Formulas & Things to Remember

Question 1

Half-life pharm formula

Answer 1

T1/2 = (0.693 x Vd)/Clearance

Question 2

Steady state concentration formula

Answer 2

Steady state (IV) = in / out

Steady state Css = (Bioavailability x Dose) / (Dose interval x Clearance)

Question 3

Oral bioavailability formula

Answer 3

Bio = AUC oral / AUC IV

Question 4

Renal dose adjustment for FU (fraction unbound)

Answer 4

Renal dose adjustment for FU of 1
= CrCl of patient / CrCl normal

Renal dose adjustment for FU <1
= (1 - FU) + FU (CrCl of patient / CrCl normal)

Question 5

Theapeutic Index formula

Answer 5

Therapeutic Index = LD50 / ED50

ED50 = median effective dose i.e. 50% sample has effect
LD50 is the amount ingested that kills 50% of test sample

Question 6

Potency vs Efficacy

Answer 6

Potency = dose required to produce 50% of maximal effect
- i.e. if 2 drugs have same maximum effect but Drug A achieves at a lower dose it is more potent than drug B

Efficacy = maximum effect expected from drug

Question 7

HLA*B1502 drug interaction

Answer 7

Carbamazepine & SJS/TEN

Question 8

HLA*B5701 drug interaction(s)

Answer 8

Abacavir hypersensitivity

Flucloxacillin drug induced liver injury

Question 9

HLA*B5801 drug interaction

Answer 9

Allopurinol in Han Chinese populations - risk of SJS/TEN

Question 10

Loading dose determinant

Answer 10

Volume of distribution the main factor

Loading dose = desired concentration x Vd

Question 11

Odds ratio

Answer 11

OR = odds of exposure in cases / odds of exposure in controls
i.e. ad / bc

Question 12

Describe the flow-volume curves for the following:

1. Normal
2. Fixed obstruction
3. Variable extra-thoracic obstruction
   - Causes?
4. Variable intra-thoracic obstruction
   - Causes?
5. Restrictive disease

Answer 12

1. Normal = upside down ice-cream cone
2. Fixed obstruction = flat top and bottom (pancake)
   - causes: goitre, tracheal stenosis, masses
3. Variable extra-thoracic obstruction = flat inspiration (stingy upside down ice cream cone)
   - causes: laryngomalacia, vocal cord palsy
   - Inspiration sucks in the upper airways
4. Variable intra-thoracic obstruction = flat expiration
   ( stingy upright ice cream cone)
   - causes: tracheal masses, tracheomalacia
   - Expiration increases pleural pressure worsening obstruction
5. Restrictive = small, low volume but normal shape

Question 13

A-a gradient formula

List causes of:
Elevated gradient
Low gradient

Answer 13

(150 - 5/4 x paCO2) - paO2
or 1.2 x pCO2

High A-a gradient:

1. V/Q mismatch (PE, pneumonia, ARDS, APO)
2. Right to left shunt
3. Alveolar hypoventilation (interstitial lung disease)

Low/normal A-a gradient:

1. Hypoventilation (e.g. COPD, NMD)
2. High altitude

Question 14

Which drugs affect renin/aldosterone ratio testing?

• False negative
• False positive

Answer 14

False negative - increase renin

• ACEi
• ARB
• Diuretics
• Dihydropine CCBs (amlodipine)

False positive - decrease renin 
ABCD suppresses
Alpha-methyldopa
Beta blockers
Clonidine
Diclofenace (NSAIDs)

Hold diuretics (incl. spironolactone 6 weeks)
Other interfering meds 2-4 weeks
Verapamil, prazosin and hydralazine are ok to use

Question 15

Describe Amiodarone effects on the thyroid

Answer 15

o Amiodarone has multiple mechanisms of interfering with thyroid function
 All patients have a transient rise in TSH due to Wolff-Chaikoff effect (temporary increase in thyroid production due to iodine load)
o Hypothyroidism occurs due to interference with T4 synthesis and action (also interferes with peripheral conversion of T4 to T3
 Treated with cessation +/- thyroxine

Thyrotoxicosis occurs by 1. Iodine load (type 1) and 2. Thyroiditis (type 2)
 Can occur anytime after starting Amiodarone (idiosyncratic)
 Amiodarone contains large amounts of iodine (200mg more than usual daily intake)  enhanced thyroid hormone production (type 1)
• More commonly in patients with underlying multinodular goitre
• Jod-Basedow phenomenon

 Amiodarone has a direct toxic effect on the thyroid follicular cells  release of excess thyroid hormone (type 2)
 Often mixed mechanism – AIT 1 more common early (e.g. <3 months) and AIT more common overall
• AIT 2 responds rapidly whereas AIT 1 responds slowly
o Management
 1. Stop Amiodarone
 2. PTU/Carbimazole (target type 1) AND steroids (target type 2)
 3. Colestyramine if desperate (blocks enterohepatic iodine circulation)
 4. Surgery if no response
 Note: Iodine radio-ablation is not helpful

Question 16

Causes of falsely high and low HbA1c?

Answer 16

High HbA1c

• True hyperglycaemia
• Low red cell turnover
  
  • Splenectomy
  • Can occur in iron deficiency/B12/folate def anaemia
  • Alcoholism

Low HbA1c

• High red cell turnover: haemolysis, chronic blood loss, chronic renal failure (variable)
• Blood transfusion

Question 17

Antibody associated with scleroderma renal crisis

Answer 17

Anti-RNA polymerase 3

Question 18

Antibodies for necrotising immune mediated myopathy

Answer 18

Anti-HMGCR

Anti-SRP

Question 19

Antibody for Inclusion body myositis

Answer 19

Anti-cN1A

Question 20

Antibodies for dermatomyositis

Answer 20

ANA 80%
Anti-Mi2
Anti-IFIH1 (MDA-5) = amyopathic DM
Anti-Jo1 = anti-synthetase 
TIF1-gamma = strong association with malignancy

Question 21

Scleroderma antibodies

Answer 21

Anti-centromere = CREST/limited scleroderma (associated with pulmonary hypertension)
Anti-RNA polymerase 3 = renal crisis
Anti U1 RNP = (high sensitivity for MCTD) but associated with SSc with pulmonary hypertension
Anti-Scl-70 (antitopoisomerase-1) = diffuse scleroderma (esp. pulmonary fibrosis)

Question 22

New agents for breast cancer
List 3 new(ish) classes
1 novel conjugate drug

Answer 22

1. CDK4/6 inhibitors = cyclin dependent kinase 4/6 inhibitors
   - Prevent cell cycle progression
   - E.g. Palbociclib, Ribociclib
   - Improve progression free survivial in HR positive, HER2 negative breast cancer
   - Neutropenia very common but infectious complications rare
2. PI3 kinase inhibitors phosphoinositide-3-kinsae inhibitor
   - Inhibit PI3/AKT/mTOR signalling pathway and tumour suppression
   - Alpelsiib (alpha specific PIK3K inh)
   - Survival benefit in HR positive, HER2 negative advanced breast cancer in combination with Fulvestrant
   - SEs: rash, hyperglycaemia, nausea/vomiting
3. PARP inhibitors (poly-ADP-ribose polymerase) inhibitors
   - Increase Ds DNA breaks (normally PARP repairs these breaks through the BRCA pathway) with resulting cancer cell death
   - Useful for BRCA positive breast cancer

T-DM1/Trastuzumab-Emtasine = antiboddy-drug conjugate (Herceptin linked to cytotoxic agent DM-1)

• On binding, internalises DM1 with local chemo activity
• Not superior to standard 1st line Trastuzumab regimens - often used as 2nd line therapy

Question 23

PI3 kinase inhibitors

Answer 23

PI3 kinase inhibitors phosphoinositide-3-kinsae inhibitor

• Inhibit PI3/AKT/mTOR signalling pathway and tumour suppression
• Alpelsiib (alpha specific PIK3K inh)
• Survival benefit in HR positive, HER2 negative advanced breast cancer in combination with Fulvestrant
• SEs: rash, hyperglycaemia, nausea/vomiting

Question 24

PARP inhibitors

Answer 24

PARP inhibitors (poly-ADP-ribose polymerase) inhibitors

• Increase Ds DNA breaks (normally PARP repairs these breaks through the BRCA pathway) with resulting cancer cell death
• Useful for BRCA positive breast cancer

Question 25

CDK4/6 inhibitors

Answer 25

CDK4/6 inhibitors = cyclin dependent kinase 4/6 inhibitors - Prevent cell cycle progression - E.g. Palbociclib, Ribociclib - Improve progression free survivial in HR positive, HER2 negative breast cancer - Neutropenia very common but infectious complications rare

Question 26

Abiraterone | Enzalutimide

Answer 26

Androgen biosynthesis inhibitors/blockers Metastatic castrate resistant prostate cancer Abiraterone – blocks 17a-hydroxylase enzyme with reduced adrenal androgens • Tends to increase ACTH and lower aldosterone (hypertension, hypokalaemia) Enzalutimide – Androgen receptor antagonist with reduced AR translocation • Hypertension, fatigue, cognitive impairment

Question 27

HCC treatment options - Very Early stage 0 - Early stage A - Intermediate stage B - Advanced stage C - Terminal stage D

Answer 27

Very early stage 0 = single <2cm, preserved liver function and ECOG 0 - Treatment = Resection or ablation if not a transplant candidate - Transplant if elevated portal pressure or bilirubin Early stage = solitary or up to 3 nodules <3cm - Transplantation or ablation Intermediate stage = multinodular, ECOG 0 & preserved liver function - TACE/chemoemobilisation - Survival usually >2-5 years Advanced stage = portal invasion, extrahepatic spread, ECOG 1-2 (survival >1yr) - Systemic therapy = Sorafenib (anti-Raf kinase, VEGFR) or Lenvatinib (multi VEGFR, FGFR) - Hypertension associated with treatment benefit - SEs: hypertension, renal dysfunction, hand-foot skin reaction, rash, poor wound healing Terminal stage = end-stage liver function, ECOG 3-4 = best palliative care (survival 3 months)

Question 28

Absolute risk

Answer 28

Absolute risk = event rate / total in group

Question 29

Absolute risk reduction

Answer 29

ARR = CER - EER

Question 30

Relative risk

Answer 30

RR = EER / CER

Question 31

Relative risk reduction

Answer 31

RRR = (CER - EER) / CER RRR = 1 - RR

Question 32

Power

Answer 32

Probability of rejecting the null hypothesis (correctly) when it is false Power = 1 - type II error Type 1 error = false positive Type 2 error = false negative rate i.e. it is like telling a heavily pregnant women she is not pregnant because the test came back negative

Question 33

Testicular cancer tumour markers

Answer 33

AFP = non-seminomatous (predmoninantly yolk sac, teratomas) - Pure seminoma and pure choriocarcinoma do not produce AFP ``` o B-HCG = Choriocarcinoma, some embryonal cell and seminomas o LDH (low specificity) ```

Question 34

In addition to cytotoxic T cells, which other immune cell is primarily dysfunctional in the pathophysiology of haemophagocytic lymphohistiocytosis? A. Dendritic. B. Macrophage. C. Mast. D. Natural killer. E. T helper.

Answer 34

Answer: D - natural killer cells

Question 35

Neuromyelitis optica antibody Multifocal motor neuropathy antibodies

Answer 35

NMO = anti-Aquaporin-4 antibody anti-MOG less common MMN = anti-GM1

Question 36

``` BCL-2 inhibitors have recently shown to have therapeutic efficacy in blood cancers. What is the function of BCL-2 protein? A. Activates cell death receptors. B. Activates cell survival proteins. C. Activates effector caspases. D. Inhibits cell apoptotic proteins. E. Inhibits cell survival proteins. ```

Answer 36

Answer: D - Inhibits cell apoptotic proteins.

Question 37

``` .If a patient has strong positive anti-dsDNA antibodies (> 100 IU/mL) and a negative screen for extractable nuclear antigens (ENA), what is the most likely pattern on antinuclear antibody (ANA) testing? A. Centromere. B. Homogeneous. C. Negative (no pattern seen). D. Nucleolar. E. Speckled. ```

Answer 37

Answer: B - homogenous

Question 38

``` The pharmacokinetic properties of which analogue insulin are largely determined by binding to and dissociation from serum albumin? A. Aspart. B. Detemir. C. Glargine. D. Glulisine. E. Lispro. ```

Answer 38

Answer: B - Detemir

Question 39

RTA type 1 vs 2 vs 4

Answer 39

 Proximal RTA (type 2) = HCO3 excretion defect Fanconi syndrome: glycosuria, phosphaturia, uricaciduria, aminoaciduria Myeloma/MGUS Drugs: tenofovir, acetazolamide pH < 5.5 (excess H+) – acidic  Distal RTA (type 1) = H+ excretion defect Causes Sjogren’s syndrome SLE Primary biliary cirrhosis, autoimmune hepatitis Urine pH pH >5.5 (no H+) – alkaline • Urine anion gap is helpful to differentiate normal AG metabolic acidosis (i.e. RTA1) vs diarrhoea o Urinary AG = Na + K – CL  Urine AG = positive in RTA type 1 (lack of H+  reduced NH4Cl)  Urine AG = negative in diarrhoea (excess H+  increased NH4Cl)