Pharmacology Flashcards
Risk factors for PONV
Patient:
- Female
- non smoker
- h/o motion sickness
Anaesthesia:
- inhaled anaesthetic
- N2O
- intra and postop opioids
Surgery:
- duration > 30 min increases risk to 60%
- types (celioscopy, ENT, Neuro, breast, strabismus, laparotomy/laproscopic, plastic surgery
Risk scores for predicting PONV
Modified Apfel score
( 1 point for - female, non-smoker, Hx of PONV/motion sickness, post op opiates)
0 = 10%, 1=40%, 3=60%, 4=80%
POVOC score (paeds) 1 point for - duration >30 mins, age >3, strabismus, Hx PONV
Classes of antiemetics
Phenothiazines (Prochlorperazine) Butyrophenones (Droperidol) Benzamides (Metoclopramide) Anticholinergic (hyoscine) Antihistamine (cyclizine) 5-HT3 receptor antagonists (ondansetron) Miscellaneous (Dex, aprepitant)
Phenothiazines (example, MoA, SEs)
- Neuroleptics
- eg chlopromazide, prochlorperazine
- MoA antagonise dopamine D2, muscarinic and histamine H1 receptors in CTz
- SE extrapyrimidal (acute dystonias), neuroleptic malignant syndrome (rare)
Butyrophenones (example, MoA, SEs)
Butyrophenones (example, MoA, SEs)
Derivates are neuroleptics and antiemetics
- eg Droperidol
- MoA: dopamine D2 receptor antagonist at CTZ
- SE: extrapyrimidal and sedation
Domperidone - peripheral D2 receptor antagonist - doesn’t cross BBB therefore safe in parkinsons disease - SEs hyperprolactinaemia
Benzamides (example, MoA, SEs)
antiemetic and prokinetic
eg metoclopramide
Dopamine D2 receptor antagonist at CTZ and peripheral D2 receptor antagonist in stomach
Poor efficacy - equivocal with placebo (NNT ~ 10 and NN to do harm ~ 10)
SEs Extrapyrimidal, more common in young females, NMS (rare)
Anticholinergic antiemetics (example, MOA, SEs)
Eg Hyoscine
Centrally acting muscarinic
Transdermal patch
SE: anticholinergic .. dry mouth, tachy, blurred vision
Antihistamine antiemetics (example, MoA, SEs)
Cyclizine
H1 receptor antagonist in CTZ and some anticholinergic properties
SE mild anticholinergic SEs
5-HT3 receptor antagonists
Ondansetron
central and peripheral 5-HT3 antagonism
SE: headache, flushing, constipation, bradycardia (prolongs QT)
Miscellaneous antiemetics
Dexamethasone - unknown MoA, SEs sleep disturbance, raised BM
Aprepitant - Neurokinin 1 receptor antagonist (found in the GI tract), SEs - expensive (used in chemo)
Propofol (physical, Pk, Pd)
Propofol is 2,6-disioprophylphenol. It is commonly used throughout anaesthesia and critical care for induction and maintenance of anaesthesia and procedural sedation.
Physical:
It is a white lipid emulsion of soy bean oil and egg phosphatide. It is stable at room temperature and stored in glass vials of 200mg and 500mg.
For induction of anaesthesia dose of 2-3mg/kg for adults and 3-7mg/kg for children
Pk:
It is administered intravenously either as a bolus or continuous infusion.
It is highly lipid soluble and has a large volume of distribution
It is extensively protein bound
It is metabolised in the liver into glucuronide - an inactive metabolite and excreted renally - limited dose adjustment is required in liver/renal failure
It has a context sensitive half life between 30 min and 4 hours (?)
Pd:
CVS: Reduction in cardiac output via decreased HR and reduction in contractility. Decreased SVR causes further decrease in BP
RESP: bronchodilation. Decrease TV but increase in RR (?) - overall increase in PaCO2
CNS - anaesthesia, analgesic, myoclonic movements, decreased IOP/ICP/CMRO/CBF
GIT - antiemetic properties
Paediatrics - PIS - avoided for prolonged infusion in children due to accumulation of triglycerides …
Ketamine (physical, Pk, Pd)
Ketamine is a phencyclidine derivative. It is an NMDA antagonist used for sedation, induction of anaesthesia and analgesia. Also has weak agonist at MOP/KOP/DOP receptors plus inhibits re-uptake of serotonin, dopamine and noradrenaline
Physical:
It is a clear colourless liquid at room temperature, stored in glass vials of 10/50/100mg/ml
It is a racemic mixture s-ketamine is the more potent isomer.
Chemical:
Avaliable as racemic and single enantiomer preparations
Weak acid. water soluble solutions - pH 3.5-5.5
Pk
It can be administered IV/IM/PO/PR/intrathecal
Induction dose 1-2mg/kg IV and 5-10mg/kg IM
distribution - bioavaliability 20%, protein binding 20-50%, Vd 3l/kg, T1/2 2.5 hours
Metabolism - liver to norketamine an 30% as potent
Norketamine conjugated to inactive compound
excreted in the urine
Pd
CVS - sympatheticomemetic, increased HR/CO/BP/Cardiac O2 consumption
RESP - bronchodilation, increased RR, no laryngeal suppression
CNS - analgesia, dissociative anaesthesia, hallucinations/amnesia/emergence phenomenon, increased CBF/ICP/CMRO
GIT - nausea/vomiting, salivation
thiopentone (physical, Pk, Pd)
Thiopentone is a thiobarbituate used for induction of anaesthesia and a classical RSI
Physical:
Stored as an anhydrous yellow powder in nitrogen enviroment in glass vial with rubber lid. Reconstituted in water to create a solution with pH 10.8
Chemical:
Weak acid - pKa 7.6 - 60% ionised at 7.4
tauterisomerism - proportions of two forms depends on ambient pH
Pk
Administered IV at dose 3-7mg/kg for induction
Distribution - 80% protein bound, Vd 2l/kg
high lipid solubility with rapid emergence due to distribution
metabolism - liver via P450 - largely inactive except phenobarbitone. (P450 inducer). Exhibits zero-order kinetics with infusions
Pd
CVS - slight increase HR otherwise decrease in CO/SV/SVR
RESP - depression/bronchospasm/laryngospasm
CNS - hypnotic/ decreased CMRO/CBF/CSF
Other: severe anaphylaxis/precipitates porphyria
INTRA-ARTERIAL injection -> severe pain and vasospasm due to crystals forming and occluding peripheral arterioles
Etomidate (physical, Pk, Pd)
Etomidate is rarely used today for induction of anaesthesia. It is an imidazole hypnotic. It increases the duration of opening of GABA channels
Physical:
clear colourless solution avaliable in 2mg/ml in 10ml vial
Pk IV administration 0.3mg/kg 75% protein bound rapid distribution Vd 3 l/kg Metabolised by hepatic esterases and plasma esterases and excreted in urine (90%) and bile (10%)
Pd
CVS - most stable. slight decrease SVR. Myocardial O2 requirement stable. CO and BP stable
RESP - depression
CNS - hypnosis, tremor, involuntary movements, EPILEPTIFORM ACTIVITY 25%, decreased ICP/CPP/CMRO/IOP
GI -nausea and vomiting
Other:
- pain on injection
- contraindicated in porphyria
- hypersensitivity and histamine release
STEROID AXIS INHIBITION
- inhibits 11 beta and 17 alpha hydroxylase for 24 hours post dose
Management of intra-arterial injection of thiopentone
Aims: “dilute, dilate, analgesia, prevent thrombosis”
Stop injecting
flush with normal saline
IV PAPAVERINE (40-80mg)
IV lidocaine
IV heparin
Consider sympathetic blockage of upper limb
Continue anticoagulation for 10-14 days
Consult vascular surgery
How is nitrous oxide produced?
Ammonium nitrate is heated to 250 degrees
It decomposes into water and nitrous oxide
How is nitrous oxide stored?
French blue cylinders as a liquid below its critical temperature (36.5 degrees)
Pharmacodynamic effects of nitrous oxide
CVS
- reduces contractility but increases sympathetic outflow so BP unchanged
- increased pulmonary vascular resistance
RESP
- Decreased TV but increased RR - MV maintained
- blunt ventilatory response to hypoxia and hypercapnea
CNS
- Increases CBF, CMRO, ICP (effects more pronounced in patients who have lost autoregulatory ability - ie those with head injuries)
What are the physiochemical properties of nitrous oxide
Boiling point -88 degrees
Critical temperature 36.5 degrees
Blood/gas partition co-efficient 0.47
Oil/gas partition co-efficient 1.4
MAC 105% (only under hyperbaric conditions can it induce anaesthesia)
What are the adverse effects of nitrous oxide?
Nausea and vomiting
Expansion of N2O into cavities - it is more soluble than nitrogen so it diffuses into air filled cavities more quickly that nitrogen already in the cavity can diffuse into blood. Therefore CI for patient with pneumothorax or middle ear
It oxidises the cobalt ion in vitamin B12 and impairs its ability to act as a co-factor for methionine synthase - leads to bone marrow suppression, megaloblastic anaemia and subacute degeneration of spinal cord
Teratogenicity in rats
Green house gas
Define a partition co-efficient
A partition co-efficient is the ratio of the amount of substance in one phase to the amount in another at a stated temperature when the two phases are in equilibrium and of equal volumes and pressures
What is the blood:gas partition co-efficient?
The B:G coefficient is a measure of the solubility of a substance in blood and influences onset/offset times.
Onset time depends upon the PARTIAL PRESSURE in blood and not the total amount.
For agents that rapidly dissolve into the blood the alveolar pressure and partial pressure remain low. More molecules are required to saturate the blood and it takes a long time for equilibrium (FA/FI = 1)
Morphine (Physical, chemical, Pk, Pd)
Morphine is a naturally occurring phenanthrene derivative
It is used extensively for analgesia, sedation on ITU, palliative care and in heart failure
It acts directly on MOP & KOP G-protein receptors causing:
- closure of voltage gated Ca channels
- stimulation of K efflux
- decreased cAMP production
- All of which decrease neuronal excitability and reduced the likelihood of neurotransmitter release
It can be administered in many ways - IV/IM/SC/PO/intrathecal/epidural
Pk:
It is a weak acid with pKa of 8.0
It is well absorbed in the alkaline small bowel but undergoes extensive 1st pass metabolism so has a BIOAVALIABILITY of 15-20%
It is lipid soluble with a Vd 3-4L/kg and protein binding 20-40%
Peak effect 10-30 mins and duration 3-4 hours
Pd
CVS - no direct effect but can decrease SVR via histamine release and cause bradycardia by decreasing SNS
RR - dose dependent respiratory depressant (RR>TV), antitussive and decrease sensitivity to pCO2.
- bronchospasm if histamine release occurs
CNS - analgesia, sedation, euphoria, hallucinations, meiosis, (muscle rigidity and seizures at high doses)
GIT - nausea/vomiting, delayed gastric emptying, decreased gastric acid and bile secretion
GU - increased uterine tone
DERM - purititis/rash
ENDO - decreased ACTH and gonadotropic hormones. Increased ADH
What is dependence and addiction?
Dependence describes the need to repeatedly administer the drug to avoid withdrawal symptoms
Addiction describes the behaviour of a person resulting from their dependence - crave/need, have no control over their drugs use, use it compulsively and continue to use despite harm it causes
Fentanyl (Physical, chemical, Pk, Pd)
Fentanyl is a synthetic phenylpiperidine derivative
It is used extensively in anaesthesia and critical care for analgesia and sedation
It is a potent MOP agonist
It can be administered IV/PO/patches/intrathecally
Chemical: it is a weak base with pKa 8.4 so is largely ionised in the stomach.
Pk
Absorbed from the small bowel and has an oral bioavaliability of 33%
It is 80-95% protein bound and has a Vd 1-4 L/kg
It is very lipid soluble - 600x more than morphine so is rapidly distributed and therefore has a short duration of action
It is metabolised into norfentanyl which is inactive and excreted in the urine
Pd Similar to morphine but is more potent Causes less histamine release Associate with Bradycardia Chest wall rigidity at high doses
MOP receptors (location, action)
Brain especially periaqueductal grey and substantia gelatinosa of spinal cord
Mue 1 - analgesia and physical dependence
Mue 2 - respiratory depression, reduced peristalsis, euphoria, meiosis
DOP receptor (location and action)
Brian
Analgesia, antidepressant, physical dependence
KOP receptors (location, action)
Brain and spinal cord
Spinal analgesia
Sedation
Meiosis
NOP receptors (location and action)
Brain and spinal cord
Anxiety, depression, affects memory, involved in tolerance, natural ligand may set body’s natural pain threshold
What is tolerance?
Tolerance describes the scenario that despite maintaining constant plasma concentrations of a drug more is required to exert the same effect
Diamorphine (Physical, chemical, Pk, Pd)
Diamorphine is a diacetylated morphine derivative and is a prodrug
It is used for analgesia, sedation, palliative care, CCF and as a drug of abuse
Its metabolites act at MOP & KOP receptors
Pk
Administered IV/SC/PO/intrathecally
Well absorbed but undergoes extensive 1st pass metabolism so has a low oral bioavaliability
Protein bound 40%
Half life 3 mins
Metabolised by plasma enzymes and RBCs (probably esterases) to 6-O-acetylmorphine
6-O-acetylmorphine glucurronidated to morphine
50-60% excreted in urine as morphine derivative
Pd
As for morphine
Less nausea/vomiting/constipation
Alfentanil (Physical, chemical, Pk, Pd)
Alfentanil is a synthetic phenylpiperidine derivative
It is short acting opioid used for analgesia, obtunding hypertensive response to airway manipulation and sedation
It is highly MOP receptor specific
It is only administered IV at dose of 5-25 microgram/kg
Pk
It’s notable feature is a pKa of 6.5 so 87% of it is UNIONISED at pH 7.4
This more of it is around to exert its effect and despite being less lipid soluble than fentanyl it has a more rapid onset time
85-92% protein bound
Vd 0.6 L/kg - this is low for opioids and means that despite of its low clearance its half life is shorter
It is metabolised in the liver to noralfetanil and excreted in the urine
Pd
As for morphine but more potent
Causes a vagary mediated bradycardia
Remifentanil (physical, Pk, Pd)
Remifentanil is a pure MOP agonist. It is used for intra-operative analgesia and sedation
Pk
It is only administered IV and has a half life of 2 hours
But its effects last only 10 minutes after end of infusion - its metabolism whereby it undergoes rapid ester hydrolysis by non-specific esterases to carboxylic acid derivatives - means that it has a context-INSENSITIVE half-life
It is excreted in the urine
Pd
As more morphine but more potent
Bradycardia
Rigid chest at high dose
How are local anaesthetics classified?
There are 2 types of local anaesthetic
- AMIDES - eg lidocaine
- ESTERS - eg (CAPE) - cocaine, amethocaine, procaine = esters
How do local anaesthetics work?
The are intracellular sodium channel blockers and therefore prevent propagation of action potentials along a neurone
Unionised drug is lipid soluble so it can cross the neuronal cell membrane. The axoplasm has a pH of 7.1 so more of the drug becomes ionised and its this portion that “block” sodium channels from the inside. It binds to receptors that are either open or inactivated so its more likely to affect nerves that have a rapid firing rate. This is called “state dependent blockade”
The membrane expansion theory postulates that in-ionised local anaesthetic dissolves in the neuronal membrane causing swelling and subsequent physical inactivation of the neuronal sodium channels
What determines local anaesthetic potency?
Lipid solubility
What determines local anaesthetic duration of action?
Protein binding
What factors affect local anaesthetic speed of onset?
This is primarily effected by pH and pKa and subsequent degree of ionisation
Local anaesthetics with a pKa closer to body pH (7.4) will have a higher proportion of unionised drug which can cross the neuronal cell membrane and exert an effect.
This explains why local anaesthetics work poorly in infected tissue which has a lower pH and therefore the unionised portion is decreased further
Bicarbonate is occasionally added to artificially increased the pH and increased the unionised portion
Detail the differences in systemic absorption of local anaesthetic for different locations
Intercostal space>Caudal>epidural>brachial plexus>femoral>subcutaneous
Tell me about lidocaine
Amide local anaesthetic
PKa 7.9 so has fast onset
70% protein bound so medium duration of action
3mg/kg alone or 7mg/kg with adrenaline
Tell me about bupivicaine
Amide local anaesthetic Racemic mixture of R and S enantiomers 95% protein bound so has a long duration of action Max dose 2mg/kg Cardiotoxic at high doses
Tell me about levobupivicaine
An amide local anaesthetic PKa 8.1 Just the s-enantiomer of bupivicaine Again 95% protein bound Less cardiotoxic that bupivicaine 2mg/kg max dose
Tell me about ropivacaine
Amide local anaesthetic
94% protein bound so long duration of action
PKa 8.1
More selective sensory neuronal blockage and less motor
Less cardiotoxic than bupivicaine
Max dose 3.5mg/kg
Tell me about prilocaine
Amide local anaesthetic
pKa 7.9 so fast onset
56% protein bound so medium duration
Contained in EMLA cream (lignocaine and prilocaine)
Methaemaglobinaemia can occur at high doses due to breakdown product O-toluidine
Less toxic that lignocaine
Used for IV local anaesthetic - Biers block
Max dose 6mg/kg
Tell me about the local anaesthetic properties of cocaine
Ester local anaesthetic
Short duration of action
Causes profound vasoconstriction
Blocks neuronal uptake and stimulates the CNS
Side effects include - IHD, HTN, seizures, hallucinations
Max dose 3mg/kg
How do NSAIDs work?
NSAIDS are cyclo-oxygenase inhibitors. They act on the arachnadonic acid pathway. They inhibit the production of prostanoids including thromboxane (vasoconstrictor and platelet aggregator), prostacyclin (vasodilator and prevents platelet plug forming) and prostaglandins . Prostaglandins would otherwise cause inflammation and decrease stimulus required to cause pain
What are the contraindications for NSAIDs?
Relative:
- renal failure, heart failure, history of GI bleeding, HTN, coagulopathy
- Enhances effects of warfarin
Absolute
- hypersensitivity
- Asthmatic in whom it precipitates exacerbations (10-20%)
- Avoid in children (except, I think, Kawasaki syndrome)
What are the side effects of NSAIDs?
Asthma exacerbation (blocking COX leads to increased leukotriennes) AKI Platelet dysfunction - reduced thromboxane production GI bleeding - prostaglandins required to gastric mucosal integrity (COX 1> COX2)
