pharmacology Flashcards
TCI
1. what is the plasma conc for propofol for induction
2. plasma conc for maintenance
3. tell me about the inital bolus
4. Tell me about maintenance
5. at steady state what replacement is needed
- 6 mcg/ml
- 3-10 mcg/ml
- The initial bolus may take up to 30s, the TCI gives a little more that what is calculated for VoD & target plasma conc to compensate for the little amount of elimination & distribution that has occurred.
- maintenance- initially the pump will deliver the same amount as what is being eliminated and distributed (sum of all three clearances) for first 5 mins
- at steady state the only replacement needed is with the TCI elimination from the central compartment.
draw & explain the three compartment model
what is the ideal drug for TCI?
- short & predictable context sensitive half life even after long infusions(CSHL -> half-time is dependent on length of infusion where the longest possible would be at steady state)
- drug is lipid soluble
- no active metabolites: effect should be predictable from plasma concentrations
- non-organ dependent metabolism so the model is minimally affected by organ failure
minimal adverse CV affects
Propofol TCI models
1.marsh (weight, & central compartment value is a linear function of weight)
- Schnider (age, lean body mass, with a fixed central compartment volume)
- Minto
remifentanil TCI model
Minto (can also be used for Propofol)
4-6 ng/ml intubation & laryngoscopy
6-8 ng/ml for painful ops eg laparotomy
10-12ng/ml for cardiac surgery
with combined propofol/remi infusions, it is best to start the propofol first as it rises slower than remifentanil
alfentanil TCI model
Maitre
fentanyl TCI model
Shafer - has no covariates
Ketamine TCI model
Domino
How does drug absorption differ in neonates
-slower transit time and pH is less acidic. There may be increased absorption due to slower transit time meaning more contact time with mucosa
-transdermal- rapid absorption because stratum corneum (most outer layer) is thin
how does neonate distribution vary compared to adults
TBW is 80% compared to adults (60%) therefore doses of water-soluble drugs may need to be increased.
lower body fat and increased BBB permeability meaning increased concentrations of lipid-soluble drugs in the brain
decreased protein binding allowing increased availability of un-bound drug
neonatal metabolism and elimination compared to adults
metabolism depends highly on liver size. enxymes are immature and phase 1 metabolism is reduced in neonates, but increases over first 6 months.
Elimination- GFR is 20-40% less that adult rate so drugs removed this was are eliminated slowly.
how drug processes are different in the elderly:
- absorption
- distribution
- metabolism
- elimination
- absorption- slower gastric emptying but appears to be clinically insignificant
- distribution- smaller TBW, therefore drugs that are water soluble need lower doses to achieve same effect due to smaller VoD (hence drug doses in elderly are often less).
Elderly also have larger body fat ratio, decreased albumin levels (may increase unbound fraction of drugs), and reduced muscle bulk (reduced blood flow and hence drugs like remifentanil will take longer to metabolise) - metabolism- reduced HBF & enzyme activity which means higher availability of drugs that undergo first pass metabolism. Slower reduction in plasma clearance of drugs dependent on hepatic blood flow.
- elimination- decrease in GFR and tubular secretion which may lead to toxicity of drugs cleared by renal route
define first pass metabolism?
what is phase 1 metabolism?
phase 1 metabolism is modification of the drug chemical structure by introducing or exposing functional groups:
-predom P450(CYP) enzyme family
-oxidation: conversion of ethanol to acetaldehyde by alcohol dehydrogenase
-reduction: conversion of ketones to alcohols under low o2 conditions
-hydrolysis: breakdown of esters or amides into acids and alcohols or amines (e.g acetylcholine hydrolysis by acetylcholinesterase
what is phase 2 metabolism?
phase 2 metabolism involves attaching a large water-soluble molecule to phase 1 product to further increase water solubility & promote excretion
How are drug processed different in pregnancy?
1. absorption
2. distribution
3. metabolism
4. elimination
- absorption- delayed gastric emptying-> increased uptake of drugs absorbed in stomach, reduced uptake of drugs absorbed in intestines (related to increased progesterone levels)
- distribution- increased TBW & fat-> increased VoD (50% increased plasma vol->dilution of albumin). Increased free fatty acids compete with acidic drugs for the binding sites on protein, therefore there is an increased fraction of free drug
- metabolism- increased CO-> enhanced clearance of drugs from increased HBF (25% CO goes to liver). Increased enterohepatic circulation which may result in potentiation of certain drugs. Placental enzymes-> may metablolise various neurotransmitters & endogenous compounds. Placental lactogen (modifies metaboloic state of mother to facilitate energy supply of the fetus-> degradation of insulin)
- elimination- no change in clearance, but and increased in VoD which will result in a prolonged half life.
How are drug processed different in obesity?
1. absorption
2. distribution
3. metabolism
4. elimination
- absorption- relative increase in body fat is difficult to obtain useful measurements to alter drug doses-> IBW,lean body mass or BSA can all be used.
- distribution- VoD changes of lipophillic drugs,, and larger organs increased blood volume and increeased in lean body mass which can affect hydrophillic drug VoD
- metabolism- increased phase II metabolism leading to reduced effectiveness of drugs metabolised by this route including lorazepam and oxazepam
- elimination: conventional clearance equations may be inaccurate in obese. Overestimations occur with actual body weight and underestimations occur with ideal body weight.
how do you calculate BSA
Body Surface Area (BSA): There are 2 common formulae for this:
* DuBois equation: Body surface area (m2) = 0.007184 x (height)^0.725 x (weight)^0.42
- Mosteller equation: Body surface area (m2) = square root of (height x weight)/3600)
how do you calculate lean body mass
male: (1.1 x weight) - (128 x(weight/height)^2)
female =(1.07 x weight) -(148 x weight/height)^2)
how do you calculate ideal body mass?
1.Broca index (calculated estimate of lean mass)
IBW=height in cm-100
Adjustments: subtract 10% for women
add 10% for large frames or muscular individuals
e.g 170cm male ==170-100= IBW 70kg
How are drug processed different in critically ill patients?
1. absorption
2. distribution
3. metabolism
4. elimination
- absorption- blood diverted away from GI tract, intestinal atrophy following starvation, motility dysfunction from hypoperfusion & opiods-> all mean less bioavailability of drugs hence IV is the preferred route
- distribution: PH changes affected ionised/unionised fraction of drugs, fluid shifts cause increase interstitial fluid and larger VoD of hydrophilic drugs, reduced plasma proteins will increase the unbound drug.
- metabolism
HER is dependent on -protein binding, enzyme activity, HBF.
-Drugs dependent on HBF (HER >0.7) will be affected by the CVS.
-drugs with low HER (<0.3) are dependent on enzyme activity which is decreased by cytokines and acute phase proteins. Enteral feeding can help increase enzyme activity and hence clearance of these drugs - elimination- dose modify drugs with renal clearance / monitor if therapeutic range is close to toxic range
explain hepatic clearance
what is high and what does that mean
what is low and what does that mean
HER is the livers efficiency in removing a drug from the bloodstream as it passes the liver.
ONLY UNBOUND DRUGS CAN BE EXTRACTED BY THE LIVER
HER=Ca-Cv/ Ca
Ca=drug conc artery (before liver)
Cv=drug conc vein (after the liver)
High HER (>0.7):
-liver extracts large prop in one pass
-clearance is flow-dependent
-e.g morphine, lidocaine, propranolol
Intermediate HER (0.3-0.7)
-both HBF & enzyme capacity influence Cl
-e.g codeine, midazolam
Low HER (<0.3):
-liver extracts only small proportion of drug
-clearance is capacity-dependent, meanign rate of removal is limited by livers enzymatic/metabolic activity (not blood flow)
-e.g warfarin, theophylline, phenytoin
cause of sux apnoea & testing
BCHE gene for butyrylcholinesterase (plasma cholinesterase/ pseudocholinestarase.)
->autosomal recessive
homozygous-> sux apnoea
Heterozygoes-> slightly prolonged
EuEu =normal
EaEa= most common homozygous abnormality
EsEs= most prolonged (6-8hr)
Dibucaine is a LA that blocks light from being emitted when plasma cholinesterase is mixed with benzoylcholine.
abnormal gene will reduce amount of light inhibited (therefore more light emitted despite dibucaine)
EuEu=> normal=80% inhibited (dibucaine number of 80)
EaEa=> 20% of light is inhibited (dibucaine number of 20)
Normal: dib >80
hetero: 50-70
Homo: <30
Genetic testing can confirm specific BCHE gene mutations
causes of sux apnoea
- Genetic deficiency due to mutation in BCHEE gene which produces plasma cholinesterase
- Acquired deficiency
-liver disease e.g cirrhosis
-pregnancy (increase plasma volume, hormonal changes- use increased dose)
-malnutrition
-renal failure
-Drugs:
-organophosphates (pesticides, nerve agents)
-anticholinesterases (neostigmine, pyridostigmine)
-Chemo e.g cyclophosphamide
give examples of drugs with high HER (>0.7)
Morphine (HER 0.75)
Propranolol (HER 0.9)
Lidocaine (HER 0.7-0.8)
Give examples of drugs with intermediate HER (0.3-0.7)
codeine- metabolised to active form morphine) by liver enzyme CYP2D6. in patient with liver disease, reduced metabolism can impair benefit, while rapid metabolised of CYP2D6 may experience enhanced effects or toxicity
midazolam- metabolism affected by CYP3A4- clearance is reduced in liver dysfunction or if patient is taking inhibitors (e.g erythromycin)
Give examples of drugs with loe HER (<0.3)
Warfarin (HER 0.03!)- clearance dependent on livers metabolic activity (CYP2C9). Inhibitors (e.g amiodarone) prolong it’s half life, increasing risk of bleeding)
Theophylline (HER = 0.1)
inducers e.g smoking, rifampicin increase clearance, reducing its effect
Phenytoin: (HER 0.1)- metabolism follows non-linear kinetics (zero-order) meaning small dose changes can result in disproportionate plasma level changes.
What is bioavailability
Bioavailability(F) is
F= 1-HER
Extensive first-pass metabolism significantly reduces oral bioavailability, requiring higher oral doses compared to IV e.g morphine.
zero order kinetics
first order kinetics
rate of elimination is directly proportional to concentration of drug. i.e if conc increases, rate of elimination increases in a predictable manner
Rate=k.c
k= first-order rate constant (fraction of drug eliminated per unit time).
drug conc decreases exponentially over time
Ct=C0.e ^-k.t
T1/2= 0.693/k
ln first order kinetics, plasma drug concentrations are proportional to the dose administered. doubling the dose doubles the plasma conc.
E.g
Paracetamol
Penicillin
What is zero order kinetics
In zero order kinetics, the proportion eliminated is constant and independent of the drug concentration.
-occurs when the elimination processes (enzymes, or transporters) become saturated.
e.g liver enzymes metabolising a drug, renal transporters excreting a drug
examples:
-ethanol
-phenytoin
-Aspirin (at high doses)
half life is not constant (increases, a drug concentration increases)
risk of drugs accumulating quickly
what are signs of phenytoin toxicity
ataxia, nystagmus, drowsiness, slurred speech, headache, GI upset, bradycardia, hypotension, coma
tell me about ultrafast metabolisers of codeine
UM of codeine means the patient has a variation in the CYP2D6 enzyme responsible for converting codeine into its active form, morphine (codeine is a prodrug)
UMs convert codeine to morphine quicker and in larger quantities therefore risk toxicity and more SE (resp depression, sedation, confustion, nausea, constipation)
Acetlytransferase
N-acetyltransferases (NAT 1 & NAT 2) are enzymes responsiblel for hepatic phase 2 acetlyation (where acetly group is added to drug to make it more water soluble)
-found on chromosome 8
slow acetlyators have NAT-2*5 allele which are autosomal recessive. 50% caucasians are slow acetylators.
Effects-> drugs metabolised more slowly which can lead to toxicity.
Drugs affected:
-isoniazid (for TB)
-Hydralazine (HTN)
-Procainamide (antiarrhythmic)
-Sulfasalazine (used for IBD)
*fast acetlylators are at higher risk of colon ca.
* slow are at higher risk of bladder ca.
Acetylation status can be determined via genetic testing or by measuring the metabolism of a probe drug e.g caffeine or isonisazid in blood or urine
What is important about PGPs
PGP (P-Glycoprotein) also called ABC transporter or Multi-drug resistance protein 1
is a protein that actively pumps drugs & toxins out of cells. A wild-type of PGP will increase its activity and reduce oral bioavailability.
PGP inhibitors bind to the transported & prevent it from expelling drugs out of the cell & include:
-Amiodarone
-Cyclosporin (immunosuppressant)
-Verapamil (CCB)
PGP inhibitors can be used to increase the bioavailability of drugs with poor oral absorption
Theses can cause drug-drug interactions by increasing levels of PGP substrates leading to toxicity. e,g digoxin toxicity
