Pharm 737 Exam 4 Flashcards
What is there that is not poison?
All substances are poisons; there is none that is not, the right DOSE differentiates a poison from remedy.
What is the Threshold of Toxicological Concern? (TTC)
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
Role of US FDA in Toxicity
Regulates the development of new drugs and their marketing
What is required for an Investigational New drug Application?
Pharmacology and Toxicology studies (pre-clinical testing) in animals to evaluate effectivess and safety.
Why is Descriptive testing in animals necessary? What are the components?
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
Describe phases of Toxicology, Safety testing and clinical trials
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
Describe Acute Exposure
Single Event/dose - monitored for 14 days; 3 doses
Describe Sub Acute Exposure
14 days - 14 doses; repeat dose
Describe 90 day Chronic Exposure
Repeated dose for 90 days, will be set up with 3 doses, animals monitored for signs of sickness, organs and tissue evaluated by pathologist.
Define Long Term Toxicity/Carcinogenicity
Evaluated at the same time, (small exposures over prolonged time/lifetime exposure >2yrs)
Describe Reproductive Toxicity
Decreased Fertility, study of adverse effects on male/female reproductive system
What is Teratogenicity?
Ability to cause congenital malformations, usually done in rats and rabbits during pregnancy
What happened with the Thalidomide Disaster?
1950-1960s, was prescribed for morning sickness as an anti-emetic and induced birth defects in 46 countries
What is LD50
Median Lethal Dose, Lethal dose for 50% of population
What is TD50
Median Toxic Dose, much preferred over LD50
What is ED50
Median Effective dose
What is the Therapeutic Index
TD50/ED50, Higher numbers = Not safe drug
What is the Certain Safety Factor (CSF)
TD1/ED99
Toxicology Hazard
An inherent property, the potential of something to cause harm
Toxicology Risk
Probability of a particular adverse outcome (e.g. Lifetime risk of cancer)
Risk vs Safety standards
Made by individuals or government acting on behalf of many people that are potentially subject to a given risk
Risk Triangle
Risk Management; Risk Assessment; Risk Communication
Risk Checkpoints
Used to identify and prevent adverse drug events
Drug-Receptor Interactions determine:
How patients respond to a given dose, Variations in Responsiveness
Pharmacokinetic considerations to Toxicology
Body weight Age Sex Pregnancy and Lactation Health and Disease
(problematic if narrow TI)
Pharmacodynamic Considerations to Toxicology
Pharmacological response changes to same concentrations of drug. Sex-related differences Circadian rhythms Drug Tolerance Drug Resistance
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.
Allergic Response causes
Adverse response to a drug as a result from a previous exposure to the same drug
Cross Sensitivity Reaction
Allergic response to a structually similar drug w/o prior exposure.
Describe Sensitization
Hypersensitivity, Immediate or delayed response
Describe Anaphylaxis
Immediate or serious allergic Response
Describe Tolerance
A change in the way the body adapts to the presence of drug over time.
Describe Classic Tolerance
Progressively decreased responseivess resulting in the need for a larger dose to elicit the same response (caffeine)
Pharmacokinetic (indirect) Tolerance
Changes at a site separate from the agonist site of action result in a decreased drug response
Pharmacodynamic (direct) tolerance
Changes due to a change at the receptor or the ability of the cell to response
Resistance
Commonly used term w/ respect to anti-tumor and anti-microbial drugs:
Insensitivity or decreased sensitivity of cells to drugs
Intrinsic resistance
Organism is inherently insensitive and responds poorly (e.g. bacterial pathogens to antibiotics)
Acquired resistance
Organism initially responds, but subsequently does not
Cross Resistance Multiple Drug Resistance
Superbugs, resistance to a wide variety of drug classes
Neoplastic Resistance
Cancer cells becoming resistant to treatment by some drug types
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)
Organ Toxicity associated w/ route of exposure
Skin
External Eye
Respiratory Tract
GI tract
Organ toxicity associated w/ metabolism and Excretion
Liver
Kidneys
Organ toxicity w/ selective vulnerability
Nervous System, Cardiovascular System, Immune system, Ear (ototoxicity)
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
Portal Triad
consists of Bile duct, portal vein and hepatic artery
Functional Lobule (inside to outside)
Further you move away from central vein, the less damage can be done (unless toxic before metabolized).
Acetaminophen Toxicity
4000mg daily limit, causes hepatic necrosis in overdose, can administer N-Acetylcysteine as an antidote should be administered in 8 hrs
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)
Stages Acetaminophen Toxicity Stages
- Day 1, GI distress
- Days 1-3, Hepatic Toxicity Develops
- Days 3-5 worsening hepatic necrosis, hepatic Encephalopathy (drowsiness-coma)
- Days 5-15 recover is treatment is effective.
Acetaminophen Toxicity Risk Factors
Alcohol Consumption
Use of Drugs that Induce P450
Liver Enzymes
ALT (ALanine aminoTransferase)
AST (ASpartate aminoTransferase)
ALP (ALkline Phosphatase)
GGT (Gamma-Glutamyl Transpeptidase)
Liver Protein Panel
Albumin - low in individuals w/ liver disease
Globulin - low in individuals w/ liver disease
Bilirubin - Leak Indicative of damage, (Jaundice)
PT indirect measure
Prolonged clotting time (liver is a source of clotting factors)
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 )
Injury to Glomerulus
Relatively Rare
Leads to altered permeability and Proteinuria
Injury to proximal tubule
Most common site of nephro-toxicity
Degeneration, inflammation and repair reactions
Degenerative changes leading to necrosis
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
Chronic Kidney Injury (renal papillary necrosis)
Major cause of renal failure in humans, cell death, scar tissue
Associated with chronic analgesic abuse
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
Therapeutic Agents that induce Nephrotoxicity
Aminoglycoside Bacteriacidal Antiobiotics (I.V.) Amphotericin B (prototypical antifungal) Calcineurin Inhibitors (Cyclosporine/Tacrolimus)
Describe Acute Renal Impairment/Failure
Vasoconstriction of the vasculature –> decreased renal blood flow, decreased glomular filtration rate, decreased production of urine (reversible upon withdrawal)
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)
What are the options for End stage renal disease and Kidney Failure
Dialysis
Transplant
Testing methods for chronic kidney disease
GFR
BP
Protein in Urine
Creatinine in Blood
Glomerular filtration rate (GFR)
Sensitive and accurate, blood creatinine levels as an indirect measure of function
Blood Pressure test for CKD
High blood pressure can be damaging to the glomerulus
Protein In Urine test for CKD
Albumin in urine can indicate proteinuria
Creatinine in blood for CKD
Health kidneys filter creatinine, so a decreased kidney function would see higher creatinine levels
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
Indications of an allergic reaction
Hives, Difficulty Breathing, swelling of face, lips, tongue or throat, itchy
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)
What is the most common adverse effect associated w/ penicillins?
Hypersensitivity Reaction
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)
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
Actions of Cardiovascular Toxicants include:
Direct Structural Damage
Functional Alteration
Indirect Action
Examples of Direct structural damage in cardiovascular toxicants
Inflamation, degeneration, necrosis
It can be dificult to distinguish from “naturally occurring” CV disease.
Functional Alteration of Cardiovascular Toxicants examples
Disruptions in Rhythm, Rate, contraction which lead to lethal arrhythmia
Examples of Indirect Actions of Cardiovascular Toxicants
Secondary changes that occur due to change in another organ system (ANS, CNS, Endocrine)
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
Angina Pectoris
(Ischemic Chest pain) Oxygen supply to myocardium is insufficient for its needs
Myocardial Infarction
Coronary vessel becomes blocked by thrombosis
Stable Angina
Most common, predictable pain on exertion, helped by rest of angina mediction (e.g. Nitroglycerin)
Unstable Angina
No pattern, not helped by rest of medication, dangeous, emergency situation, heart attack
Variant Angina
Rare, spasm rather than atherosclerosis, occurs in younger individuals, pain at rest.
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
What are the effects of Norepinephrine at Adrenergic Receptors
Increases Depolarization –> Increased Impulse transmission –> Increased heart rate and force of contraction
What are the effects of Acetylcholine at Muscarinic Receptors?
Decreases rate of depolarization –> Decreased heart rate and ventricular contraction
Adrenergic and Muscarinic Receptors
- Type
- Location
- Pathway
- G-Protein coupled receptors
- Cell Membrane
- Ligand –> Receptor –> G Protein –> Effector –> 2nd messenger –> Signal Amplification –> Biological Response
Consequences Ventricular of long QT syndrome
Increased risk of Arrhythmia
Increased risk of Ventricular Tachycardia
Decreased Blood Pressure
Risks for long QT syndrome
Female Drug Induction (Antihistamines, tricyclic antidepressants etc. ) Congenital Defect (channelopathy)
Congestive Heart Failure
Heart Cannot pump enough blood to meet demand, Ejection Vol is dramatically decreased, ventricles are most affected.
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)
Therapeutic Target of Digoxin
Na+/K+ ATPase
Regulated by Intracellular Ca++
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
Diagnostic Tests for Cardiovascular Health
EKG Chest X-ray Echocardiogram Angiogram Exercise stress test CT MRI
Blood Chemistry Biomarkers
Creatine Phosphokinase (CPK) CK-MB CK-MM Myoglobin and Troponin Lactate Dehydrogenase (LDH)
Statins Therapeutic Use:
Lower Cholesterol
Reduce risk of Cardiovascular Disease
Statin ADR
Liver Toxicitiy (rare) Muscle Pain and Tenderness
Statin Induced Myalgia Blood Chemistry
Elevated Blood Serum of Creatine Kinase (CK-MM isoform)
