Variability in drug response Flashcards
Define tachyphylaxis
Repeated administration of a drug is associated with a rapid decrease in response to that drug over a short time period
Give an example of tachyphylaxis
E,g, ephedrine or metaraminol leads to depletion of noradrenaline stores
Most common mechanism is depletion of stores of a transmitter before resynthesis can take place
What is desensitisation?
De-sensitisation refers to chronic loss fo response over a longer period and may be cause by structural change in receptor morphology or by absolute loss of receptor numbers. Often used synonymously with tachyphylaxis —> beta receptor depletion in the use of adrenaline
Give an example
Define tolerance
Increased doses of a drug are required to produce the same effect
What mechanisms have been postulated for tolerance occuring (5)
- Decreased receptor density
- Structural changes in receptor morphiology changing affinity
- Altered response to drug receptor activation
- Enzyme induction —> decreased quantity of drug reaches the site of action
- Development of physiological compensatory mechanisms
Give an example of pharmacological tolerance and the different ways it effects primary reason for use, modifications of this tolerance and side effects
- Opioids
◦ Cross tolerance
◦ Analgesia - decreased duration of analgesia and then decreased intensity of analgesia
◦ Euphoria
◦ Respiratory depression - tolerance slower less than the analgesia
◦ Less tolerance to constipation and miosis - Nitrates - sulfhydryl groups on vascular smooth muscle become depleted
Define addiction
Repetitive compulsive use of psychoactive substances known by the user to be harmful
Define dependence
Physical or psycho.logical state associated with withdrawal symptoms when the drug administered is abruptly ceased
E.g. opioids with halo one exaggerating symptoms, and the symptoms are abolished by a small dose of an opioid
Outline what idiosyncracy is in the context of drug effects, mechanisms (3) and key characteristics (2)
Examples (4)
Adverse drug reactions can be divided into? (2)
Involvement of genetics? Relationship to dose? Mechanisms 2/3
Example
Define hypersensitivity reactions
exaggerated or inappropriate immune response
Histamine structurally is what?
Low molecular weight, endogenous amine synthesised in tissued by decarboxylation of histidine
What receptors does histamine act on?
H1
H2
H3
H1 receptor activation causes what? (4)
- Smooth muscle contraction in resp + GIT
- Increase release of prostacyclin from endothelial cells AND release of nitric oxide
- CVS central - slow AVN conduction, coronary vasoconstriction
- Peripheral vasodilation, increased capillary perameability
H2 receptor activation causes what?
- Bronchodilation
- Gastric - increased H+ secretion
- Cardiac 0 increased HR and contractility, coronary vasodilation
- Peripheral vasodilation and increased permeability
H3 receptor does what
decreases synthesis and reelase of histamine
Seratonin structurally is what? Synthesised from?
Monoamine neurotransmitter
Synthesed from L trytophan
Receptor subtypes for seratonin
5HT3 ligand gated ion channel
5HT1, 2, 4,5 6, 7 GPCR
Bradykinin is structurally what?
small autocoids, polypeptide of low molecular weight synthsed from kininogens which are plasma alpha 2 globulins
What are the functions of Prostaglandins?
- Pain - inflammation, sensitise peripheral nerve endings
- Mediated pyrogenic response and inflammation
- GIT - decreased gastric acid secretion, increased protective mucous secretion
- Renal blood flow regulation
PGI2 - bronchodilates, vasodilates. plt aggregation
What is a type 2 hypersensitivty reaction? e.g.
IgG or IgM bind to a cell surface antibody –> classical pathway of complement activation leading to cell lysis, phagocytosis and inflammation
e.g. HUS, HITTS
What is the difference between anaphylaxis and non allergy anaphylactoid reactions
Anaphylaxis - IgE mediated mast cell degranulation, requiring prior sensisation, live threatening and dose independent
Anaphylactoid - mast cell degranulation by substances, no prior exposure, less severe and more linked to dose
What allergies/reactions can latex cause
Irritatnt contact dermatitis
Anaphylaxis
Delayed hypersensitivity reaction
If you were to characterise mechansism of drug reactions into 3 groups how would you do it?
1/ provide example
2. 4
3. 4 types of response
Physicochemical
* Pharmaceutical - thiopental + succ —> precipitate
* Chelation - tetracyclines +calcium —> decreased absorption
Pharmacokinetic
* Absorption e.g. second gas effect
* Distribution - compete for the same protein binding sites
* Metabolism - enzyme induction and inhibition
* Excretion - compete for the same active transport system
Pharmacodynamic
* Antagonism
* Summation - net effect is equal to the sum of the individual effects
◦ Combination of 2 drugs with identical mechanism of action
◦ E.g. two different opioids
* Potentiation
◦ One drug increases the effect of another
◦ One fo the drugs has no independent action on its own
◦ E.g. aminoglycosides increase competitive neuromuscular blockade
* Synergism
◦ The net effect is more than the sum of the individual effects
◦ Combination of drugs that exert similar effects but have different mechanisms of action
◦ E.g. NSAID and opioids
Describe an example fo absorption mediated variations due to drug interactions? Give an example of a drug affected? How to increase and decrease drug availability
- ABC (ATP binding cassette) family has a protein within it called the multi-drug resistant protein transporter known as p-glycoprotein (PGP) which is found in gut mucosa and the BBB
- Many cytotoxic, anti microbial and other drugs are ubstrates for PGP and unable therefore the penetrate the BBB
- E.g. anticoagulatant Dabigatran
- Coadminstration of PGP inhibits e.g. amiodarone, verapamil will increase Dabigatran bioavailability and therefore risk of adverse events while inducers e.g. rifampicin will reduce bioavailability
- PGP inhibitors and inducers also happen often to be inducers and inhibitors of CYP3A4
What is metabolised by CYP2B6
Inducers
Inhibitor
Propofol
Methadone
Ketamine
Cyclophosphamide (induces itself)
Clopidogrel
Inhibited by clopidogrel
Phenobarb and SMOKING induces metabolism
Propofol is metabolised by which enzyme
CYP2B6
CYP2C9
What are the drugs metabolised by CYP2C9
Inducers
inhibitors
Propofol
Phenytoin
Parecoxib
Celecoxib
Losartan
S warfarin
INduced by brbituarates and rifampicin
Inhibited by amiodarone, azoles, macrolides, metronidazole and trimethorpim
CYP2C19 metabolism
inducers
inhibitors
Losartan
Diazepam
Phenytoin
Omeprazole
Clopidogrel
Induced by barbituares and rifampicin
Inhibited by fluconazole
CYP2D6 metabolism
inducers
Inhibtors
Codeine/oxycodone/tramadol
Flecainide
Metoprolol
TCAs, Fluoxetine, Clozapine
Paroxetine and fluoxetine inhibit
histamine receptor antagonsits -0 cimetidine inhibit, amiodarone, inhibits
7% genetic absence
CYP3A4 metabolism
inducers
Inhibitors
Diazepam, temazepam, midazolam
Fentanyl, alfentanil, methadone
Paracetamol
Lignocaine
Vecuronium
Amidoarone, diltiazem, nifedipine, sprionolactone, verapamil, sildenafil, statins
Cortisol, cyclosporin, tacrolimus
Macrolides
Inducers
- Phenytoin, barbituates, carbamazpeine
- Glucocorticoids
- Rifampicin
- St Johns wart
- Mifepristone and atorvastatin
Inhibitors
- Abx - clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, ritonivir
- Grapefruit juice
- Diltiazem
CYP1A2 metabolites
Inducers
PCM
Caffeine
Tamoxifen
Warfarin 12% increase inrequirement
Clopidogrel
Theophylline
Olanzapine, fluvoxamine
Inducers - smoking, cruciferous vegetables, omeprazole
Characterize a phase 1 reaction
Non synthetic, non specific conversion of parent drug to a oplar metabolite by introducing or unmasking a functional group e.g OH, NH2, SH increasing polarity
Fate of phase 1 products
◦ Many phase 1 products are not eliminated rapidly and undergo a subsequent reaction (phase 2) in which an endogenous substrate such as glucoronic acid, sulfuric acid, acetic acid or amino acid combines with the newly incorporated functional group to form a highly polar conjugate
If you were to class phase 1 reactions into 3 main reaction types
Oxidation
Reduction
Hydorlysis
What is an example of a phase 1 oxidation reaction
Removal of electorns from moelcules, the most common
Liver predominant but also occurs in mucosa, lung, brain, kkidney
Demethylation (diazepam), hydroxylation (midazolam), desulfation of thiopental
Reduction of species is a phase 1 or 2 metabolism reaction? e.g.>
Phase 1
P450 driven
GTN is an example
What is reduction
The gain of electrons
What is a non oxidation/reduction phase 1 reaction?
hydrolysis
A moelcule is cleaved into 2 parts byt he addition of H20
Not P450 driven
Plasma cholinesterases, non specific esterases and red cell esterases do this
e.g. Succinylcholine, remifentatnil, esmolol, LA (esters)
Where are non specific esterases found?
Cytoplasm of muscle and liver
What is the microsomal oxidation system? Where is it found? What is it derived from? What 2 microsomes are key?
Drug metabolising enzymes are oftne located in the lipophilic endoplasmic reticulum of hte liver, lamellar membanes reform into vesicles called microsomes which retain morphologica and functional characteristics of intact membrane of the endoplasmic reticulum
2 microsomes key
- Flavoproetin NADPH cytochrome P450
- Haemoprotein - terminal oxidase
What dos p450 refer to
wavelenght of absorption of light when in reduced form and combined with carbon monoxide
Where is cyp450 enzymes
Smooth ER of hepatocytes
Gut mucosa
Lungs
Kidneys
Brain
What is the rbeakdown of frequency of each fo the major subfamilies of CYP 450
◦ CYP1A2 - 15%
◦ CYP2A6 - 4%
◦ CYP2B6 - 1%
◦ CYP2C9 - 20% of human liver P450 content
◦ CYP2D6 - 5% of human liver P450 content
‣ Multiple mutations, genetic polymorphisms
‣ 5-15% of the population are poor metabolisers
‣ Codeine, tramadol, oxycodone
◦ CYP2E1 - 10% of human liver P450 content
‣ Fluorine containing volatile metabolism
◦ CYP3A4 - 30% of P450 liver P450 content
‣ 50% of prescription drugs metabolised by the liver
‣ Midazolam, alfentanyl
What does carbamazapine enhance the metabolism of?
Clonazepam
itraconazole
Carbamazepine
What does phenytoin enhance the metabolism of
Cortisol, dexamethasone
Digitoxin
Itraconazole
Theophyllline
Ritonavir effects metabolism of?
Midazolam
Rifampicin affects metabolism of
Glucocorticoids, prednisone
Propanolol, metoprolol
Anticoagulants
Digitoxin
Methadone
Barbituates and phenobarbitol afffect metabolism of
Coumarin anticoagulants
Digitoxin
Itraconazole
Phenytoin
Chloramphenicol
Chlorpromazine
What is an example of a liver enzyme inhibitor? MOA?
- Imidizolecontaining drugs e.g.cimetidine, ketoconazole bind tightly to P450 heme iron and reduce the metabolism of endogenous substrates
- Macrolides e.g. erythromycin are metabolised by CYP3A to metabolites that complex the cytochrome P450 heme iron and render it catalytically inactive
How do liver enzyme inducers work? (2)
either enhance P450 synthesis or reduce is degredation
* Accelarates substrate metabolism and decrease pharmacological action OR exacerbates metabolite mediated toxicity
What is a phase 2 reaction? What characteristics the substrates and the products? e.g.?
Conjugation or coupling synthetic reactions with endogenous substances to yeild more water soluble conjugates
Either parent drugs or phase 1 metabolites, sometimes phase 2 comes before phase 1.
Generally metabolites polar, renally excreted, often inactive. Morphine 6 glucoronide would be an exception however
How are phase 2 reactions facilitated? Where in the cell?
Transferases - UDP glucuronosyl transferase (UGT) the most dominant, work int he cytosol and microsomes
How do phase 2 reactions compare to phase 1
faster, conjugation and coupling sythetic reactions
What are examples of phase 2 reaction types
◦ Glucoronidation - morphine, propofol
◦ Sulphation - BDZ, propofol
◦ Acetylation - hydralazine
◦ Methylation - catecholamines
COmpring phase 1 and 2 which loses activity in renal failure earlier
Phase 1
Plasma esterases do what? High or low capacity? Foudn where?
Non microsomal enzymes in the liver and RBC
Hydrolyse ester bonds
High capacity enzymes
3 examples of plasma esterases and their metabolites
◦ Plasma cholinesterase
‣ Succinylcholine, mivacurium,ester LA
◦ Non specific plasma esterases
‣ Remifentanil, atracurium
◦ RBC esterases
‣ Esmolol
List 5 drug factors affecting hepatic metabolism of drugs
Lipid solubility
Ionisation
protein binding
Competition of enzyme metabolism
Saturatable enzyme metabolism
Give 4 social patient factors that can be determined from history that affect drug metabolism in the liver? Give 4 factors that further affect metabolism
- Age
- Obesity
- Pregnancy
- Social- smoking. diet, alcohol
- Genetic polymorphism - slow and fast acetylation, succylcholine apnoea
- Hepatic blood flow
- Enzyme induction or inhibition
- Hepatic disease
Give 3 hepatic enzyme inhibitors
Cimetidine
Omeprazole
Antidepressants
Erythromycin
Grapefruit juice
Give 3 liver enzyme inducers
Barbituates
Phentyoin
Carbamazapine
Tobacco
Alcohol
What is Michaelis Mentin kinetics
- Enzyme kinetics - equating reaction velocity to substrate concentration for the below system
Draw a graph representing the effect of two interacting drugs reprresenitng additive, antagonitic and synergitic effects
What effect does alcohol have on metabolsim of drugs?
Enzyme inducer so icnreases their etabolism
What effect does cigarette smoking have on metabolism of drugs?
Increases as is a liver enzyme indcuer
Describe factors which influence drug distribution to the foetus
- Lipid solubility - placental membrane derived from foetal capillaries and synctiotrophoblast and is phospholipid in nature. Pethidine high lipid solubility thyen metabolised and accumula;tes
- Free drug concentration
- Placental blood flow
- pKa - foetal pH is lower than in the mother –> lignocaine has a lower pKa so is more lipophilic at lower pHs reducing trapping in foetus, however Bupivocaine is the opposite
How does noenatal/infant pharmacodynamics differ to adults
3
- Immmature NMJ until 2 months of age - smaller ACh reserves, myasthenia response to muscle relaxants nad more sensitive to non depolarising agents
- Increased MAC
- NSAIDs close ductus
Pharmacokinetic changes in infants/noenates comparted to adults
A - 3(
D - 4
M - 2
E - 1
Absorption
1. Oral absorption - delayed gastric emptying and slower intestinal transit time. Slower but increased absorption of drugs
2. IM - small muscle mass, hihg CO so fast onset
3. Voltailes - faster onset, due to VA: FRC BUT increased cardiac output reduced onset
Distribution
1. Increased Vd - increased TBW, increased BV (ECF > ICF)
2. Reduced plasma protein binding - albumin, alpha 1 acid gluycoprtoein
3. Increased cardiac output
4. Immature BBB
M
1. Immature active enzymes - despite liver size being rrelatively larger, maturitiy reached by 2 years
2. Decrease plasma cholinesterase but SCh not prolonged in action
E
1. Immature renal function in first 6 months <10% of adult
How does being a noenate affect absorption of drugs (3)
Absorption
1. Oral absorption - delayed gastric emptying and slower intestinal transit time. Slower but increased absorption of drugs
2. IM - small muscle mass, hihg CO so fast onset
3. Voltailes - faster onset, due to VA: FRC BUT increased cardiac output reduced onset
How does being a noenate affect metabolism of drugs (2)
M
1. Immature active enzymes - despite liver size being rrelatively larger, maturitiy reached by 2 years
2. Decrease plasma cholinesterase but SCh not prolonged in action
How does being a noenate affect distribution of drugs (4)
Distribution
1. Increased Vd - increased TBW, increased BV (ECF > ICF)
2. Reduced plasma protein binding - albumin, alpha 1 acid gluycoprtoein
3. Increased cardiac output
4. Immature BBB
How does being elderly affect pharmacodynamics (3)
- Brain - reduced MAC, increased responisbeness of sedatives and hypnotics ?receptor mediated
- Heart
a) reduced responisvenss to beta agonists, antagonits due to receptor downregulation
b) loss of baroreceptor reflex (vasodilators more likely to cause hypotension) - Interaction
A) other medications
B) other illnesses
How does being elderly affect pharmacokinetics?
A - 1
D - 2
M - 2
E - 2
Absorption NIL
Distribution
1. Altered Vd - reduced muscle mass, and total body water. Increased fat mass for accumulation of lipid soluble drugs
2. Decreased albumin nd increased alpha 1 acid glyocprotein
Metbaolism
1. Decreased hepatic blood flow
2. Decreased hepatic enzyme activity Phase 1 > phase 2
Eliminiation
- Reduction in CrC with age
- Reduction in hepatic funciton with age
How does being pregnant effect pharmacodynamcis? (2)
Decreased MAC
Increased sensitivty to LA
Pharmacokinetics of pregnancy
A - 3
D - 2
M - 3
E - 1
A -
1. Delayed gastric emptying with labour, nausea and vomiting
2. Increased cardiac output - increased IM and SC absorption, faster onset of action
3. Increased minute ventilation, reduced FRC = faster volatile onset.
D -
1. Increased Vd - increased TBW and plasma volume, increased ECF and increased fat mass
2. Decreased albumin and alpha 1 acid glycoprotein
M -
1. NO change in hepatic blood flow
2. Hepatic enzyme induction by progresterone and competition for hepatic metabolism by oestrogen
3. Decreased plasma cholinesterase activity
E
1. Increased renal blood flow and GFR
Obesity and its impact on pharmacokinetics
A - 3
D - 2
M - 4
E - 1
A
1. Increased GORD
2. Delayed gastric emptying
3. Increased gut perfusion due to increased cardiac output
D -
1. Increased Vd - increased fat mass, total body water, blood volume, organ mass and LBM
2. Increased alpha 1 acid glycoprotein
M
1. Increased hepatic blood flow
2. Phase 1 and 2 enzymes unchange dor increased
3. Fatty liver infiltration
E
1. Increased renal blood flow and GFR
What are some examples of drugs which are markedly affected by cardiac failure in their clearance
Cardiac disease by limiting blood flow to the liver may impair disposition of drugs whose metabolism is flow limited even where they are rapid;y metabolised
* Amitryptline
* Isoniazid
* Lidocaine
* Morphine
* Propranolol
* Verapamil
* Labetalol
How does pulmonary disease affect drug metabolsim
Pulmonary disease can affect drug metabolism
* Impaired hydrolysis of procainamide and procaine him those with chronic respiratory insufficiency and increased half life of anti-pyrine in those with lung cancer
What effect does liver disease have on drug metabolism - pharmacokinetics
A -1
D - 3
M 3
E 1
Absorption
1. Portocaval shunting - decreased first pass metabolis, increased oral bioavailability. Important for drugs with high hepatic extraction ratio
D
- Decreased protein synthesis - decreased plasma protein binding and increased unbound fraction
- Increased Vd - fluid and Na retention, ascities, decreased plasma protein binding
- Acid base changes altering ionised fraction
M -
1. Phase 1` and 2 reaction decreased (phase 1 the most), decreased drug metabolism
2. Decreased hepatic blood flow
3. Decreased plasma cholinesterase
E
- Decreased biliary excretion
How does hepatic disease affect pharmacodynamics
Increased sensitivity to hypnotics and sedatives
Renal disease effect on pharmacokinetics
A - 1
D - 2
M - 1
E - 2
Absorption
- Increased urea delays gastric emptying
Distribution
1. Increased Vd due to fluid retention and reduced plasma proteins. Higher loading doses may be required
2. Avid base changes alter the ionised fraction and protein bidning
M
- Uraemic toxins inhibit enzymes and drug transporters
E - Decreased drug clearance and drug accumulation, decreased dose and increased dosing interval
- Increased urea affects osmotic changes
How to calculate the dose required based on renal dysfunction
= usual dose x impaired clearance / normal clearance
How does cardiac failure influence pharmacokinetics?
A 2
D - 3
M 2
E 1
Absorption
1. Decreased gut perfusion
2. Decreased cardiac output
- Reduces concentration gradient between blood and alveolus, alveolar partial pressure rises more quickyl and faster uptake of volatiles
Distribution
1. Decreased Vd - increased drug concentrations, increased CNS sensitivtiy. SMaller loading doses
2. Decreased cardiac output slower arm to brain circulation time
3. Increased alpha1 acid glycoprotein in acute cardiac failure - basic drugs reduced binding
Metabolism
- reduction in hepatic blood flow
- Hepatic metabolic pathways may be altered
Elimination
- Decreased renal blood flow
What are non genetic variables influencing drug metabolism?
5
◦ Age
‣ Increased susceptibility to toxic and pharmacological activity occurs at the extremes of age
‣ Drug metabolism plays a role along with absorption, distribution and elimination
◦ Sex
‣ Ethanol, propranolol, benzodiazepaines, oestrogen and salicylates all may have sex dependent variation inmetabolism
◦ Liver size and function
◦ Body temperature
◦ Nutritional and environmental factors
‣ Charcoal broiled foods and cruciferous vegetables are known to induced CYP1A enzymes
‣ Grapefruit juice inhibits the CYP3Ametabolism of coadminstrered drugs
‣ Cigarette smokers metabolise some drugs more avidly because of enzyme induction
Define a genetic polymorphism
- Inherited differences in enzyme structure that alter the way drugs are metabolised in the body
‣ Occupancy of a variant allele of a gene at a population frequency of >1% resulting in altered expression or functional activity of a gene product
Contribute to significant differences in the metabolic rate by up to 30x
Outline genetic variability of phase 1 - 3 examples
‣ Phase 1
* Often autosomal recessive
* Debrisoquinsparteine oxidation
◦ 3-10% of caucasians
◦ Autosomal recessive
◦ CYP2D6 dependent oxidations of debrisoquin and other drugs (tamoxifen- failed activation to active metabolite)
◦ Faulty expression fo the P450 protein due to mRNA splicing or protein folding conferring a poor metaboliser phenotype ]
- Ultra rapid CYP2D6 variation
◦ Ethiopians and Saudi Arabians in 1/3
◦ Need higher doses of nortriptyline; and metabolises codeine much faster - Stereoselective aromatic 4 hydroxylation of anticonvulsant me-phenytoin
◦ CYP2C19
◦ Autosomal recessive in 3-5% of Caucasian’s and 20% of Japanese
◦ Normal = S mepheytoin is hydroxilated by CYP2C19 at the 4 position of the phenyl ring before glucoronidation and rapid excretion in the urine whereas R-mephenytoin is slowly N-demethylated to nirvanol and active metabolite
‣ Extensive metabolisers may show higher levels of tamoxifen and clopidogrel which are prodrugs activated by this mechanism
◦ Poor metabolisers lack the hydroxylase activity leading both S and R me-phenytoin e anti omens to be N-demthylated to nirvanol accumulating at high doses —> sedation, ataxia - Other genetic factors affect warfarin, and other CYP2C9 substances e.g. phenytoin, losartan, NSAIDs
Phase 2 variants in metabolism seen in what 3 examples
- Succinylcholine is metabolised only half as rapidly in persons with genetically determined deficiency in plasma-cholinesterase (BCHE)
◦ Hydrolysis in the plasma is catalysed by non specific enzyme plasma cholinesterase
◦ Autosomal recessive genes found
◦ This increases the risk of prolonged respiratory paralysis (succinylcholine apnoea)
* TPMT
◦ Encountered in 1:300 Europeans resulting in rapidly degraded mutant enzyme and consequenct deficient S methylation of aromatic and heterocyclic sulfhydryl compounds which is required for detoxification
◦ This increases the risk of this purine drug induced fatal haematopoeiteic toxicity
* UGT polypmorphisms - Gilberts syndrome
* Acetylation is a phase 2 metabolic pathway in the liver, drugs metabolised by N-acetyltransferase type 2 (NAT2) include hydralazine and isoniazid
◦ Genetically different isoenzymes of NAT2 that acetylate at a slow or fast rate
Define isomer
Compounds with the same atomic formula and same molecular weight but different structural arrangements
Structural isomer includes what types? What is a structural isomer? Define each subgroup
Same atomic formula but DIFFERENT order of atomic bonds
Positional isomers - atoms occupy different positions on identical carbon skeleton
Chain isomers
Functional group isomers
Tautomerism - a type opf strutcural isomer were balance between two isomers is determined by surrounding pH
e.g. Thiopental - enol form is water soluble, keto form lipid soluble
What is a stereoisomer
Same atomic formulae, same bond structure, different 3 dimensional configuration
What are the types of stereoisomer
Geometric - cis and trans
Optical isomers
- Enantiomer - L and D OR S and R
- Diastereoisomers
What is a geometric isomer? What subclassifications
Dissimilar groups attached to two atoms linked by structurally rigid bond e.g. double bone or ring
Cis - same side
Trans - opposite side
e.g. mivacurium
What is an optical isomer
One or more chiral centres
What is a chiral centre
Carbon atom or quaternary ntirogen surrounded by 4 different chemical groups
Enantiomer
A compound that is a mirror image of each other around a chiral centre
What are the subtypes of enantiomers
D +/- or L - or (-)
According to direction of rotation of the plane on polarised light
R and S
According to direction in whcioh groups with increasing MW are organised about a chiral centre
What is a racaemic mixture
Preprations containing equal amounts of two enantiomers e.g. bupivocaine, atropine, volatiles (except sevo)
Enantiopure preparations
Single enantiomer e.g. S ketamine, dexmeditomidine, S bupivocaine or S ropivocaine
Diastereoisomers
Compounds containing more than one chiral centre e.g. atracurium
INcidence of malignant hyperthermia
1:5000 to 1:50 000
Inheritence pattern of MH
autosomal cominant
What is the MOA of MH
Ryanodine receptor mutation on chromosome 19 on the sarcoplasmic reticulum which mediate release of Ca from the sarcoplasmic reticulum
Abnormal RY R leads to excessive efflux of Ca and generalised muscle rigidity, increasing ATP consumption to return Ca into sarcoplasmic reticulum –> increased CO2, heat and lactate –> cell lysis –> myoglobinaemia, hyperkalaemia, acidosis
What causes MH
Succinylcholine and volatile anaesthetic agents
What 3 subtypes of ryanidine receptor are there?
RY R 1 - skeletal
RYR 2 - myocardium
YR 3 brain
Early clinical features of MH
Monitor
Increased HR
Increased ETCO2
Increased temperature
Arrhythmias
Patient
Masseter spasm after ACh
Sweating
Muscle rigidity
Tests
- Hyperkalaemia
- Metabolic and respiratory acidosis
Late signs of MH
Myoglobinuria
Raised serum CK
Coagulopathy
Cardiac arrest
How to treat MH
- Stop trigger - turn off volatile, hyperventilate with 100% O2/high gas flows and start TIVA
- Dantrolene
- Treat complications
- HyperK
- Hyperthermia
- Acidosis
- Arrhtyhmias
- Renal protection
How do you test for malignant hyperthermia
Caffeine and halothane contracture test
Dantrolene preparation
20mg with 3mg mannitol in an orange powder to be reconstructed in 60ml of sterile water
Highly irritant when extravasated
Dose of dantrolene
2.5mg/kg IV every 10-15 minutes up to 10mg/kg and then 1mg/kg every 4-6 hours for 24 hours after crisis
Mechanism of dantrolene
Binds to RYR1 preventing Ca release uncoupling excitation contraction
No effect on muscle aciton potential
Pharmacokinetics of dantrolene
Protein binding 85%
Hepatic metabolism to 5-hydroxy
T1/2 B 12 hours
Renal excretion
What is a porphyria
Defect in haem synthesis - the 1st step where conjugation of succinyl CoA and glycine to gamma amino-laevulinic acid catalused by amino-laevulinic acid synthetase –> partial deficiency resulting i accumulation of porphyrin precurers
Unsafe drugs in context of porphyrias
Barbituarates
Ketamine
Clonidine
Ketorolac, diclofenac
Phenytoin
Erythromycin
?Metaraminol and ephidrine
?Volatiles
?Oxycodone
Where do you find plasma cholinesterases
Plasma, brain,. liver, kidneys
Where are plasma cholinesterases synthesised
Liver
T1/2 beta of plasma cholinesterases
8-16 hours
Plasma cholinesterase involved in the metabolism of what 3 agents
SCh
Mivacurium
Ester LAs
Describe the genetics around plasma cholinesterases
Chromosome 3 4 alleles
- Usual
- Atypical
- Silent/absent
- Fluoride resistant
Homozygenous patient prolonged paralysed after usual dose SCh 4-8 hours, dibucaine number 20. Ea/Ea
Heterozygotes have slightly prolonged paralysis after usual dose, 4% of people, 10-20 minute paralysis. Dibucaine number 60
96% of people normal response, dibucaine number 80
What commonly encountered factors lead to reduced plasma cholinesterase
- Pregnancy
- Organ failures - liver, renal, cardiac
- Malingancy and malnutrition
- Burns
- Thyrotoxicosis
- Iatrogenic - plasmapheresis, anticholinesterases, ketamine, ester LA, OCP
What is dibucaine?
Amide LA
Inhibits normal plasma cholinesterase to a greater extnet than atypical forms
Dibucaine number represents perecentage inhibition i.e. higher number = more normal plasma cholinesterase
What is p glycoprotein?
A drug efflux pump in the intestine
What inhibits P glycoprotein?
Verapamil
Amiodarone
Dabigatran
Ketoconazole
Erythromycin
Quinidine
What are subtrates for P glycoprotein>
Digoxin
CaB
Statins
Sildenafil
Calcineurin inhibitors
Diazepam
OCP
Warfarin affected by
All ABx - endogenous vitamin K production which anythign broad spectrum affects, macrolides, metrnidazole, cipro also inhibit its breakdown
PCM, ASA, NSAIDs, amiodarone, statins can also inhibit its metabolism
QTc prolongation due to
Genetic/congenital
Anti-arrhtyhmics
- 1A - procainamide
- 1X flecainide
3 - sotalol and amiodarone
SSRIs, TCA and antidepressants
Antipsychotics - chlorpromazine, haloperidol, quetiapine, olanzapine
Macrolides
Hydroxychloroquine
Fluoroquinolones
