Sandbox mir
Chest pain
First determine which sort of angina it can be classified as based on the explanation of pain by patient and your physical exam:
- Typical angina characteristics = 3:
Long duration > 20 minutes + Quality: Pressure or crushing
Provoked by physical or emotional stress
Relieved by rest or Nitroglycerin tablets
- Long duration > 20 minutes + Quality: Pressure or crushing
- Provoked by physical or emotional stress
- Relieved by rest or Nitroglycerin tablets
If 2 or 3 of the following criteria is present, the it is typical angina, if 0-1 present, it is atypical angina.
Then calculate the "pretest probability of coronary artery disease" based on:
- Patient's age
- Patient's angina type
- Patient's gender
Now based on "pretest probability of coronary artery disease", manage patient based on the following table:

## 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
- CO2, glycine, tetrahydrofolate
- Nitrogen sources
Aspartate + Glutamine
- Aspartate + Glutamine
Pyrimidines synthesis:
Aspartate + carbamoyl phosphate (1 carbon and 1 nitrogen ) + 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
- 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
- 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)
- 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
- 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
- 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
- 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
- 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
- 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
- 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.
- 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.
- 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
- 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
- Red blood cell, endothelium of RBB
- Low level basal glucose uptake
- No effect from insulin

### GLUT 2
- Regulate glucose
Beta pancreatic and hepatocytes
- Regulate glucose
- Beta pancreatic and hepatocytes

### GLUT 3
- Neurons and placenta
- Neurons and placenta

### GLUT 4
- Skeletal muscle and adipose tissue
Insulin DEPENDENT
- Skeletal muscle and adipose tissue
- Insulin DEPENDENT

### GLUT 5
- Fructose uptake (In GI tract)
- Fructose uptake (In GI tract)

## Glucolysis
Hexokinase and glucokinase  Produce glucose 6 phosphate
- Hexokinase  All cells
Low KM (High affinity)
Low VMAX
- Low KM (High affinity)
- Low VMAX
- Glucokinase Only in regulators (Liver and beta cells of pancreas)
High KM
High VMAX
Induced by insulin
- 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
- Indirectly stimulates PFK1
- Glucagon DECREASES glycolysis
Stimulates FBPase 2 (Fructose 6 biphophatase 2  Converts from Fructose 2, 6 BP to Glucose 6 P
- 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
- Phosphorylates FBP2/PFK2 complex  Activating FBP2 and inactivating PFK2
FBP2  Fructose biphosphatase
- 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
- Basophilic stippling
Pathology of atherosclerosis
- Endothelial dysfunction
Increasing vascular permeability, thrombosis and increased adhesion
- Increasing vascular permeability, thrombosis and increased adhesion
- Accumulation of lipoproteins
Accumulation of oxidized LDL
- 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
- Migration of monocytes into intima (Transformed to macrophages and foam cells)
Foam cells  Macrophages full of lipids
- Foam cells  Macrophages full of lipids
- Factor release
Inflammation and cytokines
- Inflammation and cytokines
- Smooth muscle cell proliferation
Extracellular matrix deposition
Migration of smooth muscle cells into intima
- 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
- 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
- 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
- Nitrates  Second line
- Smoking cessation

## Cytochrome P450

### CYP450 Inhibitors
- Ciprofloxacin
Ritonavir
Amiodarone
Cimetidine
Ketoconazole
Acute alcohol use
Macrolides
Isoniazid
Grapefruit Juice
Omeprazole
Sulfanamides
- Ciprofloxacin
- Ritonavir
- Amiodarone
- Cimetidine
- Ketoconazole
- Acute alcohol use
- Macrolides
- Isoniazid
- Grapefruit Juice
- Omeprazole
- Sulfanamides

### CYP450 Inducers
- Phenytoin
Carbemazepine
Griseofulvin
Barbiturates
Rifampin
St Johns wart
Chronic alcoholism
- Phenytoin
- Carbemazepine
- Griseofulvin
- Barbiturates
- Rifampin
- St Johns wart
- Chronic alcoholism
Disulfiram Reaction
- Inhibition of acetaldehyde dehydrogenase
Increase aldehyde
Flushing, sweating, nausea, headache, hypotension
- Increase aldehyde
- Flushing, sweating, nausea, headache, hypotension
- Causes
Metronidazole
Certain cephalosporins
Cefotetan
Cefamandole
Cefoperazone
1st gen sulphonylurea
Tolbutamide
- Metronidazole
- Certain cephalosporins
Cefotetan
Cefamandole
Cefoperazone
- Cefotetan
- Cefamandole
- Cefoperazone
- 1st gen sulphonylurea
Tolbutamide
- 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
- 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
- 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
- Due to initial isovolumetric contraction
- Opening snap
- Heard in apex
In left lateral decubitus
S3, S4, MR heard better on left lateral decubitus
- In left lateral decubitus
S3, S4, MR heard better on 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
- 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
Marfans
Bicuspid aortic valve
Most commonly causes AS though
Rheumatic fever
- Dilated aortic root  Syphillis
- Marfans
- Bicuspid aortic valve
Most commonly causes AS though
- 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
- Causes calcium release from SR and myocyte contraction
- Phase 3  K+ permeability increased. Closing of calcium channels
K+ efflux causes repolarization
- K+ efflux causes repolarization
- ERP
Cannot potentiate another action potential
- 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
- 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