LECTURE 8: ORGAN TOXICITY Flashcards
HEPATOTOXICITY
Liver
- Extensive blood supply and role in metabolism results in increased risk
Primary Types
* Hepatocellular necrosis- Necrotic cell loss, eg., acetaminophen
* Steatosis – abnormal accumulation of fat in hepatocytes, valproate, amiodarone
* Chronic Hepatitis – hepatic inflammation, eg., EtOH, diclofenac
* Cholestasis – obstructed flow of bile salts eg., erythromycin, statins
* Fibrosis/Cirrhosis – pathological wound healing, scarring, increase connective
tissue, eg., methyldopa, methotrexate
HEPATOTOXICITY
Drug-Induced Liver Injury (DILI)
- Uncommon but clinically important as well difficult to diagnosis and manage
- Issues - timing of onset, resolution, re-exposure
1. Direct - intrinsically toxic (latency period usually short)
2. Idiosyncratic - little or no intrinsic toxicity (rare), HLA class I and II alleles
3. Indirect - Caused by the action of the drug (what it does)
Indirect - caused by how drug is working
- Somewhat delayed usually result og fxn oof drug (protein kinase inhibitor or something that’s going to regulate checkpoint proteins
- For example, if you have a protein, kinase inhibitor, or something that’s going to regulate the checkpoint proteins.
So the drug itself is not causing a toxicity. It’s the effect. So if you’re inhibiting protein kinases in the liver. It’s going to cause adverse toxicity.
Idosync:
Really, it’s a variable it doesn’t You don’t know when it’s going to occur. It can be immediately. You can be delayed, incurred years later. , a lot of, you know, immune responses. You can get some hepatitis.
NEPHROTOXICITY
Kidney
- Extensive blood supply, critical role in
fluid/electrolytes and metabolism
Key points
* Toxins can affect any part of kidney but
not all result in loss of GFR
* Acute kidney injury
* Chronic kidney disease
* Functional kidney disorders
1. Decreased ability to excrete wastes
2. Disruption to fluid and electrolyte
homeostasis
3. Renal hormones impacted (ie,
erythropoietin)
, renal system, extensive blood supply playing a really critical role in regulating your electrolytics, fluid balance
Can have fx on glom filtration, bowman’s capsule, loop of henle, distal tubule
decreased ability to excrete waste. So you get accumulation of waste of some of the primary effects of nephron toxicity.
You’re going to disrupt that fluid and electrolyte homeostasis.
. Diuretics are going to cause a change in electrolyte balance
NEUROTOXICITY
Central and Peripheral Nervous Systems
- Complex systems that require diverse range in cells (such as, astrocytes, neurons, ependymal cells, vascular endothelial cells)
Key points
* Disruption or death can cause critical changes to function
* Cellular interdependence and high metabolic demand
* Understanding of normal chemical and molecular function is limited
1. Neuronopathies – Degeneration of neurons
2. Neuropathy – Peripheral NS, ie., sensory, motor, autonomic
3. Excitotoxicity – Energy needs exceeds production
4. Demyelination – impact production or maintenance of myelin eg., arsenic, tacrolimus
5. Interference with neurotransmission – for example, inhibit presynaptic metabolism
(MAO inhibitors), stimulate release (amphetamines), inhibit synaptic degradation
(acetylcholinesterase inhibitors), inhibit release (botulinum toxin)
RESPIRATORY TOXICITY
Lungs
- Primary function is gas exchange
- Minor role in metabolism and elimination of xenobiotics, water loss, temperature
regulation
Key points
* Pulmonary irritation
* Asthma/bronchitis
* Reactive airway disease
* Emphysema
* Allergic alveolitis
* Fibrotic lung disease
* Pneumoconiosis
* Lung cancer
Hematologic Toxicity
Blood
- Vital fluid, every organ system depends on it
- Delivers oxygen and essential substances, removes waste, transports hormones, signals and defends against infection, inflammatory response, vascular integrity through clotting
- Central compartment in PK – direct contact with every systemic xenobiotic
Key points
1. Mechanisms of toxic injury is extremely varied, reflecting complexity of the the fluid
2. Virtually all toxins come into contact – impact oxygen transport, gas exchange, immune responses, hemostasis
3. Oxygen transport impacted – oxidation of heme iron, protein globin chain disruption, shift of the oxygen-hemoglobin dissociation curve, hemolysis
4. Disrupt hemostasis – cell proliferation to cell death, immune activation and suppression, thrombophilia and thrombolysis
Dermatological Toxicity
skin
Skin
* Skin shields internal organs, maintains
homeostasis (fluid) and prevents infection
* Complex tissue – 3 main components
* Epidermis, dermis, hypodermis
(subcutis)
* Exposure can occur through different routes
You start off with sort of a rash.
it progresses to, you know, throughout the body.
And then what happens is that skin starts to slough off and you start to lose that dermal skin.
Diagnosis based on BSA
10% -> progresses to over 30% shifts to toxic epidermal necrosis (over 60% mortality )
Dermatological Toxicity
cont’d
- Transdermal xenobiotic absorption
- Passive diffusion, lipid solubility, concentration gradient, MW, skin
- Direct dermal toxicity
- ‘Burns’ – most are chemical reactivity rather than thermal damage
- Oxidizing or reducing agents, corrosives, protoplasmic poisons,
desiccants or vesicants - Often initially appear mild or superficial but subsequent 24-36h can
progress (necrosis) - Systemic injury/disease can manifest dermatologically
- Cyanosis – eg., hypoxia
- Xanthoderma – eg., carotenoids
- Pruritus – eg., codeine, cocaine,
- Flushing – eg., niacin
- Sweating – eg., cholinesterase inhibitors
- Dyspigmentation – eg., silver (Argyria)
Dermatological Toxicity
hives
bullous reactions (blistering)
- Skin is one of the most common targets for ADR
- Urticarial (hives) – Type I (IgE – mediated reaction) often angioedema and anaphylactoid
- Bullous Reactions (Blistering) – xenobiotic-related or autoimmune (visually cannot
distinguish), numerous drugs
Dermatological Toxicity
drug-induced hypersensitivity syndrome
anticoagulant-induced skin necrosis
- Drug-induced hypersensitivity syndrome – linked with systemic
immunologic diseases can be life threatening - Characterized by fever, skin eruption and internal organ
involvement - Frequency – 1 in 1000 to 1 in 10,000 with antiepileptics or
sulfonamide antibiotics, usually presents within 2 to 6
weeks (eg., phenytoin, carbamazepine, phenobarbital) - Common for patients to have underlying disease such as
hepatitis, interstitial nephritis, vasculitis, pneumonitis,
autoimmune hypothyroidism - Anticoagulant-induced Skin Necrosis – From warfarin therapy,
3-5 days after initiation, corresponding to the expected early
decline in protein C function - Risk ~1 in 10,000
- 4x higher in women, obese
- Results from antibodies that bind to complexes of heparin
and platelet factor 4 and induce aggregation -
Dermatological Toxicity
Stevens-Johnson and Toxic Epidermal Necrolysis (TEN)
– Rare, lethal eg., sulfonamide
antibiotics, carbamazepine, phenytoin – cytotoxic T lymphocytes and Fas-ligand/perforin
granzyme pathways (triggering extensive apoptosis) (exact understanding of MOA limited
- T-cell, type IV hypersensitivity)
Dermatological Toxicity
* Contact dermatitis –
Occurs when xenobiotic comes into contact with the skin
* Characterized by inflammation of the epidermis, well-demarcated
vesicular or scaly patches, bullae in direct contact
i. Allergic contact dermatitis (~20%) – delayed hypersensitivity (type IV)
* Plants, metals (nickel)
ii. Irritant contact dermatitis (~80%) – looks the same but does not require prior antigen sensitization
Cardiovascular Toxicity
NON-REVERSIBLE DAMAGE
Pathophysiology
Cell loss (necrosis/apoptosis)
Diagnosis
Injury marker release
Progressive contractile dysfunction
Cardiac remodeling
Manifestation
Cardiomyopathy/HF, MI, thrombosis
= progressive CV tox
REVERSIBLE DAMAGE
Pathophysiology
Cellular dysfunction
(mitochondria, protein)
Diagnosis
No injury marker release
Reversible contractile dysfunction
Reversible arterial hypertension
Manifestation
Temporary contractile dysfunction
Vasoplastic angina
Arterial hypertension
= normalization of CV fxn
➢Direct effects on the myocardium
➢Indirect effects through vasculature
CV Risk factors
(preexisting disease,
HTN, age)
Cardiotoxic Agent
What are the effects of ‘cardiotoxicity’?
Characteristics include:
1) Cardiac conduction and dysrhythmias - abnormalities in repolarization
2) Systolic/diastolic dysfunction - reduction in ventricular ejection
3) Cardiac structural remodeling – fibrosis
4) Cardiomyopathies - heart failure
5) Systemic and pulmonary vascular dysfunction and altered hemodynamics
6) Hemostasis and thrombosis
Cardiac Contractility - Cardiomyopathy
§ Xenobiotics impact cardiac contractility result
in changes to
- Ejection fraction
- Cardiac output
- Blood pressure
§ The mechanisms of cardiotoxicity are normally
multifactorial and/or remain unknown
Class Drug Mechanism
Cardiac glycosides Digoxin Block Na+/K+ ATPase
Beta agonists Dobutamine, isoproterenol Activate b1AR
- increased contractility
Calcium sensitizers Levosimendan Increase troponin affinity
for calcium
Sympathomimetics Cocaine Increase catecholamines
Contractility
(Inotropy)
Sympathetic NS
Parasympathetic NS
Afterload Preload
Catecholamines
Heart rate
Heart Rate Abnormalities
Xenobiotics can directly cause dysrhythmias or cardiac conduction
abnormalities usually effect the cell membranes or indirectly via metabolic
effects
Bradycardia – caused by affects on central or peripheral NS, generation
(pacemaker cells) or conduction system, changes to sympathetic outflow,
enhanced vagal tone, altered calcium handling
α1-adrenergic agonists (phenylephrine),α2-adrenergic agonists (clonidine), β-adrenergic antagonists
(blockers), CCB, Opioids, Sedatives, Anti-arrhythmics (amiodarone, sotalol), Na channel openers
Tachycardia – sinus tachycardia most common,
atropine (rise in HR without inhibitory effect of
vagal influence), direct effects (β-adrenergic
agonism) or indirect (response to hypotension,
hypoxia)
Amphetamines,β-adrenergic agonists, Anticholinergics,
Antihistamines, Metal salts, Arterial vasodilators
ARRHYTHMIAS
Arrhythmia is an abnormal heart rhythm.
Result from alterations of:
1. Impulse formation
2. Impulse conduction
Hyperkalemia
* Cardioactive steroids
* beta-adrenergic blockers
Hypokalemia
* Loop diuretics
* Insulin
* Thiazide diuretics
- K+ balance is complex, critical role in a variety of homeostatic processes
- Large intracellular store maintained by many systems, Na+/K+ ATPase
- ECG changes are common following changes in K+
ARRHYTHMIAS
hypercalcemia
hypocalcemia
Hypercalcemia
* All-trans-retinoic acid
* Androgens
* Antiacids
* Lithium
* Thaizide diuretics
Hypocalcemia
* Aminoglycosides
* Bicarbonate
* Calcitonin
* Ethanol
* Ethylene glycol
* Fluoride
* Furosemide
* Neomycin
* Theophylline
* Valproate
Xenobiotics more commonly cause hypocalcemia than hypercalcemia
* ECG abnormalities are common but life-threatening dysrhythmias are rare
hERG gene (Human ether-a-go-go-related gene)
hERG – encodes pore forming subunit of the rapidly activating delayed rectifier cardiac K+
channel (IKr) (KCNH2)
* Voltage-gated potassium channel
* Contributes to repolarization of cardiac action potential
* Common cause of withdrawal or restriction of drugs is the prolongation of the QT interval
* Major effect is loss-of-function (block channel)
* Arrhythmias (torsades de pointes)
Examples
Terfenadine
Astemizole
Droperidol
Levomethadyl
Cisapride
it’s a protein that’s going to it encodes the delayed rectifying
potassium channel. Again. Voltage. Gated potassium channel.
It’s going to contribute to that repolarization.
you’re getting that slow repolarization.
You’re getting that increase in action potential duration. The AAPD
EAD
- Delayed after depolarization
- Firing AP before the main AP pathway comes
- Can get prolongation of QT
Trigger torsade de pointes
Effects on the herd gene the the the potassium, the re-polarization channel
can cause a prolongation these prolongations could lead Tdp
Blood Pressure
Xenobiotics cause hypertension (Main mechanisms)
1.CNS sympathetic over-activity
2.Increased myocardial contractility
3.Increased peripheral resistance
Xenobiotics cause hypotension (Main mechanisms)
1.Decreased peripheral resistance
2.Decreased myocardial contractility
3.Dysrhythmias
4.Depletion of intravascular volume
DRUGS THAT TRIGGER HYPERTENSION
DRUGS THAT TRIGGER HYPOTENSION
see slide 25
Cardio-oncology
- Rapid development of anticancer treatments
- Cardiovascular morbidity in cancer patients and survivors is rising
- Common to have cancer therapy interrupted due to
cardiovascular issues - Ageing population – Pre-existing CVD can limit cancer therapy
- Use of multiple chemotherapeutic agents
Cardio-oncology
An overview of the cardiovascular side effects of chemotherapy and radiation.
you can have effect on, you know, causing various problems with the vasculature, coronary problems
you can have effects on microtubule inhibitors. You’re going to cause arrythmias.
multiple different drugs for treating cancer, a lot of them have effects on the heart.
Anthracyclines (Doxorubicin, Adriamycin)
- Quinone-containing antibiotics
- One of the most effective and commonly used cancer drugs for treatment of a
variety of cancers (breast, prostate, leukemia), >30 yrs; current est’d ~60%
children with cancer treated anthracylcines - Clinical use is associated with increased risk of cardiomyopathy or congestive
heart failure - Antitumor properties – involve inhibition of both topoisomerase and DNA
synthesis
Cardiomyopathy (doxorubicin)
Characteristic Toxic Effects
Increase LDH, CPK, troponin T
Loss of myofibrils
Cytoplasmic vacuolization
Mitochondrial damage
Oxidative stress
Reduced systolic f(x)
T-wave flattening
ST-T wave changes
Decrease voltage
Tachycardia
Long-term
(4-20yrs post treat) (450mg/m2) (5%)
Cardiomyopathy
Congestive Heart Failure
Myocarditis
n its broadest sense, myocarditis refers to any
inflammation of the myocardium. Inflammation can be
found after any form of injury to the heart, including
ischemic damage, mechanical trauma, and genetic
cardiomyopathies. More specifically, however, classic
myocarditis refers to inflammation of the heart muscle
occurring as a result of exposure to either discrete
external antigens, such as viruses, bacteria, parasites,
toxins, or drugs, or internal triggers, such as
autoimmune activation against self-antigens. Although
viral infection remains the most commonly identified
cause of myocarditis, drug hypersensitivity and toxic
drug reactions, other infections, and peripartum
cardiomyopathy also can lead to myocarditis
causes of myocarditis
Long-term CV outcomes COVID-19
COVID-19 mRNA vaccine
US Centre for Disease control (CDC)
Myocarditis following SARS CoV-2 mRNA vaccine:
* It is rare but can be serious
* USA 200 million received 2 doses, 1500 reported myocarditis
* Vast majority recover quickly, limited data post 90days
* Males>females, 12-29 age groups
Take Home Points for Cardiotoxicity
Ø Both drug and xenobiotic-mediated effects can lead to significant adverse
cardiovascular complications
Ø Key biomarkers and signs indicating cardiotoxicity
Ø Outcomes are dependent on reversibility of injury
Ø Present understanding of mechanisms is limited but rapidly increasing
Ø Emerging concepts and realities with disease management
Ø Balance between cardioprotective response and adverse effect
Ø Comprehensive understanding of cardiotoxicity will enhance therapy
Cardio-oncology
Risk Factors
- Prior anthracycline-based treatment or
combined trastuzumab/anthracycline - Elderly (>75yrs)
- Prior mediastinal or chest radiotherapy
- HTN, diabetes
- Smoker
- Very young (<10 yrs)
- Elevated cardiac biomarkers
- Baseline abnormal LV systolic function
(LVEF<50%)
HEPATOTOXICITY
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Dermatological Toxicity
* Stevens-Johnson and Toxic Epidermal Necrolysis (TEN)
SCORTEN and ABCD-10 scoring systems
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