Sandbox mir

Side effects of drugs:

• Nephrotoxicity → Cephalosporins
• Ototoxicity → Loop diuretics
• Both nephron and ototoxicity→ Aminoglycosides, vancomycin, loop diuretics and cisplatin
• Pseudomembranous colitis → Ampicillin, Clindamycin

DNA

DNA contains phosphate group, so it is negatively charged because of the negatively charged phosphate groups

DNA is composed of nucleotides, which classifies based on their properties to purines and pyrimidines:

Purine synthesis:

• You need glycine, glutamine and aspartate + tetrahydrofolate (Folic acid) + CO2
• Rate limiting step : Glutamine PRPP amidotransferase
• Carbon sources:
  • CO2, glycine, tetrahydrofolate
• Nitrogen sources
  • Aspartate + Glutamine

Pyrimidines synthesis:

Aspartate + carbamoyl phosphate (1 carbon and 1 nitrogen [glutamine]) + ATP

• Carbamoyl phosphate → Has 1 carbon and 1 nitrogen
• You need aspartate + CO2 + glutamine + ATP (Last 3 come from carbamoyl phosphate)
• Carbamoyl phosphate synthetase 2 (RATE LIMITING STEP)
• Start with orotic acid then add a base
• Carbon sources:
  • Aspartate
  • CO2
• Glutamine → Gives nitrogen

Major bases in DNA: Guanine (G), Cytosine (C), Adennine (A), Thimine (T)

• G-C : 3 Hydrogen bonds. Higher melting points
• A-T: 2 Bonds

Histones are groups of basic proteins found in chromatin. Histone → Contain lysine and arginine

Cytosine minus aminogroup = Uracil (Deamination)

RNA

Ribosomes are synthesized in the nucleus and transported into the cytoplasm.

Ribosomes are made of proteins and rRNA

• Eukaryotes → 60 and 40s = 80s
• Prokaryotes → 50 s and 30 s = 70 s
  • Have 23s in 50s

Translation

• Initiation
  • IF1, IF2, If3
    • Assist in assembly of smaller ribosomal subunit to first trna molecule
    • Methionine is always the start
    • f-Methionine in prokaryotes
    • IF-2 first binds to 30s and then to methionine tRNA. Then when 50s comes along, it hydrolyzes GTP on IF2 and allows 50s to attach to 30s
  • A site → Incoming aminoacyl TRNA binds
  • P site → Polypeptide binds (Growing chain)
    • First tRNA binds here
  • E site → Free tRNA (exit)
• Elongation
  • Incoming charged aminoacyl TRNA binds to A site
  • Elongation factor help incoming trna to bind to A site (Uses GTP)
  • 50s has peptidyl transferase transfers AA from p site to A site
    • In prokaryotes, activity is in 23s subunit of 50s rRNA
  • Translocation
    • Ribosome complex moves 3 nucleotides
    • tRNA + Peptide is moved from A site to P site
    • Newly uncharged tRNA from P side to E side
    • EF-G  → Eukaryotes
    • EF-2 in eukaryotes
      • Diptheria and exotoxin (Pseudomonas) inhibit this
• Termination
  • Stop codons
    • UGA, UAA and UAG
    • Signal to STOP
    • No new TRNA coming
    • Release factor binds to MRNA and hydrolyzes GTP and new polypeptide is released.

Orotic aciduria

• Deficiency of UMP synthase
• AR
• Elevated oritic acid
• Megaloblastic anemia
  • Not corrected with B12 or folic acid
• No hyperammonemia
• Treat with uridine

Ornithine Transcarbomylase Deficiency

• Causes hyperammonemia
• Elevated orotic acid
• Problem with urea cycle

Inhibit reuptake of norepinephrine:

• Cocaine
• TCA

GLUT receptors

GLUT 1

• • Red blood cell, endothelium of RBB
  • Low level basal glucose uptake
  • No effect from insulin

GLUT 2

• • Regulate glucose
  • Beta pancreatic and hepatocytes

GLUT 3

• • Neurons and placenta

GLUT 4

• • Skeletal muscle and adipose tissue
  • Insulin DEPENDENT

GLUT 5

• • Fructose uptake (In GI tract)

Hexokinase and glucokinase → Produce glucose 6 phosphate

• Hexokinase → All cells
  • Low KM (High affinity)
  • Low VMAX
• Glucokinase→ Only in regulators (Liver and beta cells of pancreas)
  • High KM
  • High VMAX
  • Induced by insulin

Pyruvate kinase deficiency

• Hemolytic anemia
• Inability to maintain Na K ATP ase

PFK1 deficiency

• Elevated fructose 6-P
• Low pyruvate
• High glycogen

Regulation of Glycolysis

• Fructose 2, 6 biphosphate → From PFK2
• Insulin → Increases PFK2
  • Indirectly stimulates PFK1
• Glucagon DECREASES glycolysis
  • Stimulates FBPase 2 (Fructose 6 biphophatase 2 → Converts from Fructose 2, 6 BP to Glucose 6 P

Fasting state

• Glucagon rises → Activates CAMP → Activation of Protein kinase A
  • Phosphorylates FBP2/PFK2 complex → Activating FBP2 and inactivating PFK2
    • FBP2 → Fructose biphosphatase
  • Increases F6P and gluconeogenesis
• Well fed state → High insulin → Stimulates PFK2 → Higher levels of F2,6 BP

Lead poisoning

• Inhibits delta ALA dehydratase and ferrochelatase
• Degradation of ribosomal RNA
  • Basophilic stippling

Pathology of atherosclerosis

• Endothelial dysfunction
  • Increasing vascular permeability, thrombosis and increased adhesion
• Accumulation of lipoproteins
  • Accumulation of oxidized LDL
• Monocyte adhesion to endothelium
  • Migration of monocytes into intima (Transformed to macrophages and foam cells)
    • Foam cells → Macrophages full of lipids
• Factor release
  • Inflammation and cytokines
• Smooth muscle cell proliferation
  • Extracellular matrix deposition
  • Migration of smooth muscle cells into intima
• Lipid accumulation
  • Continued accumulation of lipids extracellularly and within macrophages and smooth muscle cells
  • Can rupture

Prinzmetal Angina

• Coronary vasospasm
• Major risk factor: Smoking
  • Seen in younger patients
• Pain at rest occurring at night
• Indistinguishable from classic angina
• Diagnosed by coronary ateriography
• Transient ST elevation with no sign of stenosis on arteriography
• Calcium channel blockers → FIRST LINE. Diltiazem
  • Nitrates → Second line
• Smoking cessation

Cytochrome P450

CYP450 Inhibitors

• • Ciprofloxacin
  • Ritonavir
  • Amiodarone
  • Cimetidine
  • Ketoconazole
  • Acute alcohol use
  • Macrolides
  • Isoniazid
  • Grapefruit Juice
  • Omeprazole
  • Sulfanamides

CYP450 Inducers

• • Phenytoin
  • Carbemazepine
  • Griseofulvin
  • Barbiturates
  • Rifampin
  • St John’s wart
  • Chronic alcoholism

Disulfiram Reaction

• Inhibition of acetaldehyde dehydrogenase
  • Increase aldehyde
  • Flushing, sweating, nausea, headache, hypotension
• Causes
  • Metronidazole
  • Certain cephalosporins
    • Cefotetan
    • Cefamandole
    • Cefoperazone
  • 1^st gen sulphonylurea
    • Tolbutamide

Renin

• Stimulated by Beta 1 receptors in kidney
• Macula densa sense reduced sodium in glomerular filtrate
• JG apparatus sensing low BP
• Renin cleaves angiotensinogen into angiotensin 1
• Angiotensin 1 becomes 2
  • Enzyme: ACE (Angiotensin converting enzyme)
  • Produced in the lungs and kidneys
• Angiotensinogen produced by the liver

Angiotensin II

• Vasoconstrictor
• Stimulates aldosterone secretion
  • Causes sodium and water reabsorption

BNP

• Causes vasodilation
• Increased excretion of sodium and water in urine

Splitting

• A2 P2 →Increased split during inspiration

Hand grip

• Increases SVR and after load
• Makes MR louder

Val salva

• Decreases venous return
• Reduces preload and afterload
• Makes HOCM louder

Patent Ductus Arteriosis

• Associated with rubella
• Indomethacin closes it

Carbidopa

• Inhibits Dopa decarboxylase
• Prevents conversion from DOPA to dopamine

Heart Valve problems

Aortic stenosis

• Ejection click
• Crescendo decrescendo

Mitral regurgitation

• Increased by hand grip and squatting

Mitral valve prolapse

• Midsystolic click
• Possible systolic crescendo murmur after click
• Valsalva makes murmur start earlier

Mitral valve stenosis

• Small pause in the beginning
  • Due to initial isovolumetric contraction
• Opening snap
• Heard in apex
  • In left lateral decubitus
    • S3, S4, MR heard better on left lateral decubitus
• Caused by rheumatic heart disease
• PCWP is higher than LV diastolic pressure
  • PCWP normally  < 12
  • LA pressure < 12
  • Left ventricular diastolic pressure – Around 10 mm Hg
  • Pressure in left atrium is higher → Increasing PCWP pressure

Aortic Regurgitation

• Diastolic murmur
• Immediately after S2
• Left side of sternum
• Wide pulse pressure
• Water hammer pulse
• Causes
  • Dilated aortic root → Syphillis
  • Marfan’s
  • Bicuspid aortic valve
    • Most commonly causes AS though
  • Rheumatic fever

Ventricular action potential:

• Phase 0 → Increased sodium permeability
• Phase 1→ Repolarization. In-activation of sodium channels. K+ channels begin to open
• Phase 2 → Plataeu → K+ open, Ca2+ open
  • Causes calcium release from SR and myocyte contraction
• Phase 3 → K+ permeability increased. Closing of calcium channels
  • K+ efflux causes repolarization
• ERP
  • Cannot potentiate another action potential

Pacemaker Action Potential

• Phase 0 → Voltage gated calcium channels open after reaching threshold
  • Not due to sodium such as in myocytes
• Phase 3 → Increased potassium permeability
• Phase 4 → Freely permeable to potassium. Gradual depolarization due to sodium channel conductance

Smooth ER makes steroids, lipids, phospholipids. Involved in detoxifying as well

Pretest probability of coronary artery disease

		Typical chest pain	Atypical chest pain	Non-anginal chest pain	Asymptomatic
Younger than 40	M	10-90%	10-90%	5-10%	<5%
	F	10-90%	<5%	<5%	<5%
40-50	M		10-90%	10-90%	5-10%
	F	10-90%	5-10%	<5%	<5%
50-60	M				5-10%
	F			5-10%	<5%
More than 60	M				5-10%
	F				5-10%