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Winter P1 > Pharm 737 Exam 4 > Flashcards

Pharm 737 Exam 4 Flashcards

1
Q

What is there that is not poison?

A

All substances are poisons; there is none that is not, the right DOSE differentiates a poison from remedy.

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2
Q

What is the Threshold of Toxicological Concern? (TTC)

A

Concept used when there is no chemical-specific data, we sassume there is no appreciable risk to human health based on chemical structure and level of exposure

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3
Q

Role of US FDA in Toxicity

A

Regulates the development of new drugs and their marketing

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4
Q

What is required for an Investigational New drug Application?

A

Pharmacology and Toxicology studies (pre-clinical testing) in animals to evaluate effectivess and safety.

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5
Q

Why is Descriptive testing in animals necessary? What are the components?

A

Assumption is effects apply to human toxicity
High dose is necessary to discover possible hazards
0.01% incidence = 25,000/250million (unacceptability high)
to test risk at low dose, large doses in small populations must be done.
Animal testing selects doses for clinical trials

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6
Q

Describe phases of Toxicology, Safety testing and clinical trials

A

Pre-clinical tests in animals (10-20 chems, 2-3yrs)
Phase 1 in healthy humans for safety (5-10 chems, 1yr)
Phase 2 in diseased for safety/efficacy (2-5 chems, 1-2yrs)
Phase 3 in large groups (2 chems, 2 yrs)
Phase 4 Post marketing surveillance

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7
Q

Describe Acute Exposure

A

Single Event/dose - monitored for 14 days; 3 doses

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8
Q

Describe Sub Acute Exposure

A

14 days - 14 doses; repeat dose

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9
Q

Describe 90 day Chronic Exposure

A

Repeated dose for 90 days, will be set up with 3 doses, animals monitored for signs of sickness, organs and tissue evaluated by pathologist.

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10
Q

Define Long Term Toxicity/Carcinogenicity

A

Evaluated at the same time, (small exposures over prolonged time/lifetime exposure >2yrs)

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11
Q

Describe Reproductive Toxicity

A

Decreased Fertility, study of adverse effects on male/female reproductive system

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12
Q

What is Teratogenicity?

A

Ability to cause congenital malformations, usually done in rats and rabbits during pregnancy

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13
Q

What happened with the Thalidomide Disaster?

A

1950-1960s, was prescribed for morning sickness as an anti-emetic and induced birth defects in 46 countries

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14
Q

What is LD50

A

Median Lethal Dose, Lethal dose for 50% of population

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15
Q

What is TD50

A

Median Toxic Dose, much preferred over LD50

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16
Q

What is ED50

A

Median Effective dose

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17
Q

What is the Therapeutic Index

A

TD50/ED50, Higher numbers = Not safe drug

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18
Q

What is the Certain Safety Factor (CSF)

A

TD1/ED99

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19
Q

Toxicology Hazard

A

An inherent property, the potential of something to cause harm

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20
Q

Toxicology Risk

A

Probability of a particular adverse outcome (e.g. Lifetime risk of cancer)

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21
Q

Risk vs Safety standards

A

Made by individuals or government acting on behalf of many people that are potentially subject to a given risk

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22
Q

Risk Triangle

A

Risk Management; Risk Assessment; Risk Communication

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23
Q

Risk Checkpoints

A

Used to identify and prevent adverse drug events

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24
Q

Drug-Receptor Interactions determine:

A

How patients respond to a given dose, Variations in Responsiveness

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25
Q

Pharmacokinetic considerations to Toxicology

A 
Body weight
Age
Sex
Pregnancy and Lactation
Health and Disease

(problematic if narrow TI)

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26
Q

Pharmacodynamic Considerations to Toxicology

A 
Pharmacological response changes to same concentrations of drug.
Sex-related differences
Circadian rhythms
Drug Tolerance
Drug Resistance
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27
Q

What is an Indiosyncrasy

A

An unexpected response or unexpected sensitivity toa drug that is frequently genetically based. The response is outside a normal distribution for the population.

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28
Q

Allergic Response causes

A

Adverse response to a drug as a result from a previous exposure to the same drug

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29
Q

Cross Sensitivity Reaction

A

Allergic response to a structually similar drug w/o prior exposure.

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30
Q

Describe Sensitization

A

Hypersensitivity, Immediate or delayed response

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31
Q

Describe Anaphylaxis

A

Immediate or serious allergic Response

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32
Q

Describe Tolerance

A

A change in the way the body adapts to the presence of drug over time.

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33
Q

Describe Classic Tolerance

A

Progressively decreased responseivess resulting in the need for a larger dose to elicit the same response (caffeine)

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34
Q

Pharmacokinetic (indirect) Tolerance

A

Changes at a site separate from the agonist site of action result in a decreased drug response

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35
Q

Pharmacodynamic (direct) tolerance

A

Changes due to a change at the receptor or the ability of the cell to response

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36
Q

Resistance

A

Commonly used term w/ respect to anti-tumor and anti-microbial drugs:

Insensitivity or decreased sensitivity of cells to drugs

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37
Q

Intrinsic resistance

A

Organism is inherently insensitive and responds poorly (e.g. bacterial pathogens to antibiotics)

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38
Q

Acquired resistance

A

Organism initially responds, but subsequently does not

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39
Q

Cross Resistance Multiple Drug Resistance

A

Superbugs, resistance to a wide variety of drug classes

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40
Q

Neoplastic Resistance

A

Cancer cells becoming resistant to treatment by some drug types

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41
Q

Poison Prevention Strategies

A

Reduce Manufacture or Sale
Decrease amount of poison in consumer product (limit number of tablets in a bottle)
Prevent Access (child-resistant packaging)
Changing formulation (e.g. remove ethanol from mouthwash)

42
Q

Organ Toxicity associated w/ route of exposure

A

Skin
External Eye
Respiratory Tract
GI tract

43
Q

Organ toxicity associated w/ metabolism and Excretion

A

Liver

Kidneys

44
Q

Organ toxicity w/ selective vulnerability

A

Nervous System, Cardiovascular System, Immune system, Ear (ototoxicity)

45
Q

Hepatic Toxicity, Factors for Liver Vulnerability

A

Organization:
Hepatocytes are actively metabolizing
Blood flow from hepatic artey to central vein and from the hepatic portal vein to central vein
Solutes from sinusoids bathe the hepatocytes
Products of heaptocytic activity exit hepatocytes via blodo stream, or bile duct

46
Q

Portal Triad

A

consists of Bile duct, portal vein and hepatic artery

47
Q

Functional Lobule (inside to outside)

A

Further you move away from central vein, the less damage can be done (unless toxic before metabolized).

48
Q

Acetaminophen Toxicity

A

4000mg daily limit, causes hepatic necrosis in overdose, can administer N-Acetylcysteine as an antidote should be administered in 8 hrs

49
Q

Acetaminophen Metabolism

A

APAP metabolized into Glucuronide (safe) Sulfate Moiety (safe) and NAPQI (toxic)

NAPQI can be administered with N-Acetyl-Cysteine which biotransforms into Cysteine and Mercapturic Acid conjugates (Non Toxic)

50
Q

Stages Acetaminophen Toxicity Stages

A
  1. Day 1, GI distress
  2. Days 1-3, Hepatic Toxicity Develops
  3. Days 3-5 worsening hepatic necrosis, hepatic Encephalopathy (drowsiness-coma)
  4. Days 5-15 recover is treatment is effective.
51
Q

Acetaminophen Toxicity Risk Factors

A

Alcohol Consumption

Use of Drugs that Induce P450

52
Q

Liver Enzymes

A

ALT (ALanine aminoTransferase)
AST (ASpartate aminoTransferase)
ALP (ALkline Phosphatase)
GGT (Gamma-Glutamyl Transpeptidase)

53
Q

Liver Protein Panel

A

Albumin - low in individuals w/ liver disease
Globulin - low in individuals w/ liver disease
Bilirubin - Leak Indicative of damage, (Jaundice)

54
Q

PT indirect measure

A

Prolonged clotting time (liver is a source of clotting factors)

55
Q

Renal Toxicity, Kidney factors for vulnerability

A

Major function is to eliminate waste
Kidneys receive 25% of cardiac output
Cortex (90% blood supply) vs Medulla (nephron home, functional unit )

56
Q

Injury to Glomerulus

A

Relatively Rare

Leads to altered permeability and Proteinuria

57
Q

Injury to proximal tubule

A

Most common site of nephro-toxicity
Degeneration, inflammation and repair reactions
Degenerative changes leading to necrosis

58
Q

Injury to Distal Tubular Nephropathy

A

Relatively rare
changes in water regulation, electrolytes and acid-base balance lead to a concentrated, slightly acidic urine
Most frequent effects are crystalluria and renal papillary necrosis

59
Q

Chronic Kidney Injury (renal papillary necrosis)

A

Major cause of renal failure in humans, cell death, scar tissue
Associated with chronic analgesic abuse

60
Q

Acute or Chronic Interstitial Nephritis

A

Associated w/ allergic reaction to many drugs or analgesic abuse
Swelling of tubules (inflammation and Edema)
Decreased Urinary output
Fever, Rash, Vomitting

61
Q

Therapeutic Agents that induce Nephrotoxicity

A 
Aminoglycoside Bacteriacidal Antiobiotics (I.V.)
Amphotericin B (prototypical antifungal)
Calcineurin Inhibitors (Cyclosporine/Tacrolimus)
62
Q

Describe Acute Renal Impairment/Failure

A

Vasoconstriction of the vasculature –> decreased renal blood flow, decreased glomular filtration rate, decreased production of urine (reversible upon withdrawal)

63
Q

Describe Chronic Kidney Disease and its pathogenesis

A

Can be silent, compromised function detected b y blood and urine tests
Gradual loss of kidney function/build up of endogenous toxins produces significant complications
(e.g. analgesic nephropathy)

64
Q

What are the options for End stage renal disease and Kidney Failure

A

Dialysis

Transplant

65
Q

Testing methods for chronic kidney disease

A

GFR
BP
Protein in Urine
Creatinine in Blood

66
Q

Glomerular filtration rate (GFR)

A

Sensitive and accurate, blood creatinine levels as an indirect measure of function

67
Q

Blood Pressure test for CKD

A

High blood pressure can be damaging to the glomerulus

68
Q

Protein In Urine test for CKD

A

Albumin in urine can indicate proteinuria

69
Q

Creatinine in blood for CKD

A

Health kidneys filter creatinine, so a decreased kidney function would see higher creatinine levels

70
Q

Reye’s Syndrome

A

Rare syndrome associated w/ aspirin consumption in children w/ viral disease.
Aspirin containing products not recommended for those under 18
Target Organs = Liver
Symptoms: Flu, Vomitting, Lethargy, confusion, coma, seizures

71
Q

Indications of an allergic reaction

A

Hives, Difficulty Breathing, swelling of face, lips, tongue or throat, itchy

72
Q

Ototoxicity Signs/Symptoms (cause, Cure)

A

Ringing in the ears (tinnitus), hearing loss, inability to understand speech, loss of balance, dizziness, spatial disorientation,
(Drug induced or environmental, No cure)

73
Q

What is the most common adverse effect associated w/ penicillins?

A

Hypersensitivity Reaction

74
Q

Symptoms of Pencillin hypersensitivity

A

Maculopapular skin rash; fever; bronchospasm, dermatitis, angioedema (swelling of lips, tongue, face, periorbital tissue) asthmatic breathing, acute anaphylactic reaction (hypotension - rapid heart rate and rapid death)

75
Q

Why is Cardiovascular Toxicity an issue and what does toxicity depend on?

A

All drugs or xenobiotics entering the bloodstream will eventually be transported to the heart.
Toxic interactions depend on:
1. Concentration
2. Duration of Exposure

76
Q

Actions of Cardiovascular Toxicants include:

A

Direct Structural Damage
Functional Alteration
Indirect Action

77
Q

Examples of Direct structural damage in cardiovascular toxicants

A

Inflamation, degeneration, necrosis

It can be dificult to distinguish from “naturally occurring” CV disease.

78
Q

Functional Alteration of Cardiovascular Toxicants examples

A

Disruptions in Rhythm, Rate, contraction which lead to lethal arrhythmia

79
Q

Examples of Indirect Actions of Cardiovascular Toxicants

A

Secondary changes that occur due to change in another organ system (ANS, CNS, Endocrine)

80
Q

Function of Coronary Blood vessels

A

Supply blood to the heart muscle

partial occlusion by atheromatous deposits found in at least 75% of adult population in developed countries

81
Q

Angina Pectoris

A

(Ischemic Chest pain) Oxygen supply to myocardium is insufficient for its needs

82
Q

Myocardial Infarction

A

Coronary vessel becomes blocked by thrombosis

83
Q

Stable Angina

A

Most common, predictable pain on exertion, helped by rest of angina mediction (e.g. Nitroglycerin)

84
Q

Unstable Angina

A

No pattern, not helped by rest of medication, dangeous, emergency situation, heart attack

85
Q

Variant Angina

A

Rare, spasm rather than atherosclerosis, occurs in younger individuals, pain at rest.

86
Q

Factors that make heart vulnerable to toxicants

A

Excitable membrane (Sarcolemma)
Coupled to an intracellular contraction system.
Requires a constant supply of oxygen and nutrients.
Regulated by:
- ANS
- Epinephrine and Norepinephrine synthesized in the adrenal medulla

87
Q

What are the effects of Norepinephrine at Adrenergic Receptors

A

Increases Depolarization –> Increased Impulse transmission –> Increased heart rate and force of contraction

88
Q

What are the effects of Acetylcholine at Muscarinic Receptors?

A

Decreases rate of depolarization –> Decreased heart rate and ventricular contraction

89
Q

Adrenergic and Muscarinic Receptors

  1. Type
  2. Location
  3. Pathway
A
  1. G-Protein coupled receptors
  2. Cell Membrane
  3. Ligand –> Receptor –> G Protein –> Effector –> 2nd messenger –> Signal Amplification –> Biological Response
90
Q

Consequences Ventricular of long QT syndrome

A

Increased risk of Arrhythmia
Increased risk of Ventricular Tachycardia
Decreased Blood Pressure

91
Q

Risks for long QT syndrome

A 
Female
Drug Induction (Antihistamines, tricyclic antidepressants etc. )
Congenital Defect (channelopathy)
92
Q

Congestive Heart Failure

A

Heart Cannot pump enough blood to meet demand, Ejection Vol is dramatically decreased, ventricles are most affected.

93
Q

Digoxin (Lanoxin)

A

Widely prescribed cardiac glycoside with a low/narrow therapeutic Index
Treatments
- (0.8-2.0 ug/L for congestive Heart failure)
- (1.5-2.5 ug/L for arrhythmias)
Toxicity
- (2.6 ug/L Cardiotoxicity)
- (1.3-2.6 ug/L for Nausea, Vomiting)

94
Q

Therapeutic Target of Digoxin

A

Na+/K+ ATPase

Regulated by Intracellular Ca++

95
Q

Protein Based therapy for Digoxin toxicity relies on:

A

DigiFab/Digibind, An ovine digoxin immune serum Fab fragment obtained by injection of sheep w/ a digoxin derivative that has an affinity for digoxin and competes for binding

96
Q

Diagnostic Tests for Cardiovascular Health

A 
EKG
Chest X-ray
Echocardiogram
Angiogram
Exercise stress test 
CT
MRI
97
Q

Blood Chemistry Biomarkers

A 
Creatine Phosphokinase (CPK)
CK-MB
CK-MM
Myoglobin and Troponin
Lactate Dehydrogenase (LDH)
98
Q

Statins Therapeutic Use:

A

Lower Cholesterol

Reduce risk of Cardiovascular Disease

99
Q

Statin ADR

A 
Liver Toxicitiy (rare)
Muscle Pain and Tenderness
100
Q

Statin Induced Myalgia Blood Chemistry

A

Elevated Blood Serum of Creatine Kinase (CK-MM isoform)

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