Pharmacology Flashcards
What is a phase 1 clinical trial?
Test the toxicitiy of the drug/ maximum tolerated dose/determine side effects
What is a phase 2 clinical trial?
Determine the best dose schedule/dosing regime/determine activity
What is a phase 3 clinical trial?
Determine outcomes of the drug - progression free survival, tumou response rate ectr
What is phase 4 clinical trial?
Post-marketing monitoring - ongoing adverse effects ect
Formula for bioavailability
F(po)=AUC(po)/AUC(IV)
Formula for T1/2
T1/2= (VDx0.693)/Cl
Formula for loading dose
LD= VDx target concentration (divided by PO bioavail if PO drug)
What are the units for clearance?
Volume/Time ( e.g L/min)
How do you calculate therapeutic index?
TI= Adverse effect at EC50/Therapeutic effect at EC50
Volume of distribution is measued in what unit?
Volume = so if given VD as L/Kg - need to multiply by body weight to get the unit as L only
How do you calculate VD (without T1/2)
VD = absorption/Plasma concentration.
What happens to VD if lipid or water ?
Lipid soluble- VD increase
Water soluble- VD decreased
How to calculate steady state concentration?
CPss= F/dosing interval
What is bioequivalence?
90% confidence intervals need to be within 80-125% of the Cmax or AUC of the original drug.
HLA for abacavir metabolism?
B57:01 - TEN
Why cant you use tamoxifen and SSRI?
Tamox activated by CYP2D6, SSRI inhibit 2D6 –> tamoxifen not metabolised to active form
What are substrates for CYP3A4?
Ciclosporin, warfarin, midazolam, oestrogen
What are substrates for P-glycoprotein?
Dabigatran, digoxin
What are CYP2D6 substrates?
Codeine, tramadol, tamoxifen
What activates clopidogrel?
CYP2C19 - there is genetic variation in this so its ineffective in some
What are INDUCERS of CYP3A4
St johns wart, carbamazipine, phenytoin, rifampicin
What is the importance of an inducer?
LOWER the drug concentration by INCREASING metabolism.
What are CYP3A4 inhibitors?
Itrakonazole, ketoconazole, macrolides, ritonavir
What is the importance of CYP Inhibitors?
INCREASE drug concentration by REDUCED metabolism
What enzyme is important in Azathioprine metabolism?
TMPT activity - low TPMP = give lower dose
What enzyme is important in Azathioprine metabolism?
TMPT activity - low TPMP = need lower dose.
Otherwise make excess 6TGN leading to toxicities like marrow supression
What is the main elimination of digoxin and dabigatran?
Excreted unchanged = RENAL
What are the PK changes in the elderly?
Reduced renal flow = increased conc drugs with high FU
Higher fat = Inc VD for lipophilic drugs -> inc T1/2 (e.g benzos)
Reduced Water - Reduced VD for hydrophilic drgs - Gent
What are the features of Anti-depressant withdrawal?
F- flu-like symptoms
Insomnia
Nausea
Imbalance
Sensory disturbances
Hyperarousal
How do ACEi cause angioedema?
ACE metabolises bradykinin into degradation product, inhibition of this + lack of C1 esterase in familial angioedema
What happens to levels of valporate, phenytoin, leveteracetam and lamotragine in pregnancy?
Levles reduced either due to increased metabolism by BYP incudction or increased renal clearance
What effect does cirrhosis have on metabolism of drugs?
Fibrosis -> inc portal vein pressure –> reduced first pass metabolism/reduced hepatic flow, increased bioavailability
How does portal vein thrombosis effect hepatic metabolism?
Reduced flow, reduced metabolism, reduced clearance, increased bioavailability
How do you calculate hepatic clearance?
C; = hepatic flow ( Q) x extraction ratio
Drugs with highhepatic ratio are rapidly broken down by liver enzymes, changes to what have the most significant effect on hepatic clearance?
Hepatic blood flow - cirrhoisis/ portal vein thrombosis, shock, heart failure
Drugs with low hepatic ratio/clearance are not rapidly broken down in the liver, their metabolism is most sensitive to changes in what?
Enzyme induction/inhibition
If you alkylate the urine, what does that do to basic drug excretion?
Increase excretion
How to calculate VD?
Vd= Ab (amount of drug in the body)/CD ( concentration of drug)
How to calculate Loading dose?
Loading Dose = VD x target Cp/ Bioavailability
CL= ?
Cl = RE rate of elimination (mg/hr)/Cp concentration Mg/L)
What is zero order kinetics?
The AMOUNT of drug eliminated is a set unit per time, in first order kinetics it is a set concentration per unit time
What causes a high anion gap metabolic acidosis? MUDPILES
Methanol, Uremia, Diabetic ketoacidosis (or alcoholic ketoacidosis,) Paraldehyde, Iron (or Isoniazid,) Lactic acidosis, Ethylene glycol, and Salicylates
What causes a high anion gap metabolic acidosis? MUDPILES
Methanol, Uremia, Diabetic ketoacidosis (or alcoholic ketoacidosis,) Paraldehyde, Iron (or Isoniazid,) Lactic acidosis, Ethylene glycol, and Salicylates
What are the features of the anticholinergic toxidrome?
(TCAs) Dry mouth, dilated pupils, tachycardia, constipation, urinary retention, delirium, febrile
What are the features of the cholinergic toxidrome? (organophosphate insectisides)
Bradycardia, miosis, rhinorrhoea, diarrhoea, diaphoresis, urinary and fecal incontinence, fasciculations, vomiting, sweating.
What differentiates Neuroleptic malignant syndrome from serosonin syndrome?
LEAD pipe rigidity in NMS, not in SS
TCA overdose syndrome?
Wide QRS from Na channel blockade, bradycardia, Seizures, drowsy, delirium, agitation, mydriasis
How do you treat TCA overdose if wide QRS?
Sodium bicarb
What are fatures of serotonin syndrome>
Mental status change, agitation, myoclonus, hyperreflexia, diaphoresis, trmor, incoordination (SSRI)
What is the antidote for organophosphate poisoning?
Atropine
What is the antidote for b-blocker OD?
Glucagon/ioprenalin
What is the antidote for iron overdose?
Desferrioxamine
What is the antidote for triocyclic overdose?
Bicarbonate
What is the treatment of Methaemoglobinaemia?
Methylene blue
What Cyp enzyme leads to production of NAPQI?
Cyp2E1
What induced CYP2E1
Chronic alcoholism - leads to paracetamol toxicity as more is shunted down NAPQI pathway
What inhibits CYP2E1?
Acute alcohol intake
Rifampin, phenytoin, crabamaz, barbiturates
What is glutathione?
Active enzyme in NAC to breakdown NAPQI into non-toxic metabolites (cystine and mecapturic acid)
How can you tell CCB fr Beta blocker OD?
CCB - high BSL, insulin release dependent on calcium channels normally
Beta block - get HYPOglycaemia
What molecule is deficient in G6PD that protects against red cell oxidative stress?
Glutathione
