Drugs and Diseases
Block 1 Unit 1
Drug
Disease
Introduction to Cell Biology
None discussed
Introduction to Proteins Part 1
None discussed
Plasma Membrane 1
Cancer: alterations of membrane proteins and/or lipid are key to metastasis and invasion of tumor cells
as they spread throughout the body; specific type of membrane transporter protein (MDR) is the basis
for multi drug resistance that can occur during chemotherapy
Diabetes: defective insulin signaling, defective function of glucose transporters
Heart Disease: defective cell to cell communication (ex: connexins in arrhythmias)
Hereditary spherocytosis: detected by osmotic fragility test, autosomal dominant (1/5000), RBC have
weakened interaction of peripheral and integral membrane proteins, cells lack flexibility and “clog up”
the sinusoids of the spleen
Plasma Membrane 2
Insulin resistance and Type II diabetes: malfunction in the GLUT4 insulin receptor
Epilepsy: hyperexcitability defect (nerve cells)
Diabetes Mellitus: insulin hypersecretion defect (β cells)
Cystic Fibrosis: transport defect (epithelial cells)
Dilated cardiomyopathy
Cardiac Arrhythmias
Myasthenia gravis: autoimmune, AB formed against acetylcholine receptors; hallmark is skeletal muscle
weakness that increases with activity and improves upon rest (facial muscles are particularly
susceptible); tx: acetylcholinesterase inhibitors, andimmunosuppressives
Cardiotonic steroid drugs act by inhibiting the function of the Na+/K+ ATPase. Digitalis is a drug used for
the treatment of CHF (increases strength of heart contraction without increasing heart rate). Digitalis
steroid-based compounds are ouabain and digitoxigenin.
Ouabain: inhibits dephosphorylation of E2-P form, locking the pump in a non-functional
state; decreased pump action increases the [Na+]in cardiac muscle cells, leading to
increased [Ca+] in cells (Na+-Ca2+) transporter; these calcium-mediated signals act to
increase the contraction strength of the heart.
MDR1: MDR1 pump uses ATP energy to export drugs from the cytosol. These drugs are small and
planar, such as those used to treat cancer (adriamycin, doxorubicin, vinblastine) and malaria, and diffuse
into a cell. Since the drugs can’t get in the cell, they fail to exert their benefits; cells b/m chemo
resistantuncontrollable tumor growth/spread, poor prognosis. The MDR1 gene is often amplified in
tumor cells.
Cystic fibrosis: chronic and progressive autosomal recessive genetic disease of the body’s mucous
glands; primarily affects the respiratory and digestive systems (pt average lifespan 30 yrs). CFTR=cystic
fibrosis transmembrane regulator, novel ABC-type chloride channel. Most cases of CF are due to a
deletion of 3 base pairs and loss of a single aa. The mutated protein is made but fails to reach the
surface. The function of this protein is to pump chloride ions out of the cell (it is present on the apical
surface of epithelial cells). Chloride ions accumulate inside cell, causing Na+ and water to come in from
cell surfaceloss of water from EC space results in thick, dehydrated mucusdefective function of
respiratory tract, cilia, and infections
Introduction to Proteins 2
None discussed
Cell Structure and Function
Cytochalasins A,B,C,D,E: secreted by various fungi. The molecules bind to the ends of actin filaments and
prevent further polymerization.
Phalloidin: binds to actin filaments and stabilizes them against depolarization; “Angel of Death”; cell fails
to function
Colchicine, colcemid: inhibit addition of tubulin molecules, leading to microtubule
depolymerization
Taxol: used for cancer; stabilizes
Blood
Hereditary spherocytosis: spectrin abnormality; RBC can not deform well and get stuck in capillaries;
hemolysis of RBC and anemia
HIV infection: virus binds to CD4 and co-receptor to initiate infection, viral RNA transcribed to DNA and
integrates into the host DNA and mRNA is produced; viral replication occurs, which destroys T-helper
cells (AIDS develops when T-cell level is less than 200).
Epithelial Tissue
Primary ciliary dyskinesia: aka immotile cilia syndrome or Kartagener’s syndrome; immotile cilia lacking
structurally supportive dynein cross arms or radial spokes
Patients can’t clear respiratory tracts, get numerous lung infections, are infertile, and
have malrotation of the heart
Phemphigus vulgaris: autoimmune disease that attacks cadherin molecules (desmoglein); antibodies to
cadherin desmogleindesomosomes destroyed (particularly in skin); frequently this disease responds
to steroid therapy
Introduction to Proteins 3
Spongiform encephalopathies: caused by prion proteins
Clinical example: CJD
Prions: chromosomally encoded proteins; infectious and self-propagating; in the
absence of nucleic acid, replicates by transferring protein misfolding to form insoluble
aggregates; PrP: lacks nucleic acid
Normal prion proteins are α-helical and soluble, prion diseases are due to aggregates of
insoluble prion β-sheets
Connective Tissue
Hypercellular obesity: overabundance of adipocytes; caused from overfeeding an infant
Hypertrophic obesity: accumulation and storage of fat in unilocular fat cells (increases their size by up to
four times); cause of insulin resistance and Type II diabetes
Anaphylactic shock: caused by release of too much histamine from granules of mast cells; leads to
vasodilation and constriction of smooth muscle cells in the bronchioles
Scurvy: lack of Vitamin C (required as co-factor for hydroxylation of proline and therefore the H bonding
between α-fibers to form tropocollagen)
Ehler’s Danlos Type VII: 1 aa change in procollagen peptidase (procollagen can’t self aggregate to fibrils);
causes hyperflexible joints, dislocations, and soft skin
*Elevation of glycine levels in the urine are indicative of collagen diseases
Ehler-Danlos Type III: deficiency in Type III collagenaneurysms and intestinal rupture
Emphysema: lung dysfunction caused by breakdown of elastic fibers
Marfan’s Syndrome: poor microfibril formation in elastic fiber; aortic rupture and rupture of other blood
vessel
Edema: Potent and prolonged inflammatory response causes accumulation of excess tissue fluid within
loose CT beyond what can be returned via the capillaries and lymph vessels
Causes:
1. Blocked lymphatics (surgery, elephantiasis)
2. blocked venous return (compromised veins)
3. liver disease (insufficient albumin production by liver to pull H2O back in vessel)
4. increased vascular permeability (histamine from mast cells)
5. hypertension (due to increased hydrostatic pressure @ arterial end of capillary bed)
6. starvation (lack of plasma proteins that results in H2O remaining in ECM)
7. myxedema (mucous edema; overproduction of GAGs during hypothyroidism)
Myoglobin and Hemoglobin
Hemoglobin Diseases
Hb-S (Sickle cell disease): caused by a mutation from GluVal; sickling of cells is so dangerous because
the sickled cells occlude blood vessels resulting in serious organ damage
Hb-C disease: heterozygous Hb-SC individuals are mildly anemic; caused by a mutation from GluLys;
characterized by the presence of “target cells” and Hb-C can crystallize in RBC
Hb-SC: not as serious as sickle cell disease
α -thalassemias: deletion of genes for α-subunit; severity depends on # of genes deleted (1 in 4)
β-thalassemias: can result from gene deletion, defects in transcription, defects in mRNA processing,
defects affecting mRNA translation, unstable mRNA or unstable
Sickle cell-β-thalassemias: reduced levels the normal β-chain and presence of Hb-S β-chain
Sickle cell disease: due to released reduced levels of normal β-chain; severity depends on
severity of thalassemias
Sickle cell crisis: HbS deoxygenationHbS aggregationRBC sickling (irreversible
sickling)decreased filterability
TCA Cycle
Thiamine deficiency: deficiency of B1 vitamin can lead to disturbances in carbohydrate metabolism and
to decreased transketolase activity, particularly in erythrocytes and leukocytes; clinically, this leads to
cardiovascular and neurologic lesions and emotional disturbances
Dry Beriberi: diet chronically contains less thiamine than required; sx: peripheral neuropathy,
fatigue, impaired capacity to work
Wet beriberi: develops w/severe deficiency. Sx: neurological manifestations, cardiovascular
systems (heart enlargement, tachycardia, cardiac failure after stress) and edema and anorexia.
Wernicke-Korsakoff syndrome: chronic thiamine deficiency; seen in alcoholics; pts shown to
have defective transketolase that exhibits a reduced affinity for TPP; clinical
manifestations=weakness or paralysis and impaired mental function
Diagnostic test: abnormal levels of lactic acid-pyruvic acid in the blood
Pellegra: niacin deficiency
Sx: dermatitis, diarrhea, dementia
The Cell Cycle
HPV: causative factor of carcinomas of the uterine cervix, viral gene products E6 and E7 sequester Rb
and p53 to promote unrestrained proliferation
Retinoblastoma: rare malignant tumor of the retina in infants (to age 5 years) with an incidence of 1 in
20,000 births; caused by loss of both alleles of Rb
Rb can’t bind E2F, so cell cycle can continue
May also be caused by overexpression of MDM2 which inhibits p53 (which inhibits cell cycle)
40% of cases are heritable, 60% are sporadic
Cyclin D over-expression is associated with esophageal, breast, and gastric cancers; amplified in
colorectal cancer
CDK4 amplified in sarcomas and gliomas
CDKIs (p16 mutations) involved in development of multiple tumor type (head and neck, pancreatic, non
small-cell lung carcinomas, melanoma)
Melanoma: 10% of cases are hereditary, 20-40% of these cases can be linked to a mutation in the p16
gene (helps prevent cancer through cell senescence, a tumor suppressor mechanism)
When cells have divided too many times or become damaged in some way, an increase in p16
causes the cell to stop dividing (stops cancer cells from dividing before a tumor can form)
Li-Fraumeni syndrome: rare form of inherited cancer; affected individuals display cancers in a variety of
tissues at an early age (bone, soft tissue sarcoma, breast cancer, brain tumors, leukemia, adrenocortical
carcinoma); caused by mutations in p53
Alkaloids: prevent chromosome spindle formation and block M phase. Derived from plants and are used
to treat wilm’s tumor, breast cancer, lung cancer, and testicular cancer. Plant alkaloids are administered
via IV (ex: Vincristine and Vinblastine)
Antitumor antibiotics: bind DNA and block S phase. Used to treat a wide variety of cancers including
testicular cancer and leukemia. Antitumor antibiotic drugs are administered intraveneously. (ex:
Doxorubicin and Mitomycin-C)
Antimetabolites: block cell growth by interfering with S phase. These drugs work by mimicking
nucleotides during DNA synthesis. Antimetabolites are used to treat tumors of the GI tract, breast, and
ovary. They are administered orally or via IV. (Ex: 6-mercaptopurine and 5-fluorouracil)
CDK inhibitors: block progression of the cell cycle by inhibiting CDKs. Ongoing clinical trials testing
flavopridol, roscovitine, and other small molecules that inhibit the activity of CDKs.
Cell Motility
Leukocyte Adhesion Deficiency: improperly produced integrin and leukocytes can not effectively
migrate out of blood vessel; pts suffer from life threatening infections
Glanzman’s disease: lack of β3 integrin causes excessive bleeding due to lack of clotting
Enzymes
Phenylketonuria: phenylalanine hydroxylase
Cystic fibrosis: ion transporter
Ouabain: inhibits dephosphorylation of E2-P form, locking the pump in a non-functional
state; decreased pump action increases the [Na+]in cardiac muscle cells, leading to
increased [Ca+] in cells (Na+-Ca2+) transporter; these calcium-mediated signals act to
increase the contraction strength of the heart
Chemo resistance:
MDR1 pump uses ATP energy to export drugs from the cytosol. These drugs are small and
planar, such as those used to treat cancer (adriamycin, doxorubicin, vinblastine) and malaria,
and diffuse into a cell. Since the drugs can’t get in the cell, they fail to exert their benefits; cells
b/m chemo resistantuncontrollable tumor growth/spread, poor prognosis. The MDR1 gene is
often amplified in tumor cells.
Enzymes
Cyanide: modifies heme enzymes by forming a stable complex with heme
Diisopropylfluorophosphate: reacts with enzymes having an active site serine
Patients lose vision, potent nerve poison
Allopurinol: inactiveates xanthine oxidase, used to treat gout
Enzymes as Therapeutic Targets
Methotrexate: dihydrofolate reductase (cancer chemotherapy)
Statin drugs: Lipitor, HMG-CoA reductase (elevated serum cholesterol levels)
β-lactam antibiotics: bacterial cell wall biosynthesis (bacterial infections)
Prilosec (omeprazole): proton pump inhibitor (gastric reflux)
ACE Inhibitors: Angiotensin converting enzyme (hypertension)
Electron Transport and Oxidative Phosphorylation
Ischemia: oxygen deficiency; localized or permanent
Infarct: death or damage to tissue due to ischemia
Rotenone: instecticide and fish poison; blocks FP1CoQ in ETC
Sodium Amytal (barbiturate) blocks FP1CoQ in ETC
Antimycin: blocks the flow of e- in ETC from cytochrome b to cytochrome c1
Cyanide, CO: block flow of e- in ETC from cyt (a + a3) oxygen
Dinitrophenol: uncoupler of oxidative phosphorylation; reduces ATP production by bringing protons
back across from in the inner mitochondrial membrane, destroying the protein gradient designed to
produce ATP
Oligomycin: inhibits ATP synthase (FoFi ATPase)
Atractyloside: inhibitor of ADP/ATP exchange
Genetic Defects in Oxidative Phosphorylation
Disorders associated with defects in nuclear DNA:
Alpers syndrome
Benign infantile mortality
Fatal infantile myopathy
Leigh Syndrome
MNGIE (mitochondrial neuropaty, gastrointestinal disorder, encephalopathy) syndrome
Disorders associated with defects in mitochondrial DNA:
Kearns-Sayre syndrome
LHON (Leber Hereditary Optic Neuropathy)
MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes)
MERRF (myoclonic epilepsy and ragged red fibers)
NARP (neuropathy, ataxia, and retinitis pigmentosa)
Pearson syndrome
Clinical Manifestations: muscle cramping and weakness, fatigue, lactic acidosis, central nervous
system (CNS) dysfunction, vision problems
Treatment: difficult and often unsuccessful; sometimes therapeutic doses of substances that
may mediate electron transfer (Vitamin C, ubiquinone)