Environmental and nutritional diseases animated

Johari M. Ancheta, MD, DPSPDavao Medical School Foundation

1ST PART

• Environmental Effects on Global Disease Burden

• Health Effects of Climate Change• Toxicity of Chemical and Physical Agents• Environmental Pollution• Occupational Health Risks

Environmental Diseases• Many human diseases are caused or

influenced by environmental factors• Environment = indoor, outdoor, and

occupational settings in w/c human beings live and work

• Things which we are exposed to or consume are major determinants of health in this setting

• Individual personal behavior > ambient environment

Environmental Diseases• Refers to conditions caused by

exposure to chemical or physical agents in the ambient, workplace, and personal environment, including diseases of nutritional origin

• Examples:Dramatic• Dioxin exposure in

Italy• Methyl isocyanate gas

leak in Bhopal, India• Fukushima nuclear

meltdown

Subtle• Work related exposure

or accidents• Nutritional

deficiencies:50% of childhood mortality worldwide

Environmental Effects on Global Disease Burden

On a worldwide basis: • dramatic increases in mortality due to HIV/AIDS

and assoc. infxnsUndernutrition• single leading global cause of health loss

(defined as morbidity and premature death)Ischemic heart disease and CVD • remain the leading causes of death in

developed countriesIn developing countries• 5 of the 10 leading causes of death are

infectious dses


• In the postnatal period, about 50% of all deaths in children younger than 5 years of age are attributed to only three conditions, all preventable: Pneumonia

Diarrheal diseases

Malaria


Emerging infectious diseases• Infectious disorders whose incidence has

recently increased or could reasonably be expected to increase in the near future

• Change in envt’l and socioeconomic conditions

• Categories:Diseases caused by newly evolved

strains or organisms

Diseases caused by pathogens endemic in

other species that “jumped” to human

population

Diseases caused by pathogens that have

been present in humans but show a recent

increase in incidence

Health Effects of Climate Change

Measurements show that earth has warmed at an accelerating rate over the past 50 yrs

Since 1960, the global ave. temp. has increased by ≈ 0.6°C, with the greatest increases seen over land areas bet. 40

degrees north and 70 degrees north

9 of the 10 hottest years in the meteorologic record have occurred in the 21st century


•glaciers may disappear by the year 2025•arctic ocean will be completely ice-free in summer by the year 2040

Rapid loss of glacial and sea ice leading to predictions

that:

•particularly carbon dioxide (CO2) released through the burning of fossil fuels •as well as ozone (an important air pollutant, discussed later) and methane

Principal culprit is the rising

atmospheric level of greenhouse

gases

Health Effects of Climate Change• Greenhouse effect = absorption and re-

emission of infrared energy radiated from the earth’s surface that otherwise would be lost into space

• Atmospheric CO2 in late 2012 (about 391 ppm) was higher than at any point in ≈ 650,000 yrs

• Expected to increase to between 500 to 1200 ppm by the end of this century

• Increased CO2 production but also from deforestation and the attendant decrease in carbon fixation by plants


•also projected to increase the variability and severity of weather events, such as floods, droughts, and storms

Increased heat energy in the oceans and atmosphere

•is increasing acidity of the oceans, which may disrupt marine ecosystems and fisheries

Increased atmospheric

CO2 conc.

•will raise sea levels by at least 1 to 2 feet by 2100

Combined w/ thermal expansion

of warming oceans


• Its Extent and rapidity• Nature and severity of ensuing

consequences• Humankind’s ability to mitigate the

damage

Health impacts of climate change will depend on:

• Cardiovascular, cerebrovascular, and respiratory dses

• Gastroenteritis, cholera, and other foodborne and waterborne infectious dses

• Vector-borne infectious dses (ex: malaria, dengue)

• Malnutrition

Climate change is expected to have serious

impact on health by increasing

incidence of dses

Health Effects of Climate Change• The resulting displacement of people will

disrupt lives and commerce, creating conditions ripe for political unrest, war, and poverty, the “vectors” of malnutrition, sickness, and death

• Both developed and developing countries will suffer the consequences of climate change

• Burden will be greatest in developing countries • The urgent challenge is to develop new

renewable energy resources that stem the production of greenhouse gases

Toxicity of Chemical & Physical Agents

•Distribution•Effects•Mechanisms of action of toxic agents•Effects of physical agents such as radiation and heat

Toxicology = the science

of poisons

Only a very small proportion has

been tested experimentally for

health effects

Factors


•basically a quantitative concept strictly dependent on dosagePoisons

“All substances are poisons; the right

dosage differentiates a poison from a remedy”

– Paracelsus

Xenobiotics

Xenobiotics


Chemicals may be• excreted in

urine or feces

• eliminated in expired air

• or may accumulate in bone, fat, brain, or other tissues

Chemicals may act• at the site

of entry• or at other

sites following transport through the blood

Most solvents and drugs are lipophilic• which

facilitates their transport in the blood by lipoproteins and their penetration through the plasma membrane into cells

Most solvents, drugs, and xenobiotics are • metabolize

d to form inactive water-soluble products (detoxification)

• activated to form toxic metabolites


• Reactions that metabolize xenobiotics occur in 2 phases

• Form water-soluble compounds that are readily excreted

• Drug-metabolizing enzymes = enzymes that catalyze the biotransformation of xenobiotics and drugs

Phase I reactions

•chemicals undergo hydrolysis, oxidation or reduction

Phase II reactions

•include glucuronidation, sulfation, methylation, and conjugation with glutathione


• The cytochrome P-450 (CYP) system catalyzes reactions that either – detoxify xenobiotics – or, less commonly, convert

xenobiotics into active compounds that cause cellular injury

• Both types of reactions may produce, as a byproduct, reactive oxygen species (ROS), which can cause cellular damage


• Great variation in the activity of CYPs among individuals

• Variation may be a consequence of genetic polymorphisms in specific CYPs

• More commonly it is due to exposure to drugs or chemicals that induce or diminish CYP activity

CYP inducers: environmental

chemicals, drugs, smoking, alcohol, and

hormones

Fasting or starvation can decrease CYP

activity


• Inducers of CYP = binding to nuclear receptors, which then heterodimerize with the retinoic X receptor (RXR)

• Form a transcriptional activation complex that associates with promoter elements located in the 5′-flanking region of CYP genes

• Nuclear receptors for CYP induction:Aryl hydrocar bon receptor

Peroxisome proliferator-activated

receptors (PPAR)

Nuclear receptors: androstane receptor (CAR), and pregnane

X receptor (PXR)

Environmental Pollution• Air pollution– Air is vital to life, but also contains many

causes of disease– Significant cause of morbidity and mortality

worldwide, particularly among at-risk individuals with preexisting pulmonary or cardiac diseaseOutdoor air pollution

• Ambient air in industrialized nations is contaminated with mixture of gaseous and particulate pollutants

Indoor air pollution• “Buttoned up” homes to exclude the

environment

Environmental Pollution• Outdoor Air Pollution• “Smog” – concoction of six pollutants

• Affect mainly the lungs although other organ systems are also affected

Sulfur dioxide Carbon monoxide

Ozone Nitrogen dioxide

Pollutant Populations at Risk Effects

OzoneHealthy adults and children

Decreased lung functionIncreased airway reactivityLung inflammation

Athletes, outdoor workersAsthmatics

Decreased exercise capacityIncreased hospitalizations

Nitrogen dioxide

Healthy adults Increased airway reactivityAsthmatics Decreased lung functionChildren Increased respiratory infections

Sulfur dioxide

Healthy adults Increased respiratory symptomsIndividuals with chronic lung disease Increased mortality

Asthmatics Increased hospitalizationDecreased lung function

Acid aerosols

Healthy adults Altered mucociliary clearanceChildren Increased respiratory infections

Asthmatics Decreased lung functionIncreased hospitalizations

Particulates

Children Increased respiratory infectionsIndividuals with chronic lung or heart disease Decreased lung function

Asthmatics Excess mortalityIncreased attacks

Environmental Pollution• Good ozone (Stratospheric O3)– Produced by interaction of ultraviolet (UV)

radiation and oxygen (O2) in the stratosphere – Protects life on earth by absorbing the most

dangerous UV radiation emitted by the sun– Ozone layer decreased in both thickness and

extent due to the widespread use of chlorofluorocarbon gases in air conditioners and refrigerators and as aerosol propellants

Environmental Pollution• Bad ozone (Ground-level O3)– Formed by the reaction of nitrogen oxides and

volatile organic compounds in the presence of sunlight

– Toxicity due to production of free radicals, which injure epithelial cells along the respiratory tract & type I alveolar cells

– Cause the release of inflammatory mediators• Sulfur dioxide– Produced by power plants burning coal and oil, from

copper smelting, and as a byproduct of paper mills– Converted into sulfuric acid and sulfuric trioxide

Environmental Pollution• Particulate matter (known as “soot”)

– Particulates are emitted by coal- and oil-fired power plants, by industrial processes

– Fine or ultrafine particles less than 10 µm in diameter are the most harmful

• Carbon monoxide – Systemic asphyxiant that is an important cause of accidental

and suicidal death– Nonirritating, colorless, tasteless, odorless gas that is

produced during any process that results in the incomplete oxidation of hydrocarbons

– CO kills in part by inducing central nervous system (CNS) depression, which appears so insidiously that victims are often unaware of their plight

– Hemoglobin has 200-fold greater affinity for CO than for oxygen

Environmental Pollution

Chronic CO poisoning• Ischemic changes in the basal ganglia and

lenticular nuclei• Residual permanent neurologic sequelae

Acute CO poisoning• Characteristic generalized cherry-red color of

the skin and mucous membranes• High levels of carboxyhemoglobin

Environmental Pollution• Indoor air pollution–Wood smoke• Oxides of nitrogen and carbon particulates, • Irritant that may predispose to lung infections• Contain polycyclic hydrocarbons, important

carcinogens– Bioaerosols• Microbiologic agents capable of causing

infectious diseases • Pet dander, dust mites, and fungi and molds

responsible for rhinitis, eye irritation, and asthma.

Environmental Pollution• Indoor air pollution– Radon

• Radioactive gas derived from uranium widely present in soil and in homes

• Cause lung cancer in uranium miners– Formaldehyde

• Building materials (e.g., cabinetry, furniture, adhesives)

• Breathing difficulties and a burning sensation in the eyes and throat

• Carcinogen for humans and animals– Sick building syndrome

• May be a consequence of exposure to one or more indoor pollutants, possibly due to poor ventilation

Environmental Pollutions:METALS

LeadReadily absorbed metal that binds to sulfhydryl groups in proteins

Interferes with calcium metabolism

Lead to hematologic, skeletal, neurologic, gastrointestinal, and renal toxicities

House paints and gasoline

Low-level lead poisoning include subtle deficits in intellectual capacity, behavioral problems such as hyperactivity, and poor organizational skills

Mercury• Mercury binds to sulfhydryl groups in certain

proteins with high affinity, leading to damage in the CNS and the kidney

• 3 forms of mercury

• Main sources of exposure

Metallic mercury

•also known as elemental mercury

Inorganic mercury

•mostly mercuric chloride

Organic mercury

•mostly methyl mercury

Contaminated fish (methyl mercury)

Mercury vapors released from metallic mercury in dental amalgams & mercury used in gold mining

Mercury• The developing brain is extremely sensitive to

methyl mercury• Lipid solubility of methyl mercury and metallic

mercury facilitate their accumulation in the brain, disturbing neuromotor, cognitive, and behavioral fxns

• There are serious concerns about the effects of chronic low-level exposure to methyl mercury in food

exposure of the fetus to high levels of mercury in utero

Minamata disease (cerebral palsy, deafness, and blindness)

Arsenic• Interfere with several aspects of cellular

metabolism, leading to toxicities most prominent in GI tract, nervous system, skin, and heart

• Sources:– Naturally occurring in soils and water &

is used in products such as wood preservers, herbicides and other agricultural products

– Mines and smelting industries– Chinese and Indian herbal medicine

• Large concentrations of inorganic arsenic are present in ground water in countries such as Bangladesh, Chile, and China

“The poison of kings and the king of poisons”

ArsenicMost toxic forms of arsenic are the trivalent compounds: arsenic trioxide, sodium arsenite, and arsenic trichloride

Causes acute GI, cardiovascular, and CNS toxicities that are often fatal

Interference with mitochondrial oxidative phosphorylation

Also has pleiotropic effects on the activity of a number of other enzymes and ion channels, and these too may contribute to certain toxicities

Arsenic• Usually occur 2 to 8 weeks after

exposure • Paresthesias, numbness, and pain

Neurologic effects

• Hyperpigmentation and hyperkeratosisSkin changes • The most serious consequence of

chronic exposure • Particularly of the lungs, bladder and

skin• Arsenic-induced skin tumors - often

multiple and usually appear on the palms and soles

Increased risk for the development of

cancers

• Chronic exposure to arsenic in drinking water

Non-malignant respiratory disease

Cadmium• Preferentially toxic to kidneys and lungs

through increased production of reactive oxygen species

• Sources: Pollutant generated by mining, electroplating, and production of nickel-cadmium batteriesCan contaminate the soil and plants directly or through fertilizers and irrigation waterFood is the most important source of cadmium exposure for the general population

Cadmium• Principal toxic effects of excess

cadmium •caused by necrosis of alveolar epithelial cells

Obstructive lung disease

•may progress to end-stage renal diseaseRenal tubular damage

•associated with calcium lossSkeletal abnormalities

•combination of osteoporosis and osteomalacia•associated with renal disease“Itai-itai”•associated with an elevated risk of lung cancerLung cancer

OccupationalHealth Risks

Occupational Health Risks• Consequence of work-related

accidents and illnesses• Work-related accidents are the

biggest occupational health problem in developing countries

• Work-related diseases are more frequent in industrialized countries

Occupational Health Risks• Organic solvents

– Chloroform and carbon tetra chloride found in degreasing and dry cleaning agents and paint removers

– Cause dizziness and confusion, leading to CNS depression and even coma

– Lower levels are toxic for the liver and kidneys– Exposure of rubber workers to benzene and 1,3-

butadiene increases the risk of leukemia• Polycyclic hydrocarbons

– Released during the combustion of fossil fuels, particularly when coal and gas are burned at high temperatures

– In tar and soot– Among the most potent carcinogens, and industrial

exposures have been implicated in the dev’t of lung and bladder cancer

Occupational Health Risks• Organochlorines– Synthetic lipophilic products that resist degradation– Pesticides include DDT

(dichlorodiphenyltrichloroethane), lindane, aldrin, and dieldrin

– Nonpesticide organochlorines include polychlorinated biphenyls (pcbs) and dioxin (tcdd; 2,3,7,8-tetrachlorodibenzo-p-dioxin)

– Organochlorines disrupt hormonal balance because of antiestrogenic or antiandrogenic activity

– Dioxins and pcbs - follic ulitis and chloracne (acne, cyst formation, hyperpigmentation, and hyperkeratosis)

Occupational Health Risks• Mineral dusts

– Chronic, non-neoplastic lung disease = PNEUMOCONIOSIS

– Exposures to coal dust (e.G., Mining of hard coal), silica (e.G., Sandblasting, stone cutting), asbestos (e.G., Mining, fabrication, insulation work), and beryllium (e.G, mining, fabrication)

• Vinyl chloride– Synthesis of polyvinyl resins leads to the development

of angiosarcoma of the liver• Bisphenol A

– Synthesis of polycarbonate food and water containers and of epoxy resins that line almost all food bottles and cans

– Long been known as a potential endocrine disruptor

TOBACCO

Effects of TobaccoMost readily preventable cause of death in humans

Cigarette smoking, “snuff”, “2nd hand smoke”

30% of all smokers worldwide live in China, 10% live in India

Cause 90% of lung cancers

Tobacco contains between 2000 and 4000 substances, more than 60 of which have been identified as carcinogens

Smoking and Lung Cancer• Direct irritant effect on the

tracheobronchial mucosa• Inflammation and increased mucus

production (bronchitis)• Causes the recruitment of leukocytes to

the lung, with increased local elastase production and subsequent injury to lung tissue, leading to emphysema

• Polycyclic hydrocarbons and nitrosamines• Risk of developing lung cancer is related

to the number of pack years or cigarettes smoked per day

Smoking is linked to many other malignant and nonma lignant disorders that affect numerous organ systems

Maternal smoking increases risk of abortion, premature birth, and intrauterine growth retardation

ALCOHOL

Effects of Alcohol• Excessive amounts alcohol causes

serious physical and psychological damage

• Alcohol abuse is a far more widespread hazard and claims many more lives–Drunken driving and alcohol-related

homicides and suicides–Consequence of cirrhosis of the liver

Alcohol Concentration in the Blood• 80 mg/dl = legal definition of drunk driving – After 3 standard drinks, about three (12

ounce) bottles of beer, 15 ounces of wine, or 4 to 5 ounces of 80 proof distilled spirits

• 200 mg/dl = drowsiness occurs• 300 mg/dl = stupor • Higher levels = coma with possible

respiratory arrest• Rate of metabolism affects blood alcohol level• Chronic alcoholics can tolerate levels of up to

700 mg/dl due to accelerated ethanol metabolism

Metabolism of Alcohol• Absorbed unaltered• Metabolized by 3

enzyme systems:– CYP2E1– Alcohol

Dehydrogenase (ADH)– Catalase

• Acetaldehyde – acted upon by Aldehyde Dehydrogenase to form Acetic acid

Metabolites of Alcohol• Acetaldehyde

– Responsible for some of the acute effects of alcohol and for the development of oral cancers

– ALDH2*2 gene = low ALDH activity• Cannot tolerate alcohol, experiencing nausea,

flushing, tachycardia, and hyperventilation• NADH/NAD

– Increased NADH & decreased NAD = fatty liver & lactic acidosis

• ROS– Produced by CYP2E1 – Lipid peroxidation of plasma membrane– Causes release of endotoxin from enteric

bacteria = TNF & other cytokines resulting to hepatic damage

Adverse Effects of Alcohol

Acute alcoholism•Mainly on the CNS, but it may induce hepatic and gastric changes that are reversible if alcohol consumption is discontinued•Fatty change or hepatic steatosis•Acute gastritis and ulceration•Disordered cortical, motor, intellectual behavior & depressed, including those that regulate respiration. Respiratory arrest

Adverse Effects of Alcohol

Chronic alcoholism• Significant morbidity and have a shortened life span, related principally to damage to the liver,

gastrointestinal tract, CNS, cardiovascular system, and pancreas• Cirrhosis• Thiamine (vitamin B1) deficiency = peripheral neuropathies & Wernicke-Korsakoff Syndrome• Alcoholic cardiomyopathy• Acute and chronic pancreatitis• Fetal alcohol syndrome• Increased incidence of cancer of the oral cavity, esophagus, liver

Moderate consumption of Alcohol• 20-30 gm/day, corresponding to

approximately 250 ml of wine• ↑ high-density lipoprotein (HDL)

levels• Inhibit platelet aggregation • ↓ fibrinogen levels • Light to moderate alcohol

consumption = ↑ overall survival as compared to teetotalers and heavy drinkers

END OF 1ST PART

2ND PART

• Injury by Therapeutic Drugs and Drugs of Abuse• Injury by Physical Agents• Nutritional Diseases

INJURY BY THERAPEUTIC DRUGS AND DRUGS OF ABUSE

Injury by Therapeutic Drugs (Adverse Drug Reactions)

• Adverse drug reactions = untoward effects of drugs that are given in conventional therapeutic settings

• Due to direct actions of the drug or to immunologically based hypersensitivity reactions

Example of Adverse Drug Reaction

Anticoagulants • Warfarin (Vitamin K antagonist) and

Dabigatran (direct thrombin inhibitor)

Possibly fatal bleeding and thrombotic complications from under-treatment

Many foods and other drugs are rich in vitamin K = difficult to maintain safe therapeutic level

Menopausal Hormone Therapy• Previously known as HRT (hormone

replacement therapy)• Administration of estrogens together with a

progestogen• Counteract symptoms of menopause, could

prevent or slow the progression of osteoporosis and reduce the likelihood of myocardial infarction

Increased the risk of breast cancer, stroke, and venous thromboembolism and had no effect on the incidence of coronary heart

disease

Should not be used long term for chronic disease prevention

Oral Contraceptives• OCs nearly always contain a synthetic estradiol

and a variable amount of a progestin, but some preparations contain only progestins

• Inhibiting ovulation or preventing implantation

Increased risk of cervical cancer in HPV infected women

Threefold to sixfold increased risk of venous thrombosis and pulmonary thromboembolism

Increase in cardiovascular diseases in women (>35 yo) who smoke

Hepatic adenoma in older women with prolonged use

Anabolic SteroidsSynthetic versions of testosterone

Increase performance by base ball players, track-and-field athletes, and wrestlers has received wide publicity during the past decade

Inhibits production and release of luteinizing hormone & follicle-stimulating hormone by a feedback mechanism

Increases the amount of estrogens

Stunted growth in adolescents, acne, gynecomastia, and testicular atrophy in males, and growth of facial hair and menstrual changes in women

Psychiatric disturbances

Increased risk of myocardial infarction. Hepatic cholestasis

Acetaminophen • Most commonly used analgesic, toxicity is

common•Detoxification in the liver by phase II enzymes•Is excreted in the urine as glucuronate or sulfate conjugates

95% of acetaminophen undergoes detoxification

•NAPQI (n-acetyl-p-benzoquinoneimine) is a highly reactive metabolite•When acetaminophen is taken in large doses, unconjugated NAPQI accumulates and causes hepatocellular injury

5% or less is metabolized through CYPs

(primarily CYP2E) to NAPQI

Acetaminophen• 50% of cases of acute liver failure, with 30%

mortality• NAPQI mechanism of injury:

• Nausea, vomiting, diarrhea, and sometimes shock, followed in a few days by evidence of jaundice

• Centrilobular necrosis that may progress to liver failure

1. Covalent binding to hepatic proteins, which

causes damage to cellular membranes and

mitochondrial dysfunction

2. Depletion of GSH, making hepatocytes more susceptible to

reactive oxygen species-induced injury

Aspirin: Acetylsalicylic acid• Acute salicylate overdose causes

alkalosis as a consequence of the stimulation of the respiratory center in the medulla

• Followed by metabolic acidosis and accumulation of pyruvate and lactate, caused by uncoupling of oxidative phosphorylation and inhibition of the Krebs cycle

• Nausea to coma

Aspirin • Chronic aspirin toxicity (Salicylism) – Headaches, dizziness, ringing in the

ears (tinnitus), hearing impairment, mental confusion, drowsiness, nausea, vomiting, and diarrhea

– Acute erosive gastritis, gastric ulceration, gastric bleeding

– Bleeding tendency– Analgesic nephropathy =

tubulointerstitial nephritis with renal papillary necrosis

INJURY BY NONTHERAPEUTIC

AGENTS (DRUG ABUSE)

Injury by Nontherapeutic Agents (Drug Abuse)

• Illicit substance• Occasional users of illicit “recreational”

drugs suffer no apparent long-term health effects

• Acute effects may take a significant toll in the form of accidents, violence, or even fatal drug-related complications

• Generally involves the repeated or chronic use of mind-altering substances, beyond therapeutic or social norms, and may lead to drug addiction and overdose, both serious public health problems

Cocaine • Extracted from the leaves of the coca plant,

and is usually prepared as a water-soluble powder, cocaine hydrochloride

• Can be snorted or dissolved in water and injected subcutaneously or intravenously

• “Crack” form is far more potent• Intense euphoria and stimulation, making it

one of the most addictive drugs– Physical dependence generally does not

occur– Psychologic withdrawal is profound

& extremely difficult to treat

Cocaine • Acute and chronic effects– Tachycardia, hypertension, and peripheral

vasoconstriction, may also induce myocardial ischemia

– Precipitate lethal arrhythmias– Hyperpy rexia (thought to be caused by

aberrations of the dopaminergic pathways that control body temperature) and seizures

– Acute decreases in blood flow to the placenta, resulting in fetal hypoxia and spontaneous abortion

– Perforation of the nasal septum in snorters– Decreased lung diffusing capacity in

those who inhale the smoke– Dilated cardiomyopathy

Opiates • Opiate drugs of abuse include synthetic

prescription opiates such as oxycodone (oxycontin) and “street drugs,” most notably heroin

• An addictive opioid derived from the poppy plant that is closely related to morphine

• Even more harmful than that of cocaine• Effects on the CNS are varied and

include euphoria, hallucinations, somnolence, and sedation

Heroin • Adverse effects

•Profound respiratory depression, arrhythmia and cardiac arrest, and severe pulmonary edemaSudden death

•Severe edema, septic embolism, granulomasPulmonary injury

•S. Aureus, but fungi and a multitude of other organisms have also been implicatedInfections

•Abscesses, cellulitis, and ulcerations due to subcutaneous injections, hyperpigmentation over commonly used veinsSkin•Amyloidosis, focal and segmental glomerulosclerosis; both induce proteinuria and the nephrotic syndromeKidneys

Amphetamines and Related Drugs

Methamphetamine

•“speed” or “meth”•stronger effects in the CNS•inhibits presynaptic neurotransmission at corticostriatal synapses, slowing glutamate release•Long-term use leads to violent behaviors, confusion, and psychotic features that include paranoia and hallucinations

MDMA•3,4 methylenedioxymethamphetamine = “Ecstasy”•taken orally•effects, which include euphoria and hallucinogen-like feelings that last 4 to 6 hours•partly attributable to an increase in serotonin release in the CNS•reduces the number of serotonergic axon terminals in the striatum and the cortex, and it may increase the peripheral effects of dopamine and adrenergic agents

Marijuana • Most widely used illicit drug globally• “Pot”, “weed”• Leaves of the cannabis sativa plant,

which contain the psychoactive substance δ9-tetrahydrocannabinol (THC)

• Untoward anecdotal effects allergic or idiosyncratic reactions or possibly related to contaminants in the preparations rather than to the pharmacologic effects of marijuana

Marijuana• Beneficial effects of marijuana– treat nausea secondary to cancer

chemotherapy and as an agent capable of decreasing pain in some chronic conditions

• Distorts sensory perception and impairs motor coordination– acute effects clear in 4 to 5 hours

• With continued use cognitive and psychomotor impairments occur a potential cause of automobile accidents

• Increases the heart rate and blood pressure, and it may cause angina in a person with coronary artery disease

Marijuana • Chronic marijuana smoking– laryngitis, pharyngitis, bronchitis,

cough and hoarseness, and asthma-like symptoms have all been described, along with mild but significant airway obstruction

• Large number of carcinogens that are also present in tobacco

• Smoking a marijuana cigarette, compared with a tobacco cigarette, is associated w/ threefold increase in amount of tar inhaled

Other DrugsPCP

(phencyclidine, an anesthetic

agent) = “OOBE”

Vicodin, and ketamine, an

anesthetic agent

Spray paints, paint thinners, and some glues that contain TOLUENE •Mild to severe dementia•Bizarre and often aggressive behavior that leads to violence or depressed mood and suicidal ideation

“Bath salts”•Contain 4-methyl-meth-cathinone and methylenedioxypyrovalerone•Amphetamine-like effects when snorted or eaten•Agitation, psychosis, myocardial infarction, and suicide

INJURY BY PHYSICAL AGENTS

Mechanical trauma • Type of injury depends on the shape of

the colliding object, the amount of energy discharged at impact, and the tissues or organs that bear the impact

• Mechanical forces, and the patterns of injury can be divided into abrasions, contusions, lacerations, incised wounds, and puncture wounds

• Forensic pathology

Thermal Injury• Excessive heat and excessive cold

are important causes of injury– Thermal burns– Hyperthermia– Hypothermia

Thermal Burns• Caused by fire or by scalding• Consequence of injuries caused by fire and smoke

inhalation• Clinical significance of a burn injury:

Depth of the burns

Percentage of body surface involved

Internal injuries caused by the inhalation of hot and toxic fumes

Promptness and efficacy of therapy, especially fluid and electrolyte management and prevention or control of wound infections

Thermal Burns• According to the depth of the injury

Superficial burns

•Formerly known as first-degree burns•Confined to the epidermis

Partial thickness burns

•Formerly known as second-degree burns•Involve injury to the dermis

Full-thickness burns

•Formerly known as third-degree burns: extend to the subcutaneous tissue•Formerly known as fourth-degree burns: involve damage to muscle tissue underneath the subcutaneous tissue

Thermal Burns• Greatest threats to life

Shock, sepsis, and respirator

y insufficiency• Systemic inflammatory response syndrome

= shock• Hypermetabolic state = increased need for

nutritional support

Burns of more than 20% of the body

surface

• Pseudomonas aeruginosa• Methicillin-resistant S. Aureus• Candida species

Infection

• Early excision and grafting of the burn wound

Organ system failure resulting from burn

sepsis

• Inhalation of heated air and noxious gases in the smoke

Injury to the airways and lungs

Hyperthermia • Prolonged exposure to elevated ambient

temperatures• Heat cramps

– Loss of electrolytes via sweating– Cramping of voluntary muscles, in association with

vigorous exercise, is the hallmark– Heat-dissipating mechanisms are able to maintain

normal core body temperature• Heat exhaustion

– Most common: hyper thermic syndrome– Prostration and collapse, and it results from a failure

of the car diovascular system to compensate for hypovolemia caused by dehydration

– After a period of collapse, which is usually brief, equilibrium is spontaneously re-established if the victim is able to rehydrate

Hyperthermia • Heat stroke – Associated with high ambient

temperatures, high humidity, and exertion– Thermoregulatory mechanisms fail,

sweating ceases, and the core body temperature rises to more than 40°C, leading to multiorgan dysfunction that can be rapidly fatal

– Generalized vasodilation, with peripheral pooling of blood and a decreased effective circulating blood volume

– Hyperkalemia, tachycardia, arrhythmias, and other systemic effects

Hyperthermia• Malignant hyperthermia– Characterized by a “heat-stroke–like” rise

in core body temperature and muscle contractures following exposure to common anesthetics due to inherited mutations in RYR1

– Ryanodine receptor 1 (RYR1), which is located in the sarcoplasmic reticulum of skeletal muscle• RYR1 regulates the release of calcium

from the sarcoplasm• Heat stroke deranges RYR1 function →calcium to leak into the cytoplasm→muscle contraction and heat production

Hypothermia • Prolonged exposure to low ambient

temperature• High humidity, wet clothing, and

dilation of superficial blood vessels resulting from the ingestion of alcohol hasten the lowering of body temperature

• Body temperature of about 90°F (32.2°C): loss of consciousness occurs, followed by bradycardia and atrial fibrillation at lower core temperatures

Hypothermia • Hypothermic injury:

• Slow chilling may induce vasoconstriction and increase vascular permeability, leading to edema and hypoxia = “trench foot”

• Sudden, persistent chilling, the vasoconstriction and increased viscosity of the blood in the local area may cause ischemic injury and degenerative changes in peripheral nerves

Direct effects

•Mediated by physical disruptions within cells by high salt concentrations caused by the crystallization of intra- and extracellular water

Indirect effects

•Circulatory changes, which vary depending on the rate and duration of the temperature drop

Electrical Injury• Contact with low-voltage currents (i.e.,

at home and workplace) or high-voltage currents carried by high-power lines or produced by lightning

• Two types of injuries: 1. Burns 2. Ventricular fibrillation OR cardiac &

respiratory center failure• Depend on the strength (amperage),

duration, and path of the electric current within the body

Electrical Injury• Voltage in the household and workplace (120 or

220 V) is high enough that with low resistance at the site of contact , sufficient current can pass through the body to cause serious injury, including ventricular fibrillation

• Alternating current (AC) – Type supplied to most homes – Induces tetanic muscle spasm, so that when a

live wire or switch is grasped, irreversible clutching is likely to occur, prolonging the period of current flow

– Extensive electrical burns and spasm of the chest wall muscles, producing death from asphyxia

Electrical InjuryCurrents generated from high-voltage sources

• Cause similar damageThe large current flows generated are more likely to produce paralysis of medullary centers and extensive burns• Lightning

Magnetic fields and microwave radiation• Produce burns, usually of the skin and

subjacent connective tissue when sufficiently intense

Ionizing Radiation Injury•Energy that travels in the form of waves or high-speed particlesRadiation

•Ex: UV and infrared light, microwave, and sound waves•Can move atoms in a molecule or cause them to vibrate, but is not sufficient to displace bound electrons from atoms

Nonionizing Radiation

•Has sufficient energy to remove tightly bound electrons•X-rays and gamma rays, high-energy neutrons, alpha particles and beta particles

Ionizing Radiation

•Fibrosis, mutagenesis, carcinogenesis, and teratogenesisCauses:

Ionizing Radiation Injury• Units of radiation

Curie (Ci)

an expression of the amount

of radiation emitted by a

source

Gray (Gy)

is a unit that expresses the

energy absorbed by the target

tissue per unit mass

Sievert (Sv)

is a unit of equivalent dose

that depends on the biologic rather than the physical effects

of radiation

Ionizing Radiation Injury• Biologic effects of Radiation determinants

•Cumulative effect = fractioned dosesRate of delivery•Body area of exposure = higher doses tolerated if limited area is exposedField size•rapidly dividing cells are more vulnerable to injury than are quiescent cellsCell proliferation

•production of reactive oxygen speciesOxygen effects and hypoxia

•Damage to endothelial cells = narrowing or occlusion of blood vesselsVascular damage

Ionizing Radiation Injury

NUTRITIONAL DISEASES

Malnutrition • Consequence of inadequate

intake of proteins and calories, or deficiencies in the digestion or absorption of proteins

• Loss of fat and muscle tissue, weight loss, lethargy, and generalized weakness

• Developing nations –malnutrition, starvation, obesity

Dietary insufficiency• Appropriate diet:

• Primary malnutrition – one or all of these components are missing from the diet

• Secondary malnutrition – malnutrition results from malabsorption, impaired utilization or storage, excess loss, or increased need for nutrients

sufficient energyamino acids and fatty acids • to be used as building blocks for

synthesis of proteins and lipids

vitamins and minerals• function as coenzymes or

hormones in vital metabolic pathways

• or, as in the case of calcium and phosphate, as important structural components

Conditions that lead to malnutrition

Poverty Infections

Acute and chronic illnesses

Chronic alcoholism

Ignorance and failure of diet

supplementation

Self-imposed dietary

restriction

Other causes

Protein Energy Malnutrition (PEM)• Determined by body mass index– Weight in kilograms divided by height in meters

squared– Normal range 18.5 to 25 kg/m2

• Thickness of skin folds – fat stores• Circumference of mid-arm – muscle mass• Serum proteins – visceral protein• 2 spectrums of PEM syndromes:

Marasmus•somatic compartment, represented by proteins in skeletal muscles

Kwashiorkor•visceral compartment, represented by protein stores in the visceral organs, primarily the liver

Marasmus • Weight falls to 60% of normal

for sex, height, and age• Growth retardation and loss

of muscle• Visceral protein compartment

minimally depleted• Serum albumin levels are

either normal or only slightly reduced

• Extremities are emaciated• Anemia & immune deficiency

Kwashiorkor • Protein deprivation is relatively

more severe than the deficit in total calories

• Severe depletion of the visceral protein compartment

• Hypoalbuminemia = generalized or dependent edema

• Skin lesions = flaky paint• Hair changes = flag sign• Fatty liver, apathy, listlessness,

and loss of appetite• Defects in

immunity and secondary infections

Cachexia • PEM in AIDS or advanced cancers• Extreme weight loss, fatigue, muscle

atrophy, anemia, anorexia, and edema

• Mediators secreted by tumors and during chronic inflammatory reactions

Proteolysis-inducing factor• glycosylated

polypeptide

Lipid-mobilizing factor • TNF and IL-6

Anorexia Nervosa and Bulimia

Anorexia nervosa

•Highest death rate of any psychiatric disorder•Altered serotonin metabolism•Similar to those in severe PEM•Amenorrhea•Decreased thyroid hormone release•Bone density is decreased•Cardiac arrhythmia & sudden death

Bulimia •Large amounts of food, principally carbohydrates, are ingested, only to be followed by induced vomiting•Menstrual irregularities•Frequent vomiting and the chronic use of laxatives and diuretics•Electrolyte imbalances•Pulmonary aspiration•Esophageal and gastric rupture•Cardiac arrhythmia & sudden death

Vitamin Deficiencies• Thirteen vitamins are necessary for health– Fat soluble and water soluble

• Vitamins A, D, E, and K are fat-soluble• Fat-soluble vitamins are more readily stored

in the body• Endogenous synthesis of vitamins: D, K &

niacin• Deficiencies:– Primary = dietary insufficiency– Secondary = disturbances in absorption,

transport, storage or metabolism

Vitamin A• Retinol (alcohol), retinal

(aldehyde), and retinoic acid (acid)

• Fat soluble• Functions:

Maintenance of normal

vision

Cell growth and

differentiation

Host resistance to

infections

Adipogenesis and fatty acid

metabolism

Vitamin ADeficiency • Occurs due to:

undernutrition or malabsorption of fats

• Night blindness• Epithelial metaplasia

and keratinization– Xerophthalmia– Bitot’s spots– Keratomalacia – Squamous metaplasia

Toxicity• Liver = polar bear,

whales, sharks and tuna

• Acute– Headache, dizziness,

vomiting, stupor, and blurred vision, pseudotumor cerebri

• Increased osteoclast activity

• Teratogenic effect of retinoids

Vitamin D• Endogenously synthesized

fat soluble vitamin; deep-sea fish, plants, and grains are dietary sources

• Cholecalciferol (vitamin D3)

• Maintenance plasma levels of calcium and phosphorus – Metabolic functions– Bone mineralization– Neuromuscular

transmission

Functions:

Stimulation of intestinal calcium absorption

Stimulation of calcium reabsorption in the kidney

Interaction with PTH in the regulation of blood calcium

Mineralization of bone – osteocalcin

Vitamin DDeficiency – insufficient diet and limited sun exposure– Rickets

• Craniotabes• Frontal bossing• Rachitic rosary• Pigeon breast deformity• Bowing of the legs

– Osteomalacia• Gross fractures or

microfractures– Hypocalcemic tetany– Osteoporosis (vitamin D

insufficiency)

Vit D supplements – increased lymphocyte count, enhanced clearance of MTB in sputumToxicity – Megadoses of oral

vitamins– Not from prolonged

exposure to sunlight– Metastatic calcifications– Bone pain – Hypercalcemia

Vitamin C • Water soluble vitamin• Ascorbic acid• Entirely dependent

on the diet for this nutrient

• Milk and some animal products (liver, fish) and is abundant in a variety of fruits and vegetables

• Functions:Activation of prolyl and lysyl hydroxylases

Hydroxylation of procollagen

Promotes secretion of procollagen

Antioxidant properties – direct and indirect

Vitamin C

• Vitamin excess– Mild antihistamine action = Tx for common colds– Toxicities are rare

• Iron overload due to increased absorption• Hemolytic anemia in G6PD deficiency patients• Calcium oxalate stones

Trace Elements

Obesity• An accumulation of adipose tissue that is

of sufficient magnitude to impair health• ↑ Incidence type 2 diabetes,

dyslipidemias, cardiovascular disease, hypertension, and cancer

• BMI measurements18.5 to 25 kg/m2 Normal BMI range

25 to 30 kg/m2Overweight

> 30 kg/m2 Obese

Obesity• Distribution of the stored fat– Central, or visceral, obesity– Subcutaneous obesity

• Refined sugars, sweetened beverages, and vegetable oils

• Disease of caloric imbalance – Intake of calories ≥ calorie

consumption – Genetic influences play an

important role in weight control – But the inter action between

multiple factors

Major public health problem in developed countries and an emerging health problem in developing nations, such as

India

Obesity • Neurohumoral control of energy balance– Peripheral or afferent system – generates

signalsLeptin Peptide YYAdiponectinInsulin Ghrelin

– Arcuate nucleus in hypothalamus - processes and integrates neurohumoral signals• POMC (pro-opiomelanocortin) and CART (cocaine and

amphetamine-regulated transcripts) neurons• NPY (neuropeptide Y) and AgRP (Agouti-Related

Peptide) neurons – Efferent system

• Anabolic – control food intake• Catabolic – control energy expenditure

Components of the Afferent System• Regulates appetite and satiety• Leptin

– Product of the ob gene– 16-kd hormone synthesized by fat cells– Signal for energy sufficiency = leptin secretion is stimulated

when fat stores are abundant– Stimulates POMC/CART neurons that produce anorexigenic

neuropeptides– Stimulates physical activity, heat production, and energy

expenditure• Adiponectin (guardian angel against obesity)

– Hormone is produced mainly by adipocytes– Directs fatty acids to muscle for their oxidation– Decreases the influx of fatty acids to the liver &

decreases glucose production– Increase in insulin sensitivity – Inactivates acetyl coa carboxylase

thru binding with adipor1 and R2

Components of the Afferent System• Gut hormones• Ghrelin

– Produced in the stomach and arcuate nucleus of the hypothalamus

– The only known gut hormone that is orexigenic effect– Likely to stimulate NPY/AgRP neurons– Post-prandial level attenuation = overeating

• PYY– Secreted by endocrine cells in the ileum & colon– Reduces energy intake– Stimulates POMC/CART neurons

• Amylin – Peptide secreted with insulin by β cells– Reduces food intake and weight gain– Stimulates POMC/CART neurons

Consequences of Obesity

Consequences of Obesity• Metabolic syndrome

– Visceral adiposity, insulin resistance, hyperinsulinemia, glucose intolerance, hypertension, hypertriglyceridemia, and low HDL cholesterol

• Insulin resistance and hyperinsulinemia• ↑ Risk coronary artery disease• Nonalcoholic fatty liver disease• Cholelithiasis (gallstones)• Hypoventilation syndrome (Pickwickian

syndrome)– Hypersomnolence– Sleep apnea– Cor pulmonale

• Osteoarthritis

Obesity and Cancer• ↑ risk for cancers of the esophagus,

pancreas, colon and rectum, breast, endometrium, kidney, thyroid, and gallbladder

• Possibly due to the following:

Elevated insulin levels Effects on steroid hormone

Low adiponectin levels = Elevated

insulinPro-inflammatory state

Diet and Cancer• Incidence of cancer varies

with geographic areas• Environmental factors

clearly play a role including diet

• There are few mechanisms that link diets and specific types of cancer

• Aspects of diet concerned with Carcinogenesis – Content of exogenous

carcinogens– Endogenous synthesis of

carcinogens from dietary components

– Lack of protective factors

• Exogenous carcinogens– Aflatoxin = liver CA– Food additives, pesticides,

artificial sweeteners• Endogenous carcinogens

– Gastric CA– Nitrosamines– Nitrosamides

• High animal fat and low fiber– Colon CA– Breast CA

• Low vitamins– Vitamin C, β carotene,

selenium, Vitamin D

Diet and Atherosclerosis• Association of dietary cholesterol

and saturated animal fats with development of atherosclerosis

• Role that caloric restriction and special diets may play in the control of body weight and prevention of cardiovascular disease

• Activation of sirtuins and on lowering of insulin and IGF-1 levels

Diet and Atherosclerosis• Focus on eating an enjoyable

and healthy diet

Rich in fish

Vegetables

Whole grains Fruits

END

Health & Medicine

Environmental and nutritional diseases animated