LearnStuffs

Oral absorption

Clearance and Vd

kel = clearance / Vd = ln(2)/half-life

Therefore clearance = Vd * ln(2) / half-life -> linear line

Generally aim for 8 hour half-life

To increase half-life,

Increase Vd by increasing lipophilicity (logP)

Decrease hepatic clearance by making the molecule more stable

Acidic Molecules

Contain a carboxylic acid group (pKa 4-5) that is deprotonated, thus negative

Because it is charged, it is less lipophilic

Because it is negative, it is prone to being bound to albumin

Therefore acidity decreases Vd

Basic Molecules

Contain an amine group (pKa 10) that is protonated, thus positive (ammonium, NH4+)

Cell membranes contain phospholipids which have negative phosphate groups and thus attracted to NH4+

Thus phosphilipids draw molecules out of plasma

Therefore basic increases Vd

E.g. nifedipine is neutral and amlodipine is similar structurally other than a short basic chain, increasing half-life from 1.9 hours to 34 hours

Clearance

Total clearance = hepatic clearance + renal clearance

Also clearance depends on blood flow (Q) and extraction ratio (E)

Therefore total clearance = Qh*Eh + Qr*Er

Volume of Distribution (Vd)

Apparent volume of plasma required to contain drug in plasma

An average 70kg man has 2.7L of plasma but Vd is often much larger than 2.7L (plasma volume is 0.039L/kg) because in reality drugs redistribute to peripheral compartment

Since concentration = amount/volume and the amount and Vd of a drug is known, the concentration can be determined. Then that concentration can be used with plasma volume to determine how much of the drug is actually in the central compartment

E.g. 25mg of ranitidine is given, Vd = 1.4L/kg = 98L in a 70kg man

C = 25mg/98L = 0.255mg/L

Since plasma volume is 2.7L:

0.255mg/L = amount of drug in plasma / 2.7L

Amount of drug in plasma = 2.7L * 0.255mg/L = 0.69mg

Therefore, only 0.69mg of 25mg ranitidine given is in plasma

Protein Bound

A higher % of protein binding decreases clearance and decreases Vd

However, half life and kel (elimination constant) remain the same

Phases

Drug concentration decreases sharply during the distribution phase, then more slowly during the elimination phase (though both happen together)

The end of the distribution phase is when concentration in tissues (Ct) reaches maximum and Vss (steady state volume) is reached

The equation for the blue line is represented by the equations (A and alpha representing distribution phase and B and beta representing elimination phase, in which alpha is usually larger than beta)

Blood

Blood volume 71ml/kg

In a 70kg person:

Whole blood 5L

Plasma 2.7L

Interstitial fluid 10L

Intracellular fluid 25L

Total body water 38L

Body volume 70L

Albumin

5% of blood by weight

Binds to acidic drugs well (e.g. warfarin, ibuprofen)

Globulin

2.5% of blood by weight

Alpha-1 acid glycoprotein binds basic drugs (e.g. disopyramid, lidocaine)

Lipinski’s rules

Set of rules created by Chris Lipinski in 1997 to predict whether a molecule is likely able to diffuse across membranes

Molecular weight, max value 500

Lipophilicity (log P), max value 5

Hydrogen bond acceptors, max value 10

Hydrogen bond donors, max value 5

Lipophilicity is measured as the logP for the partitioning of a drug in a biphasic system of 1-octanol (non-polar) and water (polar)

logP > 5 means too strongly favors octanol = too non-polar

Hydrogen bond acceptors = number of oxygen and nitrogen atoms

Lone pairs of nitrogen and oxygen can accept hydrogen bond

Exceptions if lone pair is involved extensively in resonance

Clark’s occupancy theory

States that binding = response

If there is 50% binding there is 50% response

If there is 80% binding there is 80% response etc etc

Exceptions

Receptors with constituent activity, because even in 0% binding there is “response“ or activity

Spare receptors: not all receptors need to be bound for maximal response

Downregulation and desensitization

Upregulation and sensitization

Clark’s equation, in which E/Emax is 0 to 1

Alternative theory: drug residence time

koff = rate of dissociation, kon = rate of binding, tau = residence time

The greater the rate of dissociation, the shorter the residence time = less effect

For example with EGFR:

Lapatinib has greater Ki (lower potency) than gefitinib and erlotinib but has greatest activity, going against Clark’s occupancy theory

Receptor Superfamilies

Ligand gated

Membrane bound

Control ion flow across the membrane

Associated with synapses

Called “fast neurotransmitters“

G protein coupled

Membrane bound

Pass signal across membrane

Signal proteins released into cell – complex pathways

Called “slow neurotransmitters“

Tyrosine kinase linked

Membrane bound

Ligand binding causes receptor dimers

Dimers act as enzymes

Associated with cancer

Nuclear receptors

Not membrane bound

Found in nucleus; ligand must enter the cell in order to bind

Control gene expression

Ligand types

Full agonist: upgoing sigmoidal curve, reaches Emax = full effect

Partial agonist: upgoing sigmoidal curve, reaches only a fraction of Emax, tend to bind to same position on receptor as full agonist = compete with full agonist

Antagonist: downgoing sigmoidal curve, binds to same receptor as agonist but causes no response; there are competitive and non-competitive antagonists

Inverse agonist: receptor has inherent activity called constituent activity; inverse agonist causes the activity to drop to zero ; downgoing sigmoidal curve with intercept > 0

IC50 and Ki

Both used to measure how much drug is required to inhibit an enzyme

In both cases, the higher the better

IC50 = inhibitor concentration 50 = the concentration of inhibitor required to inhibit rate of conversion by 50%

In linear equation format:

Cheng-Prussoff equation:

I didn’t expect this at all, but learning the next section allowed me to explore math like the good days in high school.

Equation for a plateau: y = ax+b / cx + d

As x approaches infinity, the constants b and d become irrelevant and the limit of this equation is a/c.

To simplify, if the equation is y = ax/(x+b), then the limit is a.

If x = b, y = 1/2 * a (half of limit)

If x = b/2, y = 1/3 * a (third of limit)

if x = b/3, y = 1/4 * a (fourth of limit)

If x = b/(k-1), y = 1/k * a (kth of limit)

Michaelis-Menten Kinetics

enzyme + substrate -> enzyme-substrate complex -> enzyme + product

V = rate of reaction (y-axis), S is substrate concentration (x-axis)

Vmax is the maximum rate, when S is infinite

1/2 Vmax is reached when S=Km aka Michaelis constant

If we put values into the equation y = ax/ (x+b):

y = V, x = S

a = limit = Vmax

1/2 Vmax is reached when x= b, and b is Km

Therefore, V = Vmax * [S] / ( [S] + Km) (the Michaelis-Menten equation)

This equation can be put into a linear form to the Lineweaver-Burk equation

Inhibition

Reversible

Competitive

Vmax not changed, still reached if substrate concentration high enough

Km increases (affinity dropped)

Non-competitive

Binds to allosteric site not the active site

Binds to both enzyme and enzyme-substrate complex

Lower Vmax

Km not changed (affinity not changed)

Uncompetitive

Binds only to enzyme-substrate complex

Vmax and Km decreases

Drug discovery

Target based

Begins with a drug target aka protein, develop drug to bind to that protein

Protein binding assay measures how well drug binds to protein, and this is an in vitro test

More predominant method due to advanced molecular biology

Advantages

Relatively simple

Rapid lead optimization

Disadvantages

 Protein may turn out to be ineffective relatively late (usually phase II)

Low efficacy

Phenotype based

Begins with a lead based on phenotype

Slow lead optimization

High efficacy, less likely to turn out ineffective later

Methods of Determining Protein Structure

Two methods: X-ray crystallography and nuclear magnetic resonance

Resolution measured in angstrom; the lower the angstrom, the higher the resolution

The Ramachandran plot can be used to validate protein structures

D-amino acids, unlike L-amino acids almost certainly have an incorrect protein structure

X-ray crystallography

More common method, 3/4 of protein structure determination

It’s amazing that I’m normally completely uninterested in learning history, but when used to learn how we got to something we take for granted today, it just becomes more fascinating than any introduction.

Sulfa Drugs

This guy Paul Ehrlich comes up with the idea that dyes can be used as antibiotics as well as coining the term Ehrlich’s silver bullet (kill the invading organism without affecting the host)

Gerhard Domagk finds a dye Protonsil Rubrum, a prodrug form of an antibiotic called sulfanilamide

The beginning of sulfa drugs which contain a SO2, a nitrogen, and a benzene ring

Both scientists won Nobel prizes

This course is crazy. I’m only one class in and I’m learning so much cool stuff. This is pretty exciting!

Pharmacophore = the minimal component of a class of drugs to achieve biological activity

Ephedrine

Emperor Shen Nung, father of agriculture, used Ma Huang for anti-tussive and decongestant properties.

The active ingredient in Ma Huang is ephedrine which is a vascoconstrictor and a stimulant

Ephedrine may be an alkaloid and its pharmacophore is:

Comes from natural source

Has a base nitrogen

Has a level of complexity (subjective)

It is a phenethylamine (class)

It has a stereoisomer or diastereoisomer called pseudoephedrine (sudafed), also a decongestant and stimulant, from which if you remove one alcohol group, you get methamphetamine

Phenethylamine

Examples: ephedrine, pseudoephedrine, methamphetamine, phentermine, fenfluramine

Its pharmcophore is:

Benzene ring

Two-carbon bridge

A nitrogen

Used as vasoconstrictors (therefore decongestants) and stimulants

Because they cause energy without food, also used as diet pills, such as phentermine and fenfluramine

Fen-phen

A diet pill that combines fenfluramine and phentermine

Withdrawn because it caused congenital heart defects (might have been just fenfluramine though)

Morphine rule

Benzene ring

Quaternary carbon

Two carbon linker

Tertiary amine

원초아: id

자아: ego

초자아: superego

방어기제: defense mechanism

Being an intern, you do a lot of phlebotomy work. I’m by no means an expert, but here are a few tips and tricks I’ve gathered so far for venipuncture, IV cannulation, and ABG.

Venipuncture in general

Golden rule: feeling is more important than seeing. It’s OK if you can’t see a vein but can palpate it. But if you see a vein but can’t palpate it, chances are you won’t get blood. There are occasionally what I call phantom veins which you can seemingly see and palpate that don’t give you any blood. But most veins you can palpate, you can get blood from. Methods to make veins more palpable:

Pull the tourniquet TIGHT!

Flick on the vein (don’t slap)

Ask the patient to hold a fist

When you palpate for a vein, also estimate the DEPTH of the vein. If it is a deep vein, you may have to stick the needle a little below the point of palpation so that the needle is deep enough to hit the vein

When it comes to the elbow, the lateral veins are more stable than the medial veins. When I say stable, I mean less likely to be ballerina veins that dance away from you when you try to poke it

Your job is to get blood, not to be pretty about it. Some people have diagonal veins, some have veins most obvious in the middle of the forearm. As long as you take care to avoid arteries, you’re fine.

Venipuncture with a syringe

I became friends with the syringe first because I was first responsible for the labour ward, which didn’t carry butterflies. I’m glad I did, because now that I’m in the medical ward I have more than enough opportunities to practice with the butterfly.

Tips for using the syringe

I don’t know about you, but my hand shakes a little. I found that holding the syringe with my right hand and pulling with my left hand helps me be more stable (I’m right handed). I also rest my hand on the patient’s arm to stabilize (most don’t mind as long as you stick them only once)

Advance only until you get a flashback, then don’t move your right hand. I always think “don’t move your hand, don’t move your hand“ while staring at my right hand once I get a flashback, while pulling with my left

When you pull the syringe it’s very easy for the needle to move back. DON’T MOVE YOUR RIGHT HAND

Sometimes you don’t get a flashback even when you’ve hit the spot. The great thing about the syringe is you can try pulling anyway to see whether you’ve gotten it

Venipuncture with a butterfly

I took a long time becoming friends with the butterfly, because I found that it easily became displaced if the tubing attached to the needle moves even a little. Here’s the trick: unlike the syringe, you don’t stop the syringe as soon as you see a flashback. You have to make sure about half of the needle is inside the patient, then the needle isn’t prone to moving so much. I actually found that when you actually need to take blood from the feet, butterflies are better than syringes because they have more suction power.

IV cannulation

I struggled with this for 2 months, because I would also get the flashback, try to advance the cannula, but then I’d lose the flashback and the spot would start swelling. In other words, I had double punctured. But why?

The trick is, once you see the flashback, you keep advancing 3-5mm. I used to advance only 1mm. The revelation came to me when my fellow intern told me she usually advanced a whole 1cm. In order to make sure both the needle and cannula are safely inside the vein, you must advance more than just a tiny bit. Then you push the whole cannula in.

If you’re having trouble getting the flashback, the trick is: go superficial. That goes for all venipunctures actually. You can go deeper if need be, but once you’ve double punctured you can’t go back.

ABG

Admittedly I’m not an expert at this yet. However, tricks I’ve learned so far:

Palpate for the strongest point of pulsation

Aim the needle slightly below the strongest point, because the artery is quite deep so you’ll need to advance from below that point to hit it

Aim the syringe at approximately a 45 degree angle

My first rotation was in O&G. I really enjoyed it, and I can definitively say what made it awesome was the people. From the COS to the ACs, residents, nurses, midwives, and phlebotomists, most people were wonderful. I felt like while I respected the doctors there as my seniors, I also feel like I became friends with them. Wendy, Catherine, Ashley, and Emily were particularly great. Also helped by the fact that 2 residents who were attaching to O&G, Carly (A/E) and Vivian (FM) were 2 of the most amazing human beings ever. Also helped by the fact that I was already friends with 2/2 of the first year MOs and 2 of the 3 HO I was going to work with. The one fellow HO I didn’t know was really sweet and friendly. I feel lucky to have gotten them as my first colleagues.

I became really good friends with Sharon, who I was also next door neighbors with for 3 months. We ordered take out food and ranted about things. It was great.

Fanny is the stand-out star as far as awesome people go. She is friendly to everybody and makes everyone feel special and important. She comes to work very early, is amazing at her job, and even does work she doesn’t need to do. Sharon once said, “She has so much light in her“, which I think is an apt description.

Attaching to Caesarean sections was really fun. It was so rewarding when you put all your weight in the fundal pressure and see the baby’s head pop out.

Of course it wasn’t all roses. I was on call every 3 nights, which was absolutely exhausting and I became very irritable towards the end of each call. If it weren’t for the fact that even ACs were on call every 3 nights I would consider O&G much more enthusiastically. When old age home residents came in for postmenopausal bleeding in the middle of the night, doing a speculum exam on them felt like I was the devil’s spawn. There was one nurse called Maggie who was horrible.

Being on call is hard. Let’s compare it to going through a desert. Some people are like oases, making things a little easier. This was most people in my rotation. Some people are like sand – standard fare, what you would expect, nothing more, nothing less. Some people are like rain – people like Fanny. Some people are flaming pots flying through from the gaping pit of hell.

I didn’t enjoy admitting cases and writing discharge summaries. I also didn’t like assisting gynecological surgeries, in which my job was just holding one equipment in place and stare at someone’s vagina, surrounded by her legs.

First day as an intern and on call tomorrow.

It went like a first day, i.e. many things went wrong. For one thing, I didn’t know I was supposed to round in F8 so I only got there once they called, which meant I started late (and displeased my senior). I think I’ll try to get there early tomorrow.

Secondly, there was a lady who had given birth that I needed to take type and screen from, but I failed as the patient had very narrow veins acknowledged by 3 other people who showed up. I can forgive myself for that. What I can’t accept is not being able to take type and screen from another patient, who had large veins. I realized that my hands shake when I take blood and the syringe exits the puncture site easily. I’ll try to remedy this problem by resting the blood taking syringe on the patient’s arm, inserting more superficially, and drawing the syringe using my left hand so I could use my right hand to stabilize (instead of using my right hand to draw the syringe). I’ll see how it goes.

I was not very efficient with typing discharge summaries. I can only imagine I’ll improve with time, but I’ll try to write out templates.

I apparently need to complete mandatory training online and attend lectures, which is fine as long as it’s not too overwhelming.

On the plus side, I ran into Ben gor who is now an anes resident, which is amazing. I’m so happy for him. I’ll probably run into him since I am in charge of the surgical ward. I also hope I can finish a little earlier tomorrow so I could watch some SVD.

Dystonia can disappear during sleep

C6/C7 trans-section

Sputum retention

Diaphragmatic breathing

V/Q mismatch

Impaired cough reflex

Painful dystonia can complicate L-dopa therapy

Domperidone is the preferred treatment for nausea in Parkinson’s disease even though it is a dopamine blocker

Valproate should not be prescribed to women in reproductive age

If there is stroke with no cortical symptoms and no visual field defect, the location is highly likely to be internal capsule

Glove and stocking sensory loss if suggestive of peripheral neuropathy

Psoriasis: late onset has lower prognosis

Normal/low anion gap metabolic acidosis

If urine anion gap (urine Na + K - Cl) is 20-90, it is high

A high urine anion cap signifies inadequate acidification of urine = RTA

Elevated renal vein renin signifies fibromuscular dysplasia causing hypertension

Commonest causes of CAPD peritonitis: Staph aureus, Staph epidermidis, and Pseudomonas

Membranous Nephropathy

All patients should be treated with ACEI (+ statin if there is hyperlipidemia)

CLL commonly gives rise to autimmune phenomenon such as hemolytic anemia

Cyclosporin S/E: posterior reversible encephalopathy syndrome

Hydroxyurea causes megaloblastic anemia

Risk of VTE is higher after orthopedic than general surgery

Severe aplastic anemia is treated with allogeneic bone marrow transplant if matched sibling donor is available

HIV causes MAHA

In heparin contamination, APTT is significantly more prolonged than PT

Memory B cells express CD27

Gum hypertrophy is most commonly associated with AML (monocytic and myelomonocytic subtypes)

Rodenticide acts like warfarin

Dapsone causes intravascular hemolysis

Bone marrow with increased megakaryocytes is diagnostic of ITP

Death of a terminally ill patient who fell from the bed in hospital should be reported to the Coroner

Scrub Typhus

 Fever, muscle pain, multiple groin lymph nodes, maculopapular rash over trunk, left leg well demarted dark color skin lesion

Weil-Felix test

Pernicious Anemia

Can cause pancytopenia

Blood film shows macro-ovalocytes

Triad

Paresthesia

Malaise

Sore tongue

Polycythemia Rubra Vera

Concomitant leukocytosis and thrombocytosis (basically, pancytosis)