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Disease and Defense > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What are general reactions that are present in Phase I Metabolism?

A

Oxidation, Reduction, Hydrolysis

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2
Q

What are general reactions that are present in Phase II Metabolism?

A

Conjugations

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3
Q

What enzymes conduct metabolism for Phase I?

A

Mainly Cytochrome P450 (CYP450), but also Esterases-Amidases and Reductases

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4
Q

What enzymes conduct the metabolism for Phase II?

A

Transferases

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5
Q

Does Phase I or Phase II have higher saturability? and why?

A

Phase II has substantially higher saturability, because the cofactors for conjugation are bulky and are more energy expensive so more likely to run out

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6
Q

Is Phase I or Phase II more likely to be affected by inducers/inhibitors?

A

Phase I

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7
Q

What are the 5 main CYP that needs to be remembered and why?

A 
CYP2A4/5: most abundant metabolism
CYP2D6: codeine and antidepressants
CYP2C9: Warfarin
CYP2E1: makes acetaminophen toxic
CYP2C19: polymorphisms in Asian, poor metabolizers
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8
Q

In drug regulation, what does the federal government (FDA) control?

A

WHAT can get prescribed

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9
Q

In drug regulation, what does the state government control?

A

WHO can prescribe

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10
Q

In drug regulation, what can the local government do?

A

Can pass laws that control drug use in their jurisdictions

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11
Q

As a rule of thumb, what laws or regulation apply?

A

The strictest ones

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12
Q

What are the four categorizations of drugs?

A

Prescription drugs
Controlled substances
OTC drugs
Dietary supplements

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13
Q

What category of drugs are not evaluated for efficacy or safety by the FDA?

A

dietary supplements

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14
Q

What category of drugs must have a disclaimer to make a health claim on its advertisement?

A

dietary or herbal supplements

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15
Q

What kind of patients are needed in Phase 1 clinical trials?

A

Healthy volunteers

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16
Q

How many patients are needed in Phase 1 clinical trials?

A

20-100

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17
Q

What kind of patients are needed in Phase 2 clinical trials?

A

Select patients with the target disease

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18
Q

What is the goal of animal studies preceding the clinical trials?

A

It is to determine a safe dosage range for humans

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19
Q

What is the goal of Phase 1 clinical trials?

A

The goal is to determine the maximum tolerated dose and to see if the animal / human response differ

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20
Q

If the drug has high toxicity, what volunteers do you use in Phase 1?

A

Patients with the disease

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21
Q

How many patients are needed in Phase 2 clinical trials?

A

100-300

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22
Q

What is the goal of Phase 2 clinical trials?

A

The safety and efficacy are evaluated

  • Final dosing and regimen adjustments
  • May detect broader range of toxicities
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23
Q

What kind of patients are needed in phase 3 clinical trials?

A

Patients that are in clinical settings where the drug will be ultimately used

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24
Q

How many patients are needed in Phase 3 clinical trials?

A

1000-3000

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25
Q

During what phase do most drugs fail to get FDA approval?

A

Phase 3

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26
Q

What drugs can get accelerated or conditional approval from the FDA?

A

Drugs with the greatest potential benefit

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27
Q

What is the condition for the drugs that get accelerated or conditional approval from the FDA?

A

Clinical trials must be conducted that are definitive afterwards

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28
Q

What is something that the FDA cannot regulate?

A

How the drug is actually used by a physician or a dentist once it has been approved - “off-label” use permissible for non-approved indication

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29
Q

What does Phase 4 entail for the manufacturer of the drug?

A

Manufacturers are required to report to the FDA and adverse effects of their drug and to monitor the safety under the actual conditions of use of the drug

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30
Q

How do manufacturers increase the lifespan of the patent on the drug?

A

Most initial clinical trials omit special populations such as pregnant women and children, if the manufacturers do definitive studies for these omitted populations, they can expand the life of their patent

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31
Q

What is the role of the physician during Phase 4?

A

Physicians must play an active role in reporting adverse effects

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32
Q

What do generic products must have to be a drug for the brand name drug?

A

Generic products contain the same active ingredient, thus the pharmacologic effects are the same

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33
Q

What is the benefit of using generic drugs for the patient?

A

They are generally cheaper than the brand name drug

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34
Q

What does it mean be bioequivalent for a generic drug in comparison to the brand name drug?

A

Average variation in bioavailability < 4% among products tested and approved

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35
Q

Why are generic drugs less expensive than brand name drugs?

A

Brand name drugs have to go through the more extensive development and research when the generic drug does not

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36
Q

In general, switching from brand name to generic have no issues, but what are the 3 guidelines that physicians should follow with NOT switching?

A
  • Narrow therapeutic index (levothyroxine - antiseizure medications)
  • Non-linear (zero order) pharmacokinetics (phenytoin)
  • Poor bioavailability
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37
Q

What does a drug need to have to be pharmaceutically equivalent?

A
  • Same active ingredient(s)
  • Same dosage formulation (capsule, tablet, solution, etc.)
  • Same route of administration
  • Identical in strength or concentration
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38
Q

What does a drug have to be a pharmaceutical alternative, in which is not interchangeable?

A

Same therapeutic moiety BUT…

  • Different salts, esters, or complexes of that moiety
  • Different dosage forms (capsules vs tablets) or strengths (200 mg vs 250 mg)
  • Immediate-release products NOT equivalent to extended-release products of same active ingredient
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39
Q

What does bioequivalence mean?

A

Refers to rate and extent active ingredient is absorbed from formulation and becomes available (enters plasma)

Extent of absorption (bioavailability) is measured by the area under plasma concentration-time curve (AUC)

Rate of absorption is estimated by the maximum of peak drug concentration (Cp max)

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40
Q

In general, why does the FDA rarely pull herbal medication off the market?

A

FDA can remove any product with misleading or untruthful labeling BUT it is expensive and time-consuming and rarely completed

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41
Q

What is the purpose of the Schedule 1 drugs for controlled substances? Are doctors allowed to prescribe?

A

There is high abuse potential and there is no acceptable medical use currently, Not prescribed

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42
Q

What is the purpose of Schedule 2 drugs for controlled substances? Are doctors allowed to prescribe?

A

Accepted medical use, high abuse potential with severe dependence liability

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43
Q

What is the purpose of Schedule 3 drugs for controlled substances? Are doctors allowed to prescribe?

A

Accepted medical use, moderate abuse potential and dependence liability

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44
Q

What is the purpose of Schedule 4 drugs for controlled substances? Are doctors allowed to prescribe?

A

Accepted medical use, low potential for abuse leading to limited dependence

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45
Q

What is the purpose of Schedule 5 drugs for controlled substances? Are doctors allowed to prescribe?

A

Accepted medical use, abuse potential even less than drugs in schedule IV

Can be obtained without prescription (OTC) in some states (with restrictions)

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46
Q

In the state of Colorado, how should you treat Schedule 5 drugs?

A

Like you treat Schedule 3-4, with prescription

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47
Q

What are some suggestions for safe prescription writing?

A
  • write legibly
  • use metric system
  • use care with decimals: always lead, never trail
  • usually avoid abbreviations
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48
Q

In the metric system, what is 1 grain in grams?

A

64.8 grams

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49
Q

In the metric system, what is 1 ounce in grams?

A

28.35 grams

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50
Q

In household measurements, what is 1 kg (1000 grams) in pounds?

A

2.2 pounds

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51
Q

In the metric system, what is 1 teaspoon in mL?

A

5 mL

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52
Q

In the metric system, what is 1 tablespoon in mL?

A

15 mL

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53
Q

In the metric system, what is 1 fluid ounce in mL?

A

About 30 mL

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54
Q

What does the abbreviation ac stand for?

A

ac before meals

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55
Q

What does the abbreviation hs stand for?

A

hs at bedtime

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56
Q

What does the abbreviation pc stand for?

A

pc after meals

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57
Q

What does the abbreviation stat stand for?

A

stat immediately

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58
Q

What does the abbreviation prn stand for?

A

prn when needed

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59
Q

What does the abbreviation tid stand for?

A

tid 3 times a day

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60
Q

What does the abbreviation bid stand for?

A

bid 2 times a day

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61
Q

What does the abbreviation qam stand for?

A

qam every morning

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62
Q

What does the abbreviation IA stand for?

A

IA intra-arterial

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63
Q

What does the abbreviation po stand for?

A

po by mouth, orally

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64
Q

What does the abbreviation IM stand for?

A

IM intramuscular

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65
Q

What does the abbreviation pr stand for?

A

pr per rectum, rectally

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66
Q

What does the abbreviation IV stand for?

A

IV intravenous

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67
Q

What does the abbreviation sc or sq stand for?

A

sc-sq subcutaneous

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68
Q

What does the abbreviation IVPB stand for?

A

IVPB IV piggyback

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69
Q

What does the abbreviation vag stand for?

A

vag vaginally

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70
Q

What does the abbreviation a stand for?

A

a before

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71
Q

What does the abbreviation p stand for?

A

p after

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72
Q

What does the abbreviation c stand for?

A

c with

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73
Q

What does the abbreviation qs stand for?

A

qs sufficient quantity

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74
Q

What does the abbreviation gtt stand for?

A

gtt drop

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75
Q

What does the abbreviation s stand for?

A

s without

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76
Q

What does the abbreviation h stand for?

A

h hour

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77
Q

What does the abbreviation Sig stand for?

A

Sig label

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78
Q

What factors affect drug membrane passage?

A

molecular size, lipid solubility, degree of ionization, and concentration gradient

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79
Q

What is the main way drugs permeate cellular membrane?

A

passive diffusion of lipid soluble drug

80
Q

What does auc stand for?

A

area under the curve

81
Q

What type of route of administration always has 100% bioavailability?

A

intravenous

82
Q

What is the bioavailability for oral route of administration?

A

0 to 100%, depends on the drug

83
Q

What is the first pass effect?

A

The first pass effect is the result of elimination of a drug after administration and before it enters the systemic circulation

84
Q

Where does the first pass effect / metabolism usually occur?

A

Liver

85
Q

What two routes of administration goes through the GI system?

A

Oral and rectal

86
Q

How do you calculate the bioavailability?

A

The percent of the drug that makes it into the systemic circulation

87
Q

How can drug formulation affect rate of absorption?

A

Rate increased for liquid preparations or rapidly disintegrating tablets vs standard tablets

Rate decreased with enteric coated products or sustained release preparations vs standard tablets

88
Q

What is the ranking for rate of onset effect for parenteral routes?

A

IV = inhalational > IM > SC > oral for SOLUBLE FORMULATIONS

89
Q

What happens to the rate of onset effect for insoluble formulations?

A

Insoluble formulations (suspensions) are designed to slow rate of absorption and extend duration of action

90
Q

What are general factors that affect absorption?

A

Drug solubility in biologic fluids (aqueous environment)
- Drug formulation must have hydrophilicity to dissolve
- Drug molecule must be lipophilic to cross lipid membranes
Rate of dissolution
- Solid for oral dosage formulation (? brand vs generic)
- Suspended particles for parenteral formulation
Concentration of drug at site of administration (gradient)
Circulation at site of absorption (disease or exercise effects)
Area of absorbing surface (stomach vs intestine vs lungs)

91
Q

What are the two enteral routes of administration? Does it provide systemic or local effects?

A

Oral and rectal, systemic

92
Q

What are parenteral routes of administration that provide systemic effects?

A

Sublingual, buccal, IV, IM, inhalational (volatile gases), transdermal

93
Q

What are routes of administration that provide local effects?

A

Aural, nasal, throat, vaginal, ocular/conjunctiva, inhalational (particles), and dermal

94
Q

From the oral route, where does the drug mostly absorb and why?

A

Small intestine due to large surface area

95
Q

How does food affect drug absorption in the GI tract?

A

Food SLOWS absorption

96
Q

Besides slow absorption of the drug, what are two other reasons why enteric-coat formulations are used?

A
  • protects stomach from irritation by ulcerogenic drugs

- protects drug from the low pH of the stomach

97
Q

What is a benefit and drawback of using IV route?

A
  • It by-passes absorption barriers, but it also increases infection potential
98
Q

What are two drawbacks of using rectal route?

A
  • The patient acceptance is very low
  • the bioavailability is highly variable (but higher than oral)
  • used for patients vomiting or gastic problems
99
Q

What is the benefit and drawback of using the sublingual or buccal route?

A
  • high bioavailability for lipid soluble drugs but relatively potent
  • smaller surface area for absorption than GI
  • Onset within minutes
100
Q

What is the benefit and drawback of using intramuscular route?

A
  • aqueous solution absorbs rapidly
  • Depot forms (oil or suspensions) in other vehicles exhibit slower, more sustained absorption (hrs-days)
  • bioavailability near 100%
101
Q

What is the benefit and drawback of using subcutaneous route?

A
  • slower, more constant rate of absorption

- Absorption altered by varying particle size, pH, protein complexation, vasoconstrictor, pellet implantation

102
Q

What is the benefit and drawback of using transdermal route?

A
  • avoids first pass metabolism, prevents hepatic ADRs (adverse drug reaction)
  • prolongs drug levels
103
Q

What is the volume of distribution (Vd)? How is it calculated?

A

This is the extent of distribution and is an apparent value measured in L/kg

Vd = amount of drug in the body / concentration of drug in the plasma = dose / Cp0 (initial Cp)

104
Q

What does a high volume of distribution mean? (>50 L)

A

Drugs are highly lipid soluble and sequested in tissues

105
Q

What does a low volume of distribution mean? (1-5 L )

A

Drugs are highly bound to plasma proteins in the systemic circulation

106
Q

How does volume of distribution vary?

A

It varies from person to person, calculated from weight

107
Q

How do you calculate the loading dose from the volume of distribution?

A

LD = desired Cp x Vd

108
Q

What are factors that affect distribution of the drug in the body?

A
  • Special Anatomic Considerations: Sites requiring drugs to pass through cells, not between
  • pH of Biologic Fluids in Various Body Compartments: Determines % of drug in non-ionized (lipid-soluble) form Via use of Henderson-Hasselbach equation
  • Drug Binding to Plasma Proteins: Only free drug is diffusible, bound drug cannot leave plasma compartment
  • Lipid Solubility of Non-Ionized Form of Drug: Intrinsic physiochemical property of drug - determinant of ability to cross membranes via passive lipid diffusion
109
Q

What are the three anatomical barriers to distribution?

A

Tissues with tight junctions:

  • GI mucosa:Negligible absorption
  • Blood brain barrier - placenta: Limited distribution
  • Renal tubules: Reduced reabsorption back into blood and increased urinary excretion
110
Q

How does the pH of the tissue affect distribution?

A

Nonionized forms are more readily absorbed

Ionized forms do not cross lipid membranes -> “trapped”

111
Q

What is the Henderson-Hasselbach’s equation?

A

pH = pKa + log (non-protonated form / protonated form)

112
Q

What are the 3 clinical significances of Ion trapping?

A
  • concentration of weak bases in break milk (mildly acidic)
  • concentration of weak bases in stomach
  • alteration of the urine pH can change what gets trapped
113
Q

What is the significance of protein-binding displacement interactions?

A

Administration of 2nd drug displaces 1st drug from binding sites increasing free levels of 1st drug

Unlikely of clinical signficance unless:

  • Displaced drug has narrow therapeutic index
  • Displacing drug is started in high doses
  • Vd of the displaced drug is small
  • Response to drug occurs more rapidly than redistribution
114
Q

What is the general characteristic of drug metabolism?

A

Lipid soluble compounds are converted to more water-soluble compounds to be readily excreted

115
Q

What are other things that can happen of drug metabolism but rarely occur?

A
  • active drugs converted to more active drugs
  • inactive drugs (pro-drugs) converted to active drugs (designed drug)
  • active drugs converted to toxic metabolite
116
Q

What are the two co-factors in Phase 1 metabolism?

A

NADPH and O2

117
Q

What are the clinical relevance of genetic polymorphisms?

A
  • Increased antipsychotic drug toxicity in patients with CYP2D6 activity PMs** - inactivating enzyme
  • Decreased efficacy of PPIs for peptic ulcers in CYP2C19 PMs* - activating enzyme
  • Insufficient analgesia with codeine in CYP2D6 PMs* - activating enzyme (to metabolite morphine)
  • Codeine intoxication in CYP2D6 UMs* - activating enzyme (increased metabolism to morphine)
  • Nonresponse to antidepressants reported in CYP2D6 UMs** - inactivating enzyme
118
Q

What do the abbreviations UM and PM stand for in drug metabolism?

A

UM: ultra-rapid metabolism
PM: poor metabolism

119
Q

What are 3 kinds of chemical reactions that occur in Phase 1 drug metabolism that are CYP450 dependent?

A

Aromatic hydroxylations
Aliphatic hydroxylations
Oxidative Dealkylation (O-, N-, S-)

120
Q

What are Phase 1 oxidations that are CYP450 INDEPENDENT?

A

Amine oxidases: Monoamine oxidase, located in outer membrane of mitochondria (Important enzyme in neurotransmitter metabolism)

Dehydrogenations: Alcohol dehydrogenase, hepatic soluble fraction, different types AND Aldehyde dehydrogenase

121
Q

What are Phase 1 reactions that are less common (i.e. hydrolases and reductases)?

A

Reductases:

  • Azo reduction (sulfonamides)
  • Nitro reduction (chloramphenicol)  can produce toxic intermediates
  • Carbonyl reduction (methadone)

Esterases (commonly used for pro-drugs) : in plasma, liver

Amidases: in liver, gut

122
Q

In Phase 2 conjugations, what kind of molecule does the drug conjugate with?

A

Drug or drug metabolite is coupled (conjugated) to highly energetic endogenous reactant provided by a coenzyme

Glucuronidation, N-Acetylation, Glutathione Conjugation, Sulfate Conjugation

123
Q

Does enzyme induction occur mostly in Phase 1 or Phase 2 drug metabolism? What class of enzymes specifically?

A

Mainly Phase 1`, P450 enzymes

124
Q

How long does it take generally for enzyme inducers to see onset of effect?

A

48-72 hours

125
Q

Does enzyme inhibition occur mostly in Phase 1 or Phase 2 drug metabolism?

A

Phase 1

126
Q

What class of enzymes have the most metabolic drug-drug interactions? By what route is it most obvious?

A

CYP450 enzymes, oral route

127
Q

When do you see the maximal effects of enzyme induction?

A

Usually seen in 7-10 days, it also requires a similar time to dissipate

128
Q

What are some clinical implications of drug interactions?

A
  • Reduced therapeutic effect if inactivation reaction is accelerated
  • Increased toxicity if activation reaction is accelerated
  • Increased toxicity if toxic metabolite is produced
129
Q

What are a few clinically relevant inducers of drug metabolism?

A 
Phenobarbital [1A2, 2C9, 2C19, 3A4]
Phenytoin [2C9, 2C19, 3A4]
Carbamazepine [2C9, 2C19, 3A4]
Rifampin [1A2, 2C9, 2C18, 3A4]	
Ethanol [2E1]	
St. John’s Wort [3A4]
Tobacco smoke (not nicotine) [1A2]
130
Q

Whar are a few clinically relevant inhibitors of drug metabolism?

A 
Cimetidine [2D6, 3A4, 1A2]
Erythromycin / Clarithromycin [3A4]
Azole antifungals [3A4]
Fluoxetine (other SSRIs) [2D6,3A4]
Grapefruit juice [3A4]
HIV protease inhibitors [3A4]
Omeprazole [2C19]
131
Q

What are biological factors that can influence drug metabolism?

A
  • diet and nuitritional factors
  • sex differences
  • age: perinatal, neonatal, and old age (all lower)
  • genetic factors
  • diseased states: hepatic diseases, non-hepatic diseases, alcohol consumption, conditions affecting blood flow
132
Q

What is the signficance of p-glycoproteins in drug elimination?

A

P-glycoprotein transporters can have major roles in the movement of drugs throughout the body

Present in renal brush border membranes, bile canaliculi, astrocyte foot processes in brain microvessels, GI tract

Act primarily to move drugs out of the cell - effect varies with location

133
Q

What is passive reabsorption dependent on in the renal system?

A

pH dependent

134
Q

Explain the enterohepatic recycling of drugs.

A

Drugs can get absorbed into the bile through the bile duct, get stored in the gallbladder, excreted to the liver through bile and put back into the intestines to be absorbed into circulation

135
Q

Are majority of drugs eliminated through first or zero order kinetics?

A

First order kinetics

136
Q

What is the fundamental equation for first order elimination?

A

ln C = - ke t + ln Cp0

137
Q

What is the fundamental characteristic of first order elimination?

A

Constant Fraction of drug is eliminated per time and this is independent of the total amount of drug present

138
Q

What can you estimate when you know the half-life of a drug?

A

Time it takes a drug to be eliminated (4-5 half-lives)

Time it takes to reach steady state when drugs are administered continuously (4-5 half-lives)

Degree of fluctuations in plasma levels between doses (number of half-lives in dosing interval  τ / t½)

139
Q

What equation do you use to calculate Ke from t1/2?

A

t1/2 = 0.693 / ke

140
Q

What is the theory behind clearance?

A

Volume of plasma (Vd) which is completely cleared of drug in a given period of time by combined tissue processes such as kidney (excretion) and liver (drug metabolism) and others

Clearance is BEST THOUGHT OF: Proportionality constant that makes plasma concentration at steady state equal to the rate of administration

141
Q

What is the equation used to calculate clearance?

A

CL = Vd x ke OR CL = (Maintenance Dose / tau) / Cp (ss)

142
Q

Hepatic clearance varies with

A

Blood flow to the liver

  • For low extraction drug (metabolism not efficient), changes do not significantly influence clearance
  • For high extraction drug (metabolism very efficient), changes will have a major influence on clearance

Protein-drug binding - only free drug can be metabolized

Intrinsic hepatic metabolic activity

Subject to co-administration of inducers and inhibitors that can alter activity

Changes in renal function will alter clearance of renal eliminated drugs

143
Q

How do you calculate Ke from the graph?

A

It is the slope of the beta phase

144
Q

What happens when you increase the maintenance dose?

A

Increasing maintenance dose will not reach steady state sooner, but will cause Cpss to be higher when it is reached

145
Q

What is the equation for fold-fluctuation?

A

Fold - Fluctuation = 2ⁿ

146
Q

Increasing the dosing interval will increase or decrease the fluctuation?

A

INCREASE

147
Q

What is the bottom line in the effects of dosing interval on CPss fluctuation?

A

More half-lives (not more hours) in a dosage interval means greater fluctuation

Amount of fluctuation in Cp tolerated for any drug is determined by its Therapeutic Index

148
Q

What is the idea behind zero order kinetics?

A

Amount of drug eliminated per unit time is constant

149
Q

What are parameters that affect the drug-receptor concept?

A

Size - shape - electrical charge determine binding affinity to a particular receptor relative to other binding sites

150
Q

What are agonist drugs?

A

bind and regulate receptor function in same manner as endogenous ligands

151
Q

What are antagonist drugs?

A

bind to receptors but are unable to generate the characteristic response

Antagonist effect results from preventing binding of agonist to receptor thus blocking biologic actions

NOTE: A pharmacologic antagonist has NO effect in the absence of the agonist for receptor

152
Q

What does the drug receptor theory assumes?

A

Interaction follows simple mass action relationships

Binding is reversible

Response proportional to receptors [R] occupied by drug [D]

RD is proportional to RESPONSE

153
Q

What type of graph do you get in a dose response curve?

A

Hyperbola graph due to the saturation of receptors

154
Q

What is the advantages of using a log dose response curve?

A

Plot wide range of doses  easy comparison of different drugs

Straight line over therapeutic range of doses

155
Q

What is potency?

A

concentration (EC50) or dose (ED50) required to produce 50% of the individual drug’s Emax

156
Q

What is efficacy?

A

Indicates relationship between receptor binding and ability to initiate response at molecular, cellular, tissue or system level

157
Q

What is more important clinically, potency or efficacy?

A

Efficacy

158
Q

What is another word used for efficacy?

A

Power

159
Q

What is a partial agonist?

A

Occupy same receptor as the full agonist but produce < maximum response

160
Q

How is efficacy used in the clinical setting?

A

In therapeutics, efficacy refers to the extent a given clinical effect can be achieved in an intact patient, rather than an action at a specific target

  • can compare drugs that have different targets but provide similar therapeutic effects
161
Q

How is potency used in the clinical setting?

A

Dosage

162
Q

What is by definition a noncompetitive antagonist?

A

Antagonism by all noncompetitive antagonists cannot be surmounted by increasing agonist concentration

163
Q

What is a physiologic antagonist?

A

Activates or blocks a distinct receptor that mediates a physiologic response opposite to agonist

164
Q

What is a chemical antagonist?

A

Does NOT involve receptor binding

165
Q

What is the difference between graded and quantal dosage response curves?

A

Quantal is cumulative and all or nothing effect, whereas the graded is increasing the dose for one individual

166
Q

Do you use quantal or graded for dosing in the general population and with the FDA?

A

Quantal

167
Q

How do you calculate the therapeutic index?

A

LD50 / ED50

168
Q

How do you calculate the standard safety margin (SSM)?

A

( [LD1/ED99] - 1 ) * 100

By what the percentage to raise before you get to the LD1 and can get the therapeutic effects and not get to toxicity

169
Q

When do you use the standard safety margin?

A

Narrow therapeutic index drugs and people that are in the extremes of the response curves

170
Q

What are extension effects? And where is it on the graph?

A

Arise from therapeutic effect -> dose-related and predictable (mechanism-based)

Near the upper limit of the therapeutic window

171
Q

What are side effects? And where is it on the graph?

A

Unrelated to the therapeutic goal -> predictable, dose-dependent

Within the therapeutic window, affects a small subset of the population you are serving

172
Q

What are toxic reactions?

A

Toxic reactions - at doses outside therapeutic range

173
Q

What are idiosyncratic reactions? Are they bad?

A

Genetically determined abnormal response to drug -> unpredictable, Altered drug metabolism or unusual receptor affinity

VERY BAD

174
Q

What are allergic reactions? Are they bad?

A

Immunologic -> unpredictable, dose independent but very rare

VERY BAD

175
Q

What can pharmacokinetic drug interactions result in?

A

Elevated drug concentrations -> leading to toxicity

OR

Decreases in plasma concentrations -> subtherapeutic levels

176
Q

What can pharmacodynamic drug interactions result in?

A

Pharmacologic enhancement or antagonism of a drug’s action via same target as drug

OR

Physiologic enhancement or antagonism of a drug’s action via distinct effector system

Without changes in plasma drug concentration

177
Q

What patient category are at high risk for drug interactions?

A

The elderly, because they take on average between 6-8 drugs and their elimination pathways are impaired

178
Q

How does blood flow affect the distribution in pharmacokinetic interactions?

A

Drug-induced decrease in cardiac output -> decrease hepatic blood flow -> decrease hepatic clearance -> INCREASE plasma levels

179
Q

Where do most excretion interactions occur?

A

Kidneys

180
Q

What do the excretion interactions include?

A

Change in glomerular filtration

  • Decreased by nephrotoxic drugs (aminoglycosides) -> increase Cp
  • Increased by displacement from plasma proteins -> decrease Cp

Change in tubular secretion

  • Decreased by competition for active transport (penicillins)
  • > increase Cp
181
Q

How does a physician want to circumvent or prevent drug interactions?

A
  • minimize amount of drugs
  • be vigilant and cautious of using narrow therapeutic index drugs
  • consider DDI (drug-drug interactions) if clinical course unexpectedly goes deleterious
182
Q

What is the most important determinant in poisoning?

A

Single most important determinant of poisoning outcomes is provision of good supportive care

183
Q

What is a good predictor of which drugs can be removed by dialysis or exchange transfusion?

A

Best if Vd low as most of drug will be in plasma

184
Q

What are general treatment strategies for poisoning?

A

Prevent- decrease toxin absorption -> DEcrease RATE IN

Inhibition of toxication (prevent conversion to toxic species)

Enhancement of metabolism (detoxication of toxic species)

Increase elimination of toxin -> INcrease RATE OUT

185
Q

What is emesis?

A

Emesis: Empties stomach contents rapidly

186
Q

What do you avoid using in emesis?

A

Ipecac: no longer used at home
Apomorphine: avoid giving to children

187
Q

What are contraindications for emesis?

A

Patient comatose (lack of gag reflex  risk of aspiration)

Ingestion of corrosive poisons (i.e., strong acids or alkalis)

Ingestion of CNS stimulant such as strychnine (risk of seizures)

Ingestion of petroleum distillate (risk of pneumonitis)

Pregnancy Category C: (weigh benefit vs risk, unknown harm)

188
Q

How do you prevent absorption of a poison?

A

gastic lavage

189
Q

What percentage does emesis and lavage remove of oral poisons?

A

about only 30%

190
Q

When is activated charcoal most effective?

A

Effective without prior gastric emptying

191
Q

What are common osmotic carthartics utilized?

A

Magnesium citrate or sulfate: Avoid in renal disease or poisonings with nephrotoxic agents

Sodium sulfate: Avoid use of Na+-containing cathartics in CHF or hypertension (systemic Na+ absorption  edema)

Polyethylene glycol (Golytely): Whole bowel irrigation

  • Promotes elimination of entire contents of intestines
  • Poisoning with sustained-released drugs, metal ions, drug packets
192
Q

What two substances have minimal toxicity until metabolized? What are their toxic metabolites?

A
  1. Methanol - formic acid, causes blindness and retinal damage
  2. Ethylene glycol - oxalic acid, causes acute renal failure
193
Q

What are two treatments that can be used for methanol or ethylene glycol poisoning and what is the mechanism?

A

Ethanol (a substrate and competitive inhibitor)
Fomepizole [Antizol®] (a specific inhibitor)

  • the rate limiting step is alcohol dehydrogenase so if you competitive inhibit this enzyme, you can slow down the toxicity and decrease the amount of metabolites from forming
194
Q

What does toxic doses of acetominophen cause (mechanism)?

A

Saturate the phase II metabolic pathways

Increased formation of the phase I hepatotoxic metabolite

Depletion of glutathione stores available for detoxication

Increased likelihood of hepatocellular injury

195
Q

What are ways to enhance elimination for poison control?

A
  • forced diuresis

- block passive reabsorption

196
Q

What is a treatment for free metal ions?

A

Chelating agents

Disease and Defense (3 decks)

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