SN3 - Pharmacokinetics / Katzung Metabolism + Kinetics Flashcards
CYP450 INDUCERS (LIST 9)
1- phenobarbital/phentoin(anti epileptic)
2 - rifampicin (antibiotic)
3 - DDT / Aldrin (pesticides)
4 - Benzopirene/ 3-methylcholanthrene (combustion)
5 - Ethanol CHRONIC!
6. TCDD (dioxin) - pollutant
7. Butylated hydroxyanisole - antioxidant
8 - St Johns wort
9 - brussel sprout
CYP450 inhibitor (list
- Cimetidine - anthistamine
- Fluoxetine - antidepressant
- Isoniazide - anti tubercular
- ethanol ACUTE
- CCL4, Trichloroethylene
- Grapefruit
- Piperonyl butoxide - pesticide
- Carbon OXIDE
If people are taking inducers - what do you need to do with your dosing
UP the dose.
What happens if your patient is an alcoholic with liver cirrhosis
Cytochromes go down - NOT up.
PharmacokinEtics
ADME - what body does with drug absorption - mostly small intestine Distribution - circulation Metabo Elimination - mainly kidney
List a few factors that influence membrane passage
- membrane structure
- type of passage
- dose
- formulation
- molecular size and structure
- degree of ionisation
- lipid solubility of ionised and non-ionised forms
- binding to plasma and tissue proteins
Discuss charge and membrane crossing
CHARGED molecules CANNOT CROSS membranes, only uncharged can cross
Name the ways drugs can cross
- paracellular transport (also called filtration) - size of molecule imp
- diffusion - lipid soluble
- facilitate diffusion - passive - carrier mediated
- active - needs ATP
What is the form of crossing used by most drugs?
Passive diffusion
What is Fick’s law of diffusion
Predicts movement of molecules across a barrier::
Rate = (C1-C2) x Permeability coefficient/thickness of membrane x area
C1-C2 reflects concentration gradient
Permeability coefficient - measure of lipid solubility
Define partition coefficient
ability of drug to dissolve in lipid phase, P = ratio between concentration of drug in oil and water in pH of plasma 7.4
In the stomach, is a weak acid drug ionised or unionised
unionised,
Define henderson hasselbach equation
pKa -pH = log (protonated form)/unprotonated form
Pka - dissociation constant - half the drug is ionised and half unionised.
Are weak acids more or less water soluble if they are protonated?
Weak acids are not ionised and so are less water soluble when they are protonated RCOOH (protonated) = uncharged, more lipid soluble RCOO- + H+ (unprotonated) charged, more water soluble.
Are weak bases more or less water soluble when they are protonated’?
Weak bases are ionised and therefore more polar and more water soluble when they are protonated.
RNH3+ = protonated (charged) = water soluble
RNH2 + H+ = unprotonated (uncharged) more lipid soluble
Name a drug that inhibits the cough reflex
Codeine
Acid in acid environment will be
unionised
Basic in a basic environment will be
unionised
Acid in a basic environment will be
mostly ionised
basic in and acid environment will be
mostly ionised
How to pass an amphetamine test haha
Amphetamines are weak bases. Normally, in urine ph is 5-6 (weak acid) so in urine it is ionised and cannot go back into the blood. BUT if we alkalinise the urine, to bring it back to basic, meaning it is unionised and can be reabsorbed into the blood, not only keeping the drug in the body but also increasing its efficacy.
Thus, you take a BASE to keep a BASE in the body.
How do we treat an overdose of a weak acid (eg Tolbutamide antidiabetic)
We treat an overdose of a weak acid by decreasing absorption from the gut and reabsorption from the tubular urine by making the drug less lipid soluble. Weak acids are less ionised when protonated (in other words acidic pH). The, we need to alkalinise the environment (with bicarbonate) to create an ionised molecule that will not be able to cross the membrane, thus stopping absorption in the gut and reabsorption from the tubular urine. (alkalinising is not always the only way- might be contraindicated for other reasons)
Categorise active transports
Primary: pump mediated - uniport - cotransport Secondary: carrier mediated - antiport - symport
if a 10mg dose is 100% absorbed how do you calculate plasma concentration
Total blood volume - cell volume = plasma volume
= 5L-2.5L = 2.5l plasma
10mg/2.5L = 4mg/L
Name some of the 9 factors that influence absorption
- drug disintegration and dissolution
- chemical stability
- resistance to enzymatic degradation
- GI motility
- absence / presence / type of food
- GI barrier crossing
- GI bood flow
- Gastric emptying time
- The coarseness of the particle affects absorption
Tetracyclines discuss action, interaction with certain food and contraindications
Antibiotics, they bind calcium, so absorption decreased if taken with milk, calcium supplements, iron supplements, antacids. They have a chelating property - the chelate gets deposited in developing teeth and bone - contraindicated by children under 8 and pregnant women = NB
How do we calculate bioavailability
Curve with oral administration, use the Area under the curve
AUC after oral/AUC after IV x 100%
With oral bioavailability of 50%, if standard dose of IV is 50mg, what should oral dose be?
100mg
dose = actual plasma mass /oral bioavailability
= 50mg/50% = 100mg
Bioequivalence
if bioavailability wrt efficacy and safety will be same. Difference of bioequivalence of under 20% is considered acceptable
What affects distribution
refers to vascular to extravascular space
- blood flow
- lipid solubility
- drug size
- binding to tissue / plasma proteins
how do we calculate which organ gets the drug first?
normalise blood flow by organ mass - kidney thus first
How does liver disease affect albumin synthesis and how does this affect drug administration
less albumin produced - thus less bound drug so less drug should be administered
Discuss binding of drugs to proteins based on their pH
Acidic drugs bind albumin
Basic drugs bind alpha1-acid glycoprotein.
Warfarin
anticoagulant: prevents thrombosis, binds very heavily to albumin. Diazepam too - which will decease binding of warfarin = increased in the blood = haemorrhage
Name some drugs with high binding to plasma proteins
Warfarin
Diazepam
Heparin
Phenytoin
Name some conditions that alter protein levels:
pregnancy
kidney function
hepatic function
body composition
Name some conditions that reduces albumin
burns chronic liver disease cystic fibrosis pregnancy trauma renal failure
Name conditions with increased plasma proteins
Hypothyroidism increases albumin alpha 1 glycoprotein - celiac chrons myocardial infarction renal failure RA trauma
Volume of distribution equation
VD = Q/Cp
= quantity of drug in body/ plasma concentration
Plasma concentration equation
Cp = Q/ VD
= quantity of drug / volume of distribution
Discuss water compartments and VD and where the drug can distribute to
VD= 3L - stays in plasma VD = 13/14L = goes into interstitial VD = 42 - all cells
Your drug you want to administer needs a plasma concentration of 5mg/L, it has a Vd of 10L, how much to give
50mg of the drug
Vd = Q/Cp –> Q = VdxCp
= 5x10 = 50mg/L
Body water % of child, adult man and woman
Child 70-80%
Man 60%
Woman 55%
Name some things that disrupt the BBB or open it up
OPen BBB: hypertonic stimuli, cytokines and glutamate
Disrupt: HIE hypoxic ischemic encephalopathy and inflammatory mediators produced in sepsis.
Biotransformation - where does it occur
The liver mainly- but also GI tract, kidney, lungs, skin - wherever you have enzymes capable of converting a drug.
Phase 1 reactions
Hydroxylation
Oxidation
Oxidative deamination etc
What are oxidations catalysed by? What phase are they
Phase 1 reaction, oxidation is catalysed by Cytochrome P450 enzymes
Precisely where do you find cytochromes and what are they
Cytochrome P450 enzymes are membrane bound enzymes of the smooth ER of the hepatocytes, so we refer to them as microsomal.
Discuss phase II reactions, where it is located and its mediator and action
Different enzymes NOT in microsome catalyse conjugation reactions by linking to a compound - either glucoronic acid / sulphuric acid / glutathione / acetylated
these make compounds more soluble and are more easily excreted.
Discuss paracetamol / acetominophen metabolism in liver in terms of metabolites
three different metabolites but N-acetyl-p-benzoquinone imine is very toxic to the liver = hepatotoxicity and death.
Normally conjugated to glutathione and then excreted.
reaction catalysed by 3 different cytochromes.
Note that CYP2E1 is induced by ethanol, isoniazid = more metabolised = more toxicity.
what converts L-dopa to dopamine
decarboxylase removes the acid group generating dopamine. this classifies it as a prodrug.
Determinants of drug metabolism
- Genetics: could lack enzyme
- Age: less enzymes - more drug in body - give less dose. Children have low enzymes.
- Pregnancy
- Pathology (of liver) - Lower dose of drugs.
- Inducers /inhibitors
Is codeine a prodrug? Metabolised by?
yes - converted to morphine. CYP2D6 - 7% of caucasian lack this
Enzyme induction means
A molecule initiates or enhances the expression of an enzyme: more enzyme in liver - more metabolism. Induction accelerates drug metabolism and hence shortens drug activity.
taking a drug for a long time could actually cause pharmacokinetic tolerance as in phenobarbital.
Competitive inhibition of enzymes in liver means
Decreased metabolism due to pharmacokinetic drug interactions
Which enzyme metabolises more than 50% of drugs
CYP3A4
What is cross tolerance?
A tolerance to all drugs that are metabolised by the same enzyme (example of drug-drug interaction).
What is pharmacological tolerance
decreased responsiveness to a drug on increased administration.
Inhibition of enzymes -explain
competitive inhibition, acts only when drugs are in the body, leads to less toxic metabolites but can mean accumulation of drug in the body due to not being metabolised as fast as normal.
CYP3A4: inhibited by and induced by?
present in enterocyte of intestinal epithelium too
Inducer: phenobarbitol
Inhibitor: grapefruit juice.
First order kinetics
- increasing plasma concentration = increased drug metabolism
- rate of metabolism is PROPORTIONAL to drug concentration (50% of drug/hr)
- Rate of metabolism is NOT constant, the HALF TIME is constant.
- represents most drugs at most doses,
Downward curve.
Zero order kinetics
- increasing drug concentration has no effect on rate of drug metabolism
- Rate of metabolism is constant independent of drug
- Unusual - certain substances like alcohol or when you give too much drug and enzymes are saturated.
Calculation for renal excretion
Excretion = filtration - reabsorption + secretion
Discuss the processes of renal excretion
- filtration - metabolites and unmetabolised drugs / unbound drugs. Filtration depends on size, physical process
- passive process happens at proximal and distal convoluted tubule.
- Secretion - active saturable process affecting excretion of weak acids and bases, occurring at proximal convoluted tubule.
Only lipid soluble molecules will be reabsorbed.
Penicillin increase of duration - discuss.
you give a drug to inhibit the transporter that inhibit the reabsorption of uric acid and it also inhibits the OAT1/3 transporter so it stays in blood longer
Rate of elimination is equal to?
Clearance x drug concentration
GFR clearance is?
= CL creatine
perfusion rate of kidneys
1200ml/min, about 10% of acqeous part of blood is filtered through kidney glomeruli, therefore GFR=120ml/min
What is the lower limit of GFR
<60ml/min elimination
What is billiary excretion of drugs influenced by
drug polarity and size. Four active transport systems: anions, cations, biliary acids, neutral substances
Name 2 ways drugs get into the liver
first pass - oral administration
systemic circulation after absorption
what is enterohepatic circulation
recirculation of compounds between liver and intestine
Many compounds released in bile, reabsorbed in small intestine and returned to liver to be recycled.
Glucuronic acid conjugated metabolites often
get metabolised by intestinal flora by enzymatic hydrolysis, if you lack this gut flora, the drug cannot be deconjugated and cannot be reabsorbed and thus cannot undergo enterohepatic recycling this excreted
What limits does the steady state concentration need to be between?
above the lower limit of efficacy and below the max limit of toxicity
Dosing rate calculation?
Dosing rate = clearance x concentration (steady state).
This will be a volume / time.
How many half lives does it take to eliminate
97% of drug is eliminated after 5 half lives.
T 1/2 =
0.693 / Ke (elimination constant)
OR
0.693 x Vd/CL
Give eliminations for each of the first 5 half lives
- 50%
- 75%
- 87.5%
- 93.75%
- 97%
Time required to get to steady state concentration
After 5 half lives you get to steady state
Loading dose - when do we use this and what is calculation?
if you give a drug that takes a long time to reach steady state:
LD = Vd x Cp / BA
(bioavailability) for IV this is 1
Maintenance dose:
After the loading dose, if we give a continuous infusion;
Infusion rate = Css x CL/ BA
If we give a dose interval (repeated dose) how do we calculate
MD = Css x CL x Tao / BA
Tao is the dosing interval
Very toxic drugs where you don’t calculate the rate but instead need to actually measure the concentration are:
- cyclosporin
- theophilline
- antipsychotics
- antiepileptics
- lithium
- digitoxin /digoxin
- vancomycin
