M2C Unit 3 Diseases part 2

PDE5A inhibits cGMP, breaking it down and result in what?

decreased vasorelation

How does H2S increase vasorelaxation?

Inhibits PDE5A which increases cGMP = increasing vasorelaxation

Parkinson’s disease has low?

dopamine (give L-dopa as treatment)

Pheochromocytoma has high?

epinephrine

Carbidopa inhibits what and helps what last longer?

inhibits amino acid decarboxylase which allows longer lasting L-DOPA

Pheochromocytoma

causes excessive release of catecholamines (epinephrine and norepinephrine) = increased vasoconstriction = high BP

Severe headaches

Sweating (diaphoresis)

Palpitations (tachycardia)

Hypertension (often episodic, sometimes sustained)

Pheochromocytoma symproms

Pheochromocytoma treatment

First: α-blockade (phenoxybenzamine)

Then: β-blockade = propanolol(only after α-blockade)

Catecholamine synthesis inhibitor = metyrosine

Definitive: surgical removal

• important to follow this order, never give beta-blocker first

Retinol

• Supports reproduction

• Major transport and storage form

Retinal

Active in vision

Retinoic acid

Regulates cell differentiation, growth, and embryonic development

Beta-carotene

Antioxidant

Toxicity-Hypervitaminosis A

Birth defects due systemic use of retinoic acid analogues for severe acne or psoriasis

Deficiency -Hypovitaminosis A

Night blindness

Blindness (xerophthalmia)

Keratinization (Hyperkeratosis)

Night blindness

• Inadequate supply of retinal to retina

Blindness (xerophthalmia)

• Lack of vitamin A at the cornea

• Develops in stages

• Corneal drying (xerosis)

• Triangular gray spots on eye (Bitot spots)

• Softening of the cornea (keratomalacia)

• Corneal degenaration and blindness (xerophthalmia)

Keratinization (Hyperkeratosis)

Change in shape & size of epithelial cells

• Skin becomes dry, rough, and scaly

• Normal digestion and absorption of nutrients from GI tract falters

• Weakened defenses in the respiratory tract, vagina, inner ear, and urinary tract

Symptoms of Beta-carotene Excess

Beta-carotene from food is not efficiently converted

• Stored in the fat under skin = yellow skin

• -Not harmful

calcitriol

aka Vitamin D = 1,25-dihydroxy vitamin D3

What functions in concert with parathyroid hormone (PTH) and calcitonin to regulate serum calcium and phosphorous levels?

Calcitriol

• Dark skin

• Breastfeeding without supplementation

• Lack of sunlight

• Use of non-fortified milk

• Lose ability to activate vitamin D (elderly)

• Little or no milk in diet

• Vegan diet

Vitamin D defiency causes

Vitamin D deficiency effects

Rickets Osteomalacia Osteoporosis

Rickets

• Affects mainly children worldwide

• Symptoms

– Inadequate calcification of bones

– Growth retardation

– Misshapen bones including bowing of the legs

– Lax muscles (resulting in a protruding abdomen) and muscle spasms, beaded ribs

Vitamin D toxiicty

Elevated Calcium

• Calcification of soft tissues such as blood vessels, kidney, heart, lungs and tissues around joints

Vitamin E deficiency

• Rare

• Primary deficiency due to inadequate intake is rare

• Secondary deficiency due to fat malabsorption such as cystic fibrosis, pancreatic insufficiency

• Erythrocyte hemolysis

• Due to oxidation of polyunsaturated fatty acids

• Hemolytic anemia can be treated with vitamin E.

Vitamin K Deficiency

• deficiency in infants is a hemorrhagic syndrome

• slow clotting of blood

• hemmorrge, especially in newborns

Nitric Oxide (NO) Amino acid precurser

Arginine

Creatine precursor

Glycine

B6 or Pyridoxal Deficience will result in?

increased = DOPA, 5-hydroxytryptophan, Glutamate, and histdine

decreased = Dopamine, Serotonin, GABA, Histamine

Norepinephrine Deficit

Low energy, depression

Degradation of Catecholamines products

Vanillylmandelic acid (VMA) from epi/norepinephrine

Homovanillic acid (HVA) from dopamine

Monoamine oxidase A deficiency

• Low levels of vanillylmandelic acid and homovanillic acid

• mild intellectual disability and behavioral difficulties (including aggressive and sometimes violent behaviors

Monoamine oxidase inhibitors (MAOIs)

a class of medication used to treat depression

Cheese effect –Tyramine

• degraded by MAO.

• If individuals are taking MAO inhibitors, tyramine levels can accumulate.

• Tyramine is taken up into nerve terminals by NET (the norepinephrine reuptake transporter) and causes the release of catecholamines.

5-HIAA=5-hydroxyindoleacetic acid precursor

Seratonin

5-HIAA=5-hydroxyindoleacetic acid enzymes

Monoamine oxidase (MAO) + Aldehyde dehydrogenase

Serotonin

regulate behaviors, such as eating, sleep, appetite, mood, cognitive functions, body temperature, circadian rhythmicity and neuroendocrine function.

Glutamate- γ-amino butyric acid (GABA)

main inhibitory neurotransmitter counterbalancing neuronal excitation in the cerebral cortex.

• anxiety reduction, calming, and release of tension.

• When this balance is perturbed, seizures may develop

GABA positive allosteric modulator

• benzodiazepines, barbiturates, ethanol, and induction anesthetics

• cause sedation, anticonvulsant, anxiolytic, and muscle relaxant effects.

Creatine

levels in urine can be used to estimate muscle mass and kidney damage.

• If muscle mass decrease, then creatinine levels in the urine also decreases. On the other hand, accumulation of creatinine is an indication of renal damage.

Marasmus

• Severe, chronic, overall malnutrition

• Fat and muscle depleted

• Skin hangs loose and bones are clearly visible

• Alert and ravenously hungry at first - eventually lose appetite and become apathetic

Protein-energy malnutrition (PEM)

• Typically deficient in one or more micronutrients as well

• Many implications for child health

• WHO estimates PEM plays a role in 5 million child deaths per year

Kwashiorkor

• Sudden and recent deprivation of protein

• Severe edema

• Ascites - fluid accumulation in abdominal cavity

• Apathetic

• Cracked and peeling skin

• Enlarged, fatty liver

• Sparse, unnaturally blond or red hair

Kwashiorkor

Protein deficiency

Marasmus

Energy deficiency

Thiamin deficiency = Beriberi

– Malnourished, homeless

– Alcohol abuse

• Wernicke Korsakoff syndrome

– Weight loss regimens

• poor appetite, irritability, apathy, confusion and weight loss

B2 = Riboflavin Deficiency

• Inflammation of membranes

– Sore throat

– Cheilosis (kye-LOH-sis)

– Glossitis

– Stomatitis

– Seborrheic dermatitis

• Bloodshot eyes, sensitivity to bright light

B3 = Niacin mild deficiency cause

Alcoholics – Corn-based diets

B3 = Niacin deficiency

Pellagra (rough skin) – Diarrhea, dermatitis, dementia and death (“4Ds”)

• Bilateral symmetrical rash (sunlight exposure) of pellagra)

• Casal’s necklace

Niacin (B3) toxicity

From supplementation

• Used for lowering LDL

• Niacin flush and itching

– Can be treated with low dose aspirin or ibuprofen (Advil)

Pyridoxine (Vitamin B6) Deficiency

Cheliosis, glossitis, pellagra-like dermatitis, depression, confusion

Pyridoxine (Vitamin B6) Deficiency causes

• Rare

• Newborn infants fed formulas low in B6

• Women taking oral contraceptives

• Alcoholics

• Consequence of drug therapy

– Tuberculosis

• Isoniazid

– Rheumatoid arthritis

• Penicillamine

Pyridoxine (Vitamin B6) toxicity

Irreversible nerve degeneration

Pharmacological Use of Pyridoxine

Claims include help for symptoms of PMS, asthma, carpal tunnel syndrome, depression, pregnancy to control nausea and diabetic neuropathy

Side effects of high doses of Pyridoxin (toxicity)

Irreversible nerve damage

• Severe sensory nerve damage

• Walking difficulties

• Numbness of hands and feet

Folate (B9) deficiency

• Macrocytic anemia

• Weakness, fatigue, headache, palpitations and shortness of breath

• Neural tube defects

Causes of Folate (B9) deficiency

• Suboptimal intake

• Increased utilization

– Pregnancy

• Inadequate absorption

– Celiac disease

– Crohn disease

• Antifolate therapy

– Methotrexate

• Alcoholics

• Elderly with poor diet

• Antacids

Cobalamin (B12) deficiency causes

• Decreased Intake:

– Pure vegan diet

– Malnutrition

• Malabsorption

– Decreased intrinsic factor

• Autoimmune disease

• Elderly

– Decreased gastric acid

• Proton pump inhibitors

– Removal of terminal ileum

• Bariatric surgery

• Crohn’s Disease

• Cancer

Cobalamin (B12) deficiency

• Pernicious anemia – Autoimmune inactivation of IF

• Symptoms – Megaloblastic anemia – Nerve damage (tingling in the hands and feet) – Painful swollen tongue

Biotin (B7) Deficiency

rare

– Biotinidase enzyme deficiency

– Excessive consumption (>12) of

raw eggs (avidin)

Biotinidase Deficiency

①Body is unable to reuse and recycle the vitamin biotin.

①An inherited disorder

• Autosomal recessive

②Chief characteristics:

• Weak muscles (hypotonia), seizures, hair loss (alopecia), an inflammatory skin rash (eczema), developmental delays, and lactic aciduria

Vitamin C deficiency

• Scurvy

– Muscle weakness

– Joint pain

– Impaired wound healin

– Loose tooth

– Bleeding and swollen gums

– Bruised skin

– Fatigue

Vitamin C deficiency causes

Urban or poor older adults • Severe burns, fractures • Alcohol decreases absorption • Smoking depletes tissue levels

Thiamin (B1) uses = TPP

Enzymes involved:

• A- α-ketoglutarate dehydrogenase

• T- Transketolase (HMP pathway)

• P-Pyruvate dehydrogenase

• B-Branched-chain α-ketoacid dehydrogenase

Acute Intermittent Porphyria

• Episodic, variable expression

• Anxiety, confusion, paranoia

• Acute abdominal pain

• No photosensitivity

• Port-wine urine in some patients

• Never give barbiturates

Acute Intermittent Porphyria inhibits what enzyme

Porphobilinogen deaminase aka Hydroxymethylbilane synthase

Porphyria cutanea tarda

• Most common porphyria

• Inflammation, blistering, shearing of

skin area exposed to light

• Hyperpigmentation

• Exacerbated by alcohol

• Photosensitivity

• Red-brown to deep-red urine

• Never give barbiturates

Porphyria cutanea tarda inhibited enzyme

Uroporphyrinogen decarboxylase

Acquired Porphyria: Plumbism

Pb poisoning

• Pb inhibits the last enzyme, Ferrochelatase

• Ferrochelatase may also not work in severe Fe deficiency.

Zn protoporphyrin

Zn goes in when Ferrochelatase is down

Hemochromatosis

Hemosiderin deposits in:

Liver - cirrhosis

Pancreas - diabetes

Joints - arthritis

Skin - dermatitis

His-93 is complexed to the atom, and His-64 forms a hydrogen bond with

iron, oxygen

2,3 Bisphospho-D-glycerate (2,3BPG) effect on Hb

lowers its affinity for oxygen by stabalizing the T state