptors?

A

Acetylcholine (Ach), GABA, serotonin, glutamate

Involved in neurotransmission; high levels of expression in the brain

107
Q

Define pharmacotherapeutics

A

The therapeutic use of drugs (clinical response: efficacy and toxicology)

108
Q

Where is norepinepherine a vasoconstrictor?

A

The renal blood vessels

109
Q

What are pharmacodynamic genetic sources of individuality?

A

Receptors, enzymes, ion channels

110
Q

What is active efflux and what molecule accomplishes this?

A

Active transport of drugs out of a cell so the drug cannot reach its targeted receptor

This is accomplished by P-glycoprotein

111
Q

Does a non-competitive inhibitor change the potency or efficacy?

A

Efficacy

The agonist can still bind, but it can’t produce the same maximal effect with the allosteric inhibitor present

112
Q

What is a “loading dose”?

A

Administration of a large dose of a medication to provide immediate relief to the patient

Calculated by multiplying the drug’s apparent volume of distribution (Vd) by the desired steady-state plasma concentration (Css)

Initial Loading Dose = Vd * Css

113
Q

What are two examples of non-cyp enzymes found in the liver that are used for alcohol metabolism?

A

alcohol and aldehyde dehydrogenases

114
Q

What happens to patients deficient in acetylation capacity (aka slow acetylators)?

A

They may have prolonged or toxic responses to normal doses of certain drugs because of decreased rates of metabolism

115
Q

What are pharmacokinetic genetic sources of individuality?

A
  1. A person can be a poor metabolizer of coedine (failure to convert to morphine) or they can be a rapid metabolizer and be at risk for respiratory distress
  2. A person can also be a slow vs. fast acetylator; important when considering Isoniazid (therapeutic level vs. toxicity)
116
Q

As drug concentration falls and we get into the region where [drug] <<< Km, what type of elimination are in?

A

First order

117
Q

How long does it take a drug to act on nuclear receptors?

A

Hours

118
Q

What is a key factor in clearance rates?

A

Blood flow

119
Q

What is bioavailability?

A

The measure of the drug available to the systemic circulation over time after administration (usually oral)

120
Q

What can you inject into a patient to determine how well their kidneys are functioning/clearing drugs?

A

Inulin

Clearance rate of 7.8 L/hr

121
Q

What G-protein subunit typically acts on effectors like adeneylyl cyclase?

A

Alpha

122
Q

What is the equation for zero-order elimination?

A

elimination rate = -kel

(its just a constant!)

123
Q

What G-protein subunit typically acts on ion channels?

A

BY (beta gamma)

124
Q

What are symptoms of organophosphate poisioning?

A

Excessive muscarinic activity (aka too much parasympathetic action)

Nicotinic effects varibale due to desensitization and depolarization-block of the nicotinic receptors

125
Q

What is assessed during phase I clinical testing? Who are the subjects in this phase?

A

Safety and pharmacokinetics are assessed (typically not efficacy because the subjects are healthy volunteers)

Subjects: healthy volunteers (20-100 subjects)

126
Q

Does a competitive inhibitor change the potency or efficacy?

A

The potency

You will still get the same effect when the agonist binds, but you just need more of it/need it to be more potent to achieve the same effect

127
Q

What is it called when rate of drug infusion = rate of drug elimination?

A

Steady state

128
Q

Define Km

A

the amount of drug required to activate 50% of the enzyme

129
Q

What does zero-order elimination depend on? Drug concentration or the enzyme?

A

The enzyme and how fast it can work

Zero-order elimination is indepdent of drug concentration (when [drug] >>> Km). The elimination rate is what it is

rate of catalysis = kcat[enzyme]

130
Q

What does inhibition of the P-glycoprotein pump accomplish?

A

Improvement in the delivery of therapeutic agents

131
Q

What are the two types of adrenergic receptors?

A
  1. Muscarinic
  2. Nicotinic
132
Q
A
133
Q

What are the three classes of sympathomimetics? Include examples for each

A
  1. Direct acting: act directly on a receptor- norepinephrine, epinephrine, Isoproterenol
  2. Indirect acting: effect catecholamine levels in the synapse - Amphetamine, Tyramine, Cocaine, Imipramine
  3. Combination: have mixed actions - dopamine, ephedrine
134
Q

What is a schedule 5 drug? What is its abuse/dependence rating?

A

Lowest abuse/dependence potential

Example: diphenoxylate (anti-diarrhea medication)

135
Q

What does EC50 indicate? Efficacy or potency?

A

Potency

136
Q

What amino acid is norepinepherine derived from?

What is the rate limited enzyme in norepipherine’s production from this enzyme?

A

Tyrosine

Tyrosine hydroxylase

137
Q

Where are a2 receptors found?

A

Nerve endings, some smooth muscle

138
Q

What happens to GI motility/tone under the actions of the parasympathetic nervous system?

A

Increase

(sphincters relax)

139
Q

What is the benefit of a loading dose?

A

It gets patients into the therapeutic range quickly

140
Q

What is phase 1 metabolism?

A

Usually involves “activation” of the molecule so that it can be subsquently conjugated with a more polar group

More info via Google: Oxidation (via cytochrome P450), reduction and hydrolysis reactions

Convert a parent drug to a more polar, water-soluble, active metabolite by unmasking or inserting a polar functional group (-OH, -SH, -NH2)

141
Q

How do you calculate the maintenance rate of infusion?

A

Cl * [drug]ss

142
Q

What is the value of having molecules like estrogen be able to bind to a kinase receptor AND a nuclear receptor?

A

The body doesn’t need to make a bunch of different ligands for various receptors; we can utilize fewer genes to make molecules that then act on multiple receptors/pathways

143
Q

In what method of drug administration will side effects develop rapidly?

A

IV administration

144
Q

Define clearance and provide the equation

A

The amount of blood per unit of time that is completely cleared of the drug

Clearance (Cl) = kel * Vd

Or you can substitute in the half-life equation for:

Cl = (0.693 / t1/2) * Vd

145
Q

Describe the mechanism of action of a ligand binding to a tyrosine kinase receptor

A

A ligand will bind to the extracellular side of the TKR. This will cause dimerization and autophosphorylation on the intracellular side

Example: EGF rceptor

146
Q

How is steady state most accurately and rapidly achieved?

A

Via IV infusion

147
Q

What determines the rate and extent of drug absorption?

A

Drug factors & biological factors

148
Q

When does urinary manipulation of pH work?

A

It’s limited to alkalization (with IV sodium bicarb)

Only works for a few chemicals with the right pKa values (i.e. salicylates)

149
Q

What are the four receptor drug targets?

A
  1. Ion channels
  2. G-protein coupled receptors
  3. Kinase-linked receptors
  4. Receptors linked to gene transcription (nuclear receptors)
150
Q

What are the three mechanisms of catecholamine removal from the synapse?

A
  1. Reuptake (primary) and then storage or breakdown via MAO
  2. Diffusion into ciruclation
  3. Active transport and then breakdown via COMT or MAO
151
Q

Do we get a half life value for zero-order elimination?

A

Not usually

(and he didn’t tell us how to)

152
Q

What are the clinical uses of antimuscarinics?

A

Eye examinations (dilation), asthma (blocks cholinergic component of bronchoconstriction), MI (blocks vagal response to pain), insecticide poisoning (antidote for anticholinesterases), oral surgery (to inhibit salivation)

153
Q

What is the liver blood flow per hour? Combined kidney blood flow per hour?

A

Liver = 90 L/hr

Combined kidney = 70 L/hr

154
Q

Define toxicology

A

The study of the deleterious effects of chemical agents on living systems

155
Q

What are two examples of desensitization?

A
  1. Phosphorylation of the g-protein stops it from binding again/maintains the uncoupled state
  2. Arrestin sequesters the receptor from the cell surface (it’s physically removed!)
156
Q

What is the main reaction in phase 1?

A

Oxidation

157
Q

What is better: a higher or lower therapeutic index?

A

Higher

158
Q

What considerations should you keep in mind when prescribing to newborns and infants?

A

They have lower levels of plasma proteins, lower P450 enzymes, and lower GFR

159
Q

Can you achieve similar effects by using an agonist and an antagonist?

A

Yes

The Leuprolide example demonstrates this. Continous use of Leuprolide desensitizes the pathway (GnRH to LH to testosterone) & inhibits testosterone synthesis. An antagonist would do the same thing.

So you can achieve the same effect by using different methods of attack

160
Q

How long does it take a drug to act on ion channels?

A

Milliseconds

161
Q

Does the plateau principle tell us how long until the plateau is reached or what the plateau is? Or both?

A

Just how long until it’s reached

162
Q

Define pharmacodynamics

A

What the drug does to the body physiologically (mechanism, potency, efficacy, toxicity)

163
Q

What is physiological set point?

A

From body temperature to blood pressure to levels of certain nutrients, each physiological condition has a particular set point. A set point is the physiological value around which the normal range fluctuates. A normal range is the restricted set of values that is optimally healthful and stable.

164
Q

Most orally administered drugs have bioavailabilities in what range?

A

Greater than 10%

165
Q

What patient population has difficulty with phase 1 metabolism?

A

geriatric patients

  • drugs metabolized via phase I reactions have longer half-lives
  • geriatric patients metabolism drugs by phase II reactions
166
Q

What are our four sources of toxicology information?

A
  1. Human studies
  2. Animal studies
  3. In vitro studies
  4. COmputer modeling
167
Q

What three things have a dominant sympathetic tone?

A
  1. arterioles
  2. veins
  3. sweat glands (don’t forget: cholinergic!!)
168
Q

What are common phase I metabolism reactions?

A

Oxidation, epoxidaiton, o-dealkylation (and n-dealkylation), reduction, dehalogenation, and hydrolysis of esters and amides

169
Q

What is a schedule 4 drug? What is its abuse/dependence rating?

A

Drugs like benzodiazepines

Can prescribe 5 refills within 6 months

Low abuse/dependence potential

170
Q

What type of foods delay gastric emptying?

A

Fatty foods

171
Q

What is a schedule 3 drug? What is its abuse/dependence rating?

A

Drugs like ketamine, low-dose codeine

Can prescribe 5 refills within 6 months

Moderate abuse/dependence potential

172
Q

Define adrenergic

A

A nerve ending that releases norepinepherine as the primary transmitter; also, a synpase in which norepinepherine is the primary transmitter

173
Q

What is the Apparent Volume of Distribution (Vd) and how is it measured?

A

Vd = IV dose/Co

IV concentration (100%) versus the concentration you can immediately measure in the plasma after ingestion

Idea is the affinity of a drug for a tissue. More affinity = larger volume in tissue

174
Q

How are drugs metabolized via phase II excreted?

A

Renally excreted

175
Q

What are three examples of zero-order elimination?

A

Ethanol

Salicylate

Phenytoin

(ESP)

176
Q

After administering a chronic agonist, what happens to the receptors? Are they up-regulated or down-regulated?

A

Down-regulated

177
Q

Define volume of distribution (Vd) and give the equation

A

An apparent (or theoretical) volume that measures the drug distribution between plasma and the rest of the body

Vd = dose/plasma concentration

178
Q

What two organs have the highest blood flow rate? What two have the lowest?

A

Highest: lung and kidney

Lowest: Muscle, skin and adipose

179
Q

What is a schedule 2 drug? What is its abuse/dependence rating?

A

Drugs like morphine, high-dose codeine, amphetamines

No refills are allowed, written prescriptions only

High abuse/dependence potential

180
Q

Can various types of G-proteins couple to the same effector or is it a one G-protein/one effector system?

A

Different types of G-proteins can couple to the same effector

(And conversely, the same type of G-proteins can couple to different effectors)

181
Q

What enzyme terminates the action of ACh in the synaptic cleft?

A

Acetylcholinesterase

182
Q

What are the signs that a Muscarinic antagonist has been used?

A

“Hot as a hare (inhibition of sweating), red as a beet (vasodilation - CNS effect), dry as a bone (xerostomia/dry eyes), mad a wet hen (hallcuinations - CNS effects)”

Also pupil dilation, blurred vision due to loss of accommodation, and urinary retention

183
Q

If the drug concentration is much greater than Km, what will you expect of the line on the graph?

A

It will approach an asyptompe as the enzyme is saturated and there can be no increase in the rate of metabolism

184
Q

What does Emax indicate? Efficacy or potency?

A

Efficacy

185
Q

What is the equation for calulating the loading dose?

A

Vd x desired plasma concentration

186
Q

After adminstering a chronic antagonist what happens to receptor regulation? Is it up-regulated or down-regulated?

A

Up-regulated

187
Q

What is the rate-limiting step in catecholamine synthesis?

A

Tyrosine to L-DOPA (tyrosine hydroxylase)

188
Q

What can signal amplification do to potency?

A

Increase it (shift the curve to the left)

189
Q

What happens to GI motility/tone under the actions of the sympathetic nervous system?

A

Decreases

(sphincters constrict)

190
Q

What are three cellular responses that activation of the muscarinic receptors can accomplish?

A
  1. The activation of phospholipase C
  2. Opening or closing of ion channels
  3. The regulation of adenylyl cyclase

(remember, muscarinic receptors are G-proteins!)

191
Q

At what molecular weight can molecules passively diffuse through channels?

A

150-200 MW

192
Q

What is the most important tone and reflex controlled by the ANS?

A

Blood pressure

193
Q

Name a nicotinic ganglionic receptor agonist

A

Nicotine

Stimulates ganglionic nicotinic receptor, stimulation followed by depression, also a CNS stimulant

194
Q

What is “trapping” of a drug?

A

Excessive concentration of the ionized form of a drug in certain compartments

Example: cocaine can be readily detected forensically in gastric fluid due to the much higher concentration of the ionized form in the acidic stomach environment

195
Q

What do adrenergic drugs elicit in addition to their primary effects?

A

Reflex effects (like baroreceptors increasing or decreasing BP)

196
Q

What adrenergic receptor is responsible for increased renin secretion in the kidney?

A

B1

197
Q

What is therapeutic index?

A

TD50/ED50

TD50 = The toxic dose (dose at which 50% of individuals exhibit a toxic effect like vomitting)

ED50 = the dose at which 50% of individuals exhibit the therapeutic effect

198
Q

Define pharmacology

A

effect of small molecules or chemicals on biological systems

199
Q

Which two methods of enteral administration avoid first-pass metabolism?

A

Sublingual and rectal

200
Q

How can blood pressure be quickly regualated? Slowly?

A

Quickly: through ANS pathways

Slowly: through renal pathway/blood volume effect

201
Q

What type of patient population do we typically see in phase II/III trials? Why is that?

A

A homogenous patient population so you can limit the confounding variables. You can achieve this via inclusion/exclusion criteria (i.e. select those breast cancer patients who have the exact receptor your drug is targeting)

“Stack the cards in your favor”

202
Q

If your drug concentration is less than Km, what will you expect of the line on the graph on that area?

A

It will be a straight line when the drug concentration is less than Km

203
Q

What are four sources of individuality?

A
  1. Condition or State of Being
  2. Genetics
  3. Enviornment
  4. Drug Combinations (drug interactions)

“C’s get GEDs”

204
Q

How are controlled substances classified?

A

Into schedule groups: 1 - 5

205
Q

For a first-order process, the higher the drug concentration, the _______ the rate of elimination

A

higher

206
Q

If the rate of excretion of a drug is independent of the drug concentration then it is first or zero order?

A

Zero

207
Q

If excretion is directly proportional to the amount of the drug is this first order or zero order?

A

First

208
Q

_______ is the primary transmitter at the sympathetic postganglionic neuron effector cell synapses in most tissues

A

Norepinepherine

209
Q

What is the mechanism of action of sympatholytics?

A

They deplete the stores of catecholamines, block sympathetic transmission

(Block some step in the biosynthesis)

210
Q

What are the two methods of drug administration?

A
  1. Enteral
  2. Parenteral
211
Q

What is a modulatory transmitter in the ENS and kidney?

A

Dopamine

212
Q

What diseased-states can affect pharmacokinetics?

A

Impaired renal or hepatic function (ex: cirrhosis)

Circulatory insufficiency (ex: HF or shock)

Altered drug binding proteins (ex: too little or too much plasma proteins like albumin)

213
Q

How do ganglionic blockers affect the tone in a given organ?

A

They act as an antagonist of the dominant tone

214
Q

What is responsible for the differentiaton of a sympathetic progenitor cell into an adrenergic neuron?

A

NGF (neuron growth factor)

215
Q

How is prognosis of acetaminophen toxicity assessed?

A

The Rumack-Matthew nomogram

216
Q

What is assessed during phase II clinical testing? Who are the subjects in this phase?

A

Efficacy, safety, and pharmacokinetics (“is there a therapeutic benefit?”)

Subjects: Patients with the condition (< 300)

217
Q

How can adrenergic receptors be subclassified?

A
  1. Alpha (1 and 2)
  2. beta (1, 2, and 3)
218
Q

What two phase I transformations don’t involve cyp enzymes?

A

Reduction and hydrolysis

219
Q

Which is saturating: first order or zero order?

A

Zero

220
Q

What happens during phase IV clinical trials? What are the subjects?

A

Evaluate long-term effects of drugs over a lengthy period of time

No specific subjects, but heterogeneous patient population. Reporting is voluntary and usually done by physicians

Rare adverse events are observed & off-label uses are discovered

221
Q

What enzyme is responsible for the synthesis of Acetylcholine?

A

Choline-acetyl transferade (CAT) from Acetyl-CoA and choline

222
Q

What is responsible for the differentiaton of a sympathetic progenitor cell into an cholinergic neuron?

A

Ciliar neurotrophic factor

223
Q

What is efficacy?

A

The maximum response produced by a drug

It is proportional to the number of receptors occupied and is reversible

224
Q

When do basic drugs have a charge: low pH or high pH?

A

Low pH

They are neutral at higher pHs

225
Q

What are the six methods of parenteral administration?

A
  1. Intravenous
  2. Subcutaneous
  3. Intramuscular
  4. Topical
  5. Transdermal
  6. Inhalation
226
Q

Drugs eliminated by which type of elimination process will reach a plateau with repeated doses?

A

First-order

227
Q

What is an agonist?

A

A substance that binds and activates a receptor producing a response

228
Q

What two functional groups are readily conjugated in glucuronidation (the most common phase II rxn)?

A

Hydroxyl and carboxyl groups

229
Q

How long does it take a drug to act on GPCRs?

A

Seconds

230
Q

What is an antagonist?

A

A substance that produces no response when bound to a receptor

By binding to the receptor, the antagonist prevents the binding of an agonist and thus the agonist from activating the receptor

231
Q

Where are P-glycoproteins active?

A
  1. They reduce entry into the systemic circulation from the GI tract
  2. Reduce entry from the blood into the nervous system
  3. Reduce entry from the blood into malignant cells
232
Q

What amino acid do all endogenous catecholamines originate from?

A

Phenylalanine

233
Q

Are drugs equally distributed to all tissues and organs?

A

No. Blood flow/perfusion rates vary greatly between organs

234
Q

Where are B1receptors found?

A

Cardiac muscle, juxtaglomerular apparatus

235
Q

What clinical use dose nicotine as a nicotinic ganglionic receptor agonist have?

A

Cigarette smoking withdrawal (transdermal or oral), Chantix/Varenicline

236
Q

Define pharmacokinetics

A

What the body does to drugs (absorption, distribution, metabolism, and excretion)

237
Q

What is the most important absorptive mechanism?

A

Passive lipid diffusion

238
Q

What is an example of a cytokine receptor?

A

JAK-STAT signaling (JAK is bound intracellularly to the kinase-linked receptor)

Growth hormone

Leptin

239
Q

Which phase of drug development often compares a new therapy to the current standard of care?

A

Phase III

240
Q

What are the two types of antagonists?

A
  1. Competitive (reversible)
  2. Non-competitive (irreversible)
241
Q

Where are B3 receptors found?

A

Adipose

242
Q

What are the three classifications of drugs?

A
  1. OTC drugs: self administration
  2. Prescription drugs
  3. Orphan drugs: rare diseases
243
Q

What is responsible for transforming a neural crest cell progenitor into a sympathetic progenitor?

A

FGF2 (Fibroblast Growth Factor)

244
Q

What body compartment(s) have a pH generally lower than plasma pH?

A

Stomach, vaginal secretions, urine, milk, and prostatic secretions

245
Q

What drug is acetylated at different rates depending on a person’s genetic make up?

A

Isoniazid

246
Q

What are common phase II metabolism reactions?

A

Acetylation, glucuronidation, sulfation, glutathionation, glycination, and methylation

247
Q

What suffix is given to beta-blocks?

A

-lol

Examples: metoprolol, timolol, bisprolol

248
Q

How long does it take a drug to act on kinase-linked receptors

A

Minutes

249
Q

Phase I enzymes generally begin with what prefix?

A

cyp-

250
Q

What affects the extent of passive reabsorption of a drug in the distal tubules/collecting?

A

Drug ioniation

Ionizied, lipid-insoluble drugs are excreted in the urine

So ionized drugs can be “trapped” in this manner (ex: Aspirin)

251
Q

What do most molecular drugs target?

A

Receptors (45%), then enzymes (28%), and hormones & factors (11%)

252
Q

What is a catecholamine?

A

An adrenergic agonist

Substances which can produce a sympathomimetic response (mimics the sympathetic nervous system)

May be endogenous or synthetic

MS1 Fall (23 decks)

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