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Winter P1 > Pharm 737 Exam 4 > Flashcards

Pharm 737 Exam 4 Flashcards

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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
Pharmacokinetic considerations to Toxicology
``` Body weight Age Sex Pregnancy and Lactation Health and Disease ``` (problematic if narrow TI)
26
Pharmacodynamic Considerations to Toxicology
``` Pharmacological response changes to same concentrations of drug. Sex-related differences Circadian rhythms Drug Tolerance Drug Resistance ```
27
What is an Indiosyncrasy
An unexpected response or unexpected sensitivity toa drug that is frequently genetically based. The response is outside a normal distribution for the population.
28
Allergic Response causes
Adverse response to a drug as a result from a previous exposure to the same drug
29
Cross Sensitivity Reaction
Allergic response to a structually similar drug w/o prior exposure.
30
Describe Sensitization
Hypersensitivity, Immediate or delayed response
31
Describe Anaphylaxis
Immediate or serious allergic Response
32
Describe Tolerance
A change in the way the body adapts to the presence of drug over time.
33
Describe Classic Tolerance
Progressively decreased responseivess resulting in the need for a larger dose to elicit the same response (caffeine)
34
Pharmacokinetic (indirect) Tolerance
Changes at a site separate from the agonist site of action result in a decreased drug response
35
Pharmacodynamic (direct) tolerance
Changes due to a change at the receptor or the ability of the cell to response
36
Resistance
Commonly used term w/ respect to anti-tumor and anti-microbial drugs: Insensitivity or decreased sensitivity of cells to drugs
37
Intrinsic resistance
Organism is inherently insensitive and responds poorly (e.g. bacterial pathogens to antibiotics)
38
Acquired resistance
Organism initially responds, but subsequently does not
39
Cross Resistance Multiple Drug Resistance
Superbugs, resistance to a wide variety of drug classes
40
Neoplastic Resistance
Cancer cells becoming resistant to treatment by some drug types
41
Poison Prevention Strategies
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
Organ Toxicity associated w/ route of exposure
Skin External Eye Respiratory Tract GI tract
43
Organ toxicity associated w/ metabolism and Excretion
Liver | Kidneys
44
Organ toxicity w/ selective vulnerability
Nervous System, Cardiovascular System, Immune system, Ear (ototoxicity)
45
Hepatic Toxicity, Factors for Liver Vulnerability
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
Portal Triad
consists of Bile duct, portal vein and hepatic artery
47
Functional Lobule (inside to outside)
Further you move away from central vein, the less damage can be done (unless toxic before metabolized).
48
Acetaminophen Toxicity
4000mg daily limit, causes hepatic necrosis in overdose, can administer N-Acetylcysteine as an antidote should be administered in 8 hrs
49
Acetaminophen Metabolism
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
Stages Acetaminophen Toxicity Stages
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
Acetaminophen Toxicity Risk Factors
Alcohol Consumption | Use of Drugs that Induce P450
52
Liver Enzymes
ALT (ALanine aminoTransferase) AST (ASpartate aminoTransferase) ALP (ALkline Phosphatase) GGT (Gamma-Glutamyl Transpeptidase)
53
Liver Protein Panel
Albumin - low in individuals w/ liver disease Globulin - low in individuals w/ liver disease Bilirubin - Leak Indicative of damage, (Jaundice)
54
PT indirect measure
Prolonged clotting time (liver is a source of clotting factors)
55
Renal Toxicity, Kidney factors for vulnerability
Major function is to eliminate waste Kidneys receive 25% of cardiac output Cortex (90% blood supply) vs Medulla (nephron home, functional unit )
56
Injury to Glomerulus
Relatively Rare | Leads to altered permeability and Proteinuria
57
Injury to proximal tubule
Most common site of nephro-toxicity Degeneration, inflammation and repair reactions Degenerative changes leading to necrosis
58
Injury to Distal Tubular Nephropathy
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
Chronic Kidney Injury (renal papillary necrosis)
Major cause of renal failure in humans, cell death, scar tissue Associated with chronic analgesic abuse
60
Acute or Chronic Interstitial Nephritis
Associated w/ allergic reaction to many drugs or analgesic abuse Swelling of tubules (inflammation and Edema) Decreased Urinary output Fever, Rash, Vomitting
61
Therapeutic Agents that induce Nephrotoxicity
``` Aminoglycoside Bacteriacidal Antiobiotics (I.V.) Amphotericin B (prototypical antifungal) Calcineurin Inhibitors (Cyclosporine/Tacrolimus) ```
62
Describe Acute Renal Impairment/Failure
Vasoconstriction of the vasculature --> decreased renal blood flow, decreased glomular filtration rate, decreased production of urine (reversible upon withdrawal)
63
Describe Chronic Kidney Disease and its pathogenesis
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
What are the options for End stage renal disease and Kidney Failure
Dialysis | Transplant
65
Testing methods for chronic kidney disease
GFR BP Protein in Urine Creatinine in Blood
66
Glomerular filtration rate (GFR)
Sensitive and accurate, blood creatinine levels as an indirect measure of function
67
Blood Pressure test for CKD
High blood pressure can be damaging to the glomerulus
68
Protein In Urine test for CKD
Albumin in urine can indicate proteinuria
69
Creatinine in blood for CKD
Health kidneys filter creatinine, so a decreased kidney function would see higher creatinine levels
70
Reye's Syndrome
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
Indications of an allergic reaction
Hives, Difficulty Breathing, swelling of face, lips, tongue or throat, itchy
72
Ototoxicity Signs/Symptoms (cause, Cure)
Ringing in the ears (tinnitus), hearing loss, inability to understand speech, loss of balance, dizziness, spatial disorientation, (Drug induced or environmental, No cure)
73
What is the most common adverse effect associated w/ penicillins?
Hypersensitivity Reaction
74
Symptoms of Pencillin hypersensitivity
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
Why is Cardiovascular Toxicity an issue and what does toxicity depend on?
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
Actions of Cardiovascular Toxicants include:
Direct Structural Damage Functional Alteration Indirect Action
77
Examples of Direct structural damage in cardiovascular toxicants
Inflamation, degeneration, necrosis | It can be dificult to distinguish from "naturally occurring" CV disease.
78
Functional Alteration of Cardiovascular Toxicants examples
Disruptions in Rhythm, Rate, contraction which lead to lethal arrhythmia
79
Examples of Indirect Actions of Cardiovascular Toxicants
Secondary changes that occur due to change in another organ system (ANS, CNS, Endocrine)
80
Function of Coronary Blood vessels
Supply blood to the heart muscle | partial occlusion by atheromatous deposits found in at least 75% of adult population in developed countries
81
Angina Pectoris
(Ischemic Chest pain) Oxygen supply to myocardium is insufficient for its needs
82
Myocardial Infarction
Coronary vessel becomes blocked by thrombosis
83
Stable Angina
Most common, predictable pain on exertion, helped by rest of angina mediction (e.g. Nitroglycerin)
84
Unstable Angina
No pattern, not helped by rest of medication, dangeous, emergency situation, heart attack
85
Variant Angina
Rare, spasm rather than atherosclerosis, occurs in younger individuals, pain at rest.
86
Factors that make heart vulnerable to toxicants
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
What are the effects of Norepinephrine at Adrenergic Receptors
Increases Depolarization --> Increased Impulse transmission --> Increased heart rate and force of contraction
88
What are the effects of Acetylcholine at Muscarinic Receptors?
Decreases rate of depolarization --> Decreased heart rate and ventricular contraction
89
Adrenergic and Muscarinic Receptors 1. Type 2. Location 3. Pathway
1. G-Protein coupled receptors 2. Cell Membrane 3. Ligand --> Receptor --> G Protein --> Effector --> 2nd messenger --> Signal Amplification --> Biological Response
90
Consequences Ventricular of long QT syndrome
Increased risk of Arrhythmia Increased risk of Ventricular Tachycardia Decreased Blood Pressure
91
Risks for long QT syndrome
``` Female Drug Induction (Antihistamines, tricyclic antidepressants etc. ) Congenital Defect (channelopathy) ```
92
Congestive Heart Failure
Heart Cannot pump enough blood to meet demand, Ejection Vol is dramatically decreased, ventricles are most affected.
93
Digoxin (Lanoxin)
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
Therapeutic Target of Digoxin
Na+/K+ ATPase | Regulated by Intracellular Ca++
95
Protein Based therapy for Digoxin toxicity relies on:
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
Diagnostic Tests for Cardiovascular Health
``` EKG Chest X-ray Echocardiogram Angiogram Exercise stress test CT MRI ```
97
Blood Chemistry Biomarkers
``` Creatine Phosphokinase (CPK) CK-MB CK-MM Myoglobin and Troponin Lactate Dehydrogenase (LDH) ```
98
Statins Therapeutic Use:
Lower Cholesterol | Reduce risk of Cardiovascular Disease
99
Statin ADR
``` Liver Toxicitiy (rare) Muscle Pain and Tenderness ```
100
Statin Induced Myalgia Blood Chemistry
Elevated Blood Serum of Creatine Kinase (CK-MM isoform)

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