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)
Tell me about paracetamol
Paracetamol is commonly used for simple analgesia and as an antipyretic
It has central action via COX 3 inhibition leading to decreased brain PGE2 and also modulates cannabinoid system
Pk
It is administered PO/PR/IV
It’s absorbed in the small bowel and has an oral bioavaliability of 80% with protein binding 10%
It’s metabolism is important - particularly in overdose cases:
The majority of it is metabolised to glucuronide and sulphate metabolites (30%) but approximately 10% is metabolised to N-acetyl-p-amino-benzoquinoneimine (NAPQI). This is a toxic metabolite.
In normal doses and with normal genetic polymorphism it is rapidly conjugated by glutathione but when this system is saturated NAPQI accumulates causing liver failure.
Pd
CVS - IV can cause bradycardia and hypotension
CNS - analgesia and antipyretic
Other - rash, ITP, nephropathy
Tell me about aspirin
Aspirin is a salicylic acid derivative
It is used for analgesia, as an antipyretic and an anti platelet
It is a prodrug that causes irreversible COX 1 inhibition and modified COX 2 activity. It also selectively inhibits thromboxane A2 in platelets and therefore inhibits their aggregation
Pk
It is a weak acid with a pKa of 3.0 therefore it is poorly ionised in the stomach and is not readily absorbed until it reaches the small bowel
85% protein bound
Metabolised in the liver and intestine by ester hydrolysis to salicylic acid
Exhibits 1st order kinetics at low dose but zero order at high dose
Renal excretion
Pd
CVS - decreased platelet aggregation and vasodilation is cardio protective
RESP - bronchospasm in 10-20% asthmatics
GI - risk of GIB, can cause hepatic transaminitis
RENAL - local hypoxia and decreased RBF
Drug interactions:
- warfarin - as NSAIDs are highly protein bound this can displace warfarin and increase its action
- Lithium - may increase levels
Tell me about diclofenac
Diclofenac is a phenylacetic acid derivative
It’s used for analgesia and as an antipyretic
It inhibits COX1&2 equally
Administered PO/PR/IV
Pk Well absorbed Bioavaliability of 60% PB 99.5% so can displace oral anticoagulants Low Vd 0.12-17 L/kg Hepatic metabolism and renal excretion
Pd
Caution in asthmatics
GIB
Decreased renal perfusion due to decreased prostaglandins
Reversible inhibition of platelet function
Reduces renin and aldosterone concentration by 70%
Increased risk of thrombosis
What is the Vaughn-Williams classification? Give examples
The VW classification classifies antiarrhythmics according to electrolyte they act on.
Group 1 act on fast acting sodium channels
1a - Quinidine, procainamide, disopyramide - increased refractory period
1b - lignocaine, phenytoin, mexiletine - shortens refractory period
1c - Flecainide, propfenone - no effect on refractory period
Group 2 - beta blockers
Group 3 - K channel blockers (amiodarone, sortalol)
Group 4r - Ca channel blockers (verapamil, diltiazem)
How do class I antiarrhythmics work?
They act on fast sodium channels in the cardiac myocyte
This increases the time it takes to reach threshold potential, decreases the slope of phase 0 and the cardiac conduction velocity.
These sodium channels are not present in the SAN so can be used for abolishing re-entrant arrhythmias
Further classified according to their effect on the refractory period - this is usually mediated by the drugs effect on K channels responsible for repolarisation in phase 3
How to class II antiarrhythmics work?
Beta-blockers work by inhibiting beta adrenergic receptors and therefore reducing sympathetic tone on the heart. This reduces the slope on phase 4 of the SAN action potential
B-receptors are coupled via G-proteins to calcium channels that open when the receptor is activated. By blocking them less Ca enters the cell and the rate of depolarisation of phase 4 is slower and therefore chronotropy and (due to reduced intracellular calcium presumably) inotropy
Also inhibit action of light chain kinase and so decrease the hearts relaxation rate
How do class III anti-arrhythmics exert their effects?
K channel blockers prevent K efflux out of the cell at the SAN during depolarisation. This decreases the slope of phase 3 of the SAN action potential. This increases the refractory period and reduces arrhythmogenicity
How do class IV antiarrythmics exert their effect?
Calcium channel blockers block L-type calcium channel blockers (they do not effect T/N/P calcium channels)
Blocking them reduces the phase 0 slope of the SAN action potential, decreasing heart rate.
They are also found in cardiac myocytes and blood vessels. By decreasing Ca flux reduces cardiac conduction velocity and contractility
Tell me about Quinidine
Class 1a antiarrythmic that blocks fast Na channels, increases refractory period and vagal tone
Used for termination of SVTs and ventricular arrhythmias
Pk - bioavaliability 75%, 90% protein bound and T1/2 5-9 hours, hepatic metabolism and renal excretion
Pd
CVS - can cause other arrhythmias & hypotension
ECG - prolonged PR, wide QRS, long QT
CNS - tinnitus, blurred vision, hearing loss, headache, confusion
CAUTION!!:
- displaces digoxin from binding sites so can cause toxicity
Tell me about lignocaine
Lignocaine is a amide local anaesthetic and a class Ib anti arrhythmic
It is a sodium channel blocker which decreases phase 0 of cardiac action potential and decreases refractory period
Pk 33% ionised, pKa 7.9, Vd 0.7-1.5 l/kg, hepatic metabolism and renal excretion
Local anaesthetic toxicity (lidocaine) signs
> 4micrograms/ml = perioral tingling, dizziness, tinnitus, parasthesia
> 5 micrograms/ml = altered consciousness, coma, seizures
> 10micrograms/ml = AV block, refractory hypotension, cardiac arrest
Tell me about flecainide
Flecainide is a class Ic anti arrhythmic used for the management of SVT/AF/WPW
It blocks fast Na channels prolonging phase 0 of action potential
Pk Well absorbed with oral bioavaliability of 90% and protein binding 50%, hepatic metabolism with active metabolites and unchanged drug excreted in the urine
Pd
CVS - can precipitate conduction disorders, use with caution in patients with AV node disease, negative inotrope so can precipitate heart failure
OTHER - headache, dizziness, parasthesia
Tell me about amiodarone
Amiodarine is a class III anti arrhythmic but also has properties of class I, II and IV. It is used for a wide number of arrhythmias including SVT/VT/WPW
Can be given IV or PO
Pk - poorly absorbed. Protein binding of 95%, Vd 2-70 L/kg, T1/2 20-100 days!!, hepatic metabolism, expressed in bile, tears and via skin
Pd
CVS - prolonged QT, hypotension, bradycardia
RESP - pneumonitis and fibrosis
CNS - peripheral neuropathy and myopathy. Corneal microdeposits
GI - metallic taste, hepatitis, cirrhosis
SKIN - grey skin, hypersensitive skin
ENDO - hypo and hyperthyroidism
DRUG INTERACTIONS:
- Highly protein bound so can displace other drugs from protein binding
- Avoid with other QT prolonging medications
- Can cause heart block with other AV node blockers
Tell me about digoxin
Digoxin is a glycoside extracted from foxgloves
It inhibits the Na/K- ATPase pump meaning there’s less intracellular potassium and more intracellular sodium. There is therefore less Calcium extrusion by the Na/Ca exchange pump because this relies on the concentration gradient.
The higher intracellular calcium leads to increased inotropy and the decreased intracellular potassium decreases conduction in the SA and AV nodes slowing heart rate
Pk
Administered IV or oral (Bioavaliability >70%)
Protein binding 25%
Vd 5-10 l/kg
Half life 35 hours (increased in renal failure)
Minimal hepatic metabolism
Excreted largely unchanged in the urine
Pd
CXS - arrhythmias
ECG - toxic = long PR, inverted tick; normal = flattened T wave, short QT
OTHER:
- Anorexia, nausea, diarrhoea, headache, lethargy, visual disturbance, rashes, eosinophilia, gynaecomastia
TOXICITY
- Treat bradycardia with atropine and pacing
- Treat ventricular arrhythmia with phenytoin
- “Digibind” - IgG antibody fragments against digoxin. Expensive - used if >20micrograms/l
- note Digibind can cause anaphylaxis
Tell me about verapamil
A calcium channel antagonist used for the management of SVT/AF/prophylaxis of angina and hypertension
It is a class 4 antiarrhythmic that blocks L-type calcium channels so reduces the slop of nodal action potential. It also decreases contractility and causes coronary dilation
Pk
Well absorbed 90% but undergoes extensive 1st pass metabolism so 25% bioavaliability
90% protein bound
Vd 3-5 l/kg
Half life 3-7 hours
Hepatic metabolism but subject to zero order kinetics
Active and unchanged metabolites excreted in urine
Pd
CVS - can precipitate VF/VT in WPW, CCF in patients with poor LV
Caution with b-blockers/digoxin/halothane - can cause severe bradycardia
Hypotension
Cerebral vasodilation
Tell me about beta blockers
Beta-blockers block beta adrenergic receptors. Some also have some sympathomimetic activity. There activity is largely governed by their affinity for different Beta receptors (B1 cardioselective)
Wide range of uses:
HTN, angina, tachycardia, obtund hypertensive reflex, phaeochromocytoma, HOCUM, anxiety, glaucoma, migraine
PK
Different agents have varying lipid solubility. Atenolol is poorly lipid soluble so poorly absorbed from the gut. But those with high lipid solubility (eg metoprolol) are well absorbed but cross the BBB so cause more CNS side effects.
CVS
- negative inotrope - increase time in diastole, decreases cardiac O2 demand
- Hypotension
RESP
- bronchospasm
CNS
- those that cross the BBB causes hallucinations, nightmares, depression, fatigue and decrease IOP
GI - dry mouth and GI upset
Metabolic - rise in resting BMs, mask signs of hypoglycaemia
Tell me about adenosine
Adenosine is a naturally occurring purine nucleoside
It is used to differentiate between SVT and VT. If the rhythm is re-entrant it may terminate it.
MoA - binds to adenosine (A1) receptors coupled to K channels that open causing hyperpolarised membrane. They are only found in SAN and AVN so adenosine selectively decreased conduction velocity in the nodes. Also decreases cAMP mediated catecholamine stimulation of ventricles
Rapid offset
Pd
RESP - increased PVR, SoB, flushing, bronchospasm, impending doom
Can you classify anti hypertensive drugs?
Antihypertensive drugs can be classified according to their location of action: Central vs peripheral
Centrally acting - clonidine, methyldopa and reserpine (?)
Peripherally acting can be subclassified to heart, vascular and renal
Tell me about benzodiazepines
Benzodiazepines are a class of psychotropic drug that have hypnotic, sedative, amnesic and muscle relaxant properties.
They act to propagate the effects of GABA A receptors increasing chloride uptake and hyperpolarising the cell membrane. Benzodiazepine receptors are coupled to GABA receptors. These receptors are found widely in the CNS.
They can be classified according to their duration of action - short <12 hours (midazolam), medium 12-24 lorazepam and long >24 diazepam
Tell me about inotropes
Inotropes describes a range of different drugs that all increase the contractility of the heart. They can be classified in 3 subgroups:
1. Drugs that increase intracellular calcium
I. Calcium ions
II. Drugs that increase intracellular calcium - adrenergic receptor agonists, PDE inhibitors and glucagon
III. Drugs effecting the sodium/potassium ATPase
2. Calcium sensitising drugs - Levo
3. Act via metabolic pathways - T3
Classify adrenergic receptor agonists used as inotropes
They can be naturally occurring or synthetic
Naturally occurring include - adrenaline, noradrenaline and dopamine
Synthetic inotropes include - dobutamine, dopexamine, isoprenaline and salbutamol
How does digoxin act as an inotrope?
Digoxin inhibits the Na/K-ATPase pump on the sarcolemnal membrane and causes an increase in intracellular sodium. Sodium would normally be pumped into the cell by a sodium-calcium exchange pump but this relies on a the concentration gradient of sodium.
By increasing intracellular sodium digoxin reduces this gradient meaning less sodium enters the cell and more calcium remains inside.
Intracellular calcium causes the positive inotropic effect. This is slightly offset by digoxins other effect to activate the parasympathetic nervous system
What is the mechanism of action of adrenaline
Adrenaline is a naturally occurring catecholamine. It is produced in the adrenal medulla and acts on alpha 1, Beta 1 and Beta 2 adrenoreceptors.
Adrenoreceptors are G-protein coupled receptors that act to increase influx of calcium.
- Alpha receptors are linked to a Gq protein that stimulates phospholipase C to produce IP3 and DAG - Beta receptors are liked to Gs protein that stimulates adenyl cyclase to produce cAMP. this activate protein kinase A (?)
Low dose activates beta receptors -> smooth muscle relaxation, glycogenolysis
Mid range -> Beta 1 receptors -> inotropy/chronotropy/increased renin release
High dose -> alpha receptors -> generalised vaso and veno constriction increasing SVR. Increased after load and preload.
Tell me about dopamine
Dopamine is a naturally occurring catecholamine and neurotransmitter.
At low dose it acts on D1 and D2 receptor and at higher doses it stimulates beta and then alpha receptors.
Previously it had been hoped that low dose dopamine would achieve both an increased inotropy and increased renal blood flow due to the distribution of dopamine receptors. This has not been demonstrated in clinical trials and its use now is fairly limited occasionally used in the paediatric population.
Dopamine is a precursor of noradrenaline. It has a half life of minutes and is metabolised by COMT
Pd
CVS
- <5 micrograms/min - low dose D1 receptors - decreased renal vessel resistance
- 5 - 10 micrograms/min - Beta 1 - increased HR/contractility/CO/CA blood flow
- >10 - alpha - increased SVR
RESP - decreased response to hypoxia
CNS - modulates extrapyramidal movements, nausea and vomiting
RENAL - diuretic effect
Tell me about milrinone
Milrinone is a selective phosphodiesterase III inhibitor
It is used in cases of low cardiac output
By inhibiting PDE III it reduces the degradation of cAMP in cardiac and smooth muscle
- Increased intracellular calcium leads to increased biventricular contractility - It alters Ca flux into smooth muscles causing relaxation of vessels (including pulmonary)
Pk IV administration, 70% protein bound, T 1/2 2.5 hours, hepatic metabolism and renal excreation (85% unchanged)
Pd
CVS - increased SV/contractility/No increased cardiac oxygen consumption/Decreased SVR
RESP - pulmonary vasodilation
How is adrenaline synthesised
Adrenaline is synthesised from tyrosine via a sequence of steps.
Tyrosine: from diet or hydroxylation of phenylalanine in liver
Tyrosine -> L-DOPA -> Dopamine -> noradrenaline -> adrenaline
Enzymes:
- Tyrosine hydroxylase
- DOPA decarboxylase
- Dopamine Beta-hydroxylase
- PNMT (only in adrenal medulla)
Tell me about levosimendan
Levosimendan acts as a calcium sensitiser - it binds to troponin C and stabilises the cross bridges between it and actin-myosin cross bridges. It increases contractility and vasodilation without increase in calcium concentration or oxygen demand
Administered as bolus and infusion 98% protein bound T1/2 1 hour hepatic metabolism Renal excretion (85% unchanged)
Caution - contra-indicated in severe hepatic/renal failure, ventricular outflow obstruction, severe hypotension/tachycardia, history of torsades de pointes
Tell me about oxytocin
Synthetic produced analogue of oxytocin
Used for induction of labour, following c-section or abortion
MoA: It stimulates uterine contraction by binding to sites on muscle cells. Agonist at oxytocin G-protein coupled receptors
Effects GU - uterine contraction, can cause hyper stimulation, mild anti-diuretic effect when prolonged CVS - increased SVR, BP, tachycardia GI - nausea/vomiting Rash, anaphylaxis
Tell me about ergometrine
Ergometrine is an ergot alkaloid derivative.
It stimulates uterine and vascular smooth muscle by binding to 5-HT3 receptors but also agonises dopamine 2 receptors causing emesis
Used as second line uterotonic following C-section or uterine tone
Effects:
GU - uterine contraction (1 min IV and 5 min IM)
CVS - increased SVR and BP (CI in pre-eclampsia), bradycardia and arrhythmias
CNS - tinnitus, headache, dizziness
GI - severe vomiting and nausea
Tell me about carboprost
Carboprost is a prostaglandin analogue that stimulates uterine contraction and is used in post-Parton haemorrhage
Given IM
Effects:
- GU - uterine contraction
- RESP - bronchospasm (CI in asthmatics)
- CVS - cardiovascular collapse, pulmonary oedema
- CNS - headache, dizziness
- GI - nausea and vomiting
Classify the major categories of antihypertensive drugs
Antihypertensive drugs can be classified by their location of action
- Cardiac
I - Beta blockers (cardioselective/non-cardioselective/labetalol) - Blood vessels
I - Direct acting - produce NO which act is of G protein coupled receptors to upregulate guanylate Cyclades and increasing intracellular cGMP -> vasodilation
examples - sodium niroprusside and hydralazine (arterial and venous dilation) & GTN/ISMN (predominantly venous dilation)II - Indirect - reduce SVR and preload by various mechanisms
CCBs - antagonist at L-type calcium channels in vascular smooth muscles
Alpha blockers - prazosin
Potassium channel activators - (nicorandil) activators of ATP-sensitive K channels within arterioles causing hyperpolarisation and reduced intracellular calcium -> arteriolar vasodilation.
Magnesium - Renal
- Diuretics
- RAAS
- CNS
- centrally acting drugs (eg clonidine and methyldopa)
- Ganglion blockers - competitive antagonists at nACh receptors located in parasympathetic and sympathetic ganglia
What are the different types of heparin?
There are three different forms of heparin:
- Naturally occurring heparin
- Unfractionated heparin - binds to and potentiates antithrombin
- Low molecular weight heparin - directly inhibit factor Xa
What are the side effects of heparin therapy?
- Haemorrhage
- Non-immune thrombocytopaenia
- HIT
- IgG antibodies made against heparin after it binds to platelet factor 4 (PF4)
- Antibodies consequently bind to and activate platelets causing thrombi and the platelets count to fall
- Hypotension
- Osteoporosis
What can potentiate the effects of warfarin?
Warfarin is vulnerable to potentiation owing to its high protein binding and metabolism
Drugs that potentiate warfarin include:
NSAIDs and simvastatin - drugs with high protein binding compete with warfarin and can displace it and increase its anticoagulant effects
Similarly states with low plasma protein such as sepsis and pregnancy can do the same
Drugs that decrease warfarins metabolism (metronidazole, macrolides and alcohol) will increase the effect
Some antibiotics affect the vitamin K producing bacteria in the gut flora and so increase the effect of warfarin
Diet - foods such as St. John’s wort, ginger and ginseng can increase the effect
Thyroid status also has an impact - hypothyroidism reduces its effect
What are the different classes/types of anticoagulant?
- Antiplatelet
- Heparins
- Oral anticoagulants
- Fibrinolytics
Name the different platelet inhibitors and their MoA
Aspirin - COX inhibitor - prevents platelet thromboxane release
Dipyridamole - platelet phosphodiesterase inhibitor - inhibits platelet adhesion to damaged vessel walls (inhibits adenosine uptake), potentiates the effect of prostaglandins and, at high doses, inhibits phosphodiesterase causing lower intra-platelet calcium
Clopidogrel - ADP binding inhibitor - Irreversibly binds to P2Y12 receptor (ADP receptor) and prevents the glycoprotein IIb/IIIa receptor from transforming into its active form
(prasugrel and ticagrelor also ADP binding inhibitors)
Tirofiban/Abciximab/Eptifinatide - glycoprotein IIb/IIIa receptor antagonists so block the final common pathway of platelet aggregation
Tell me about unfractionated heparin
Anionic, mucopolysaccaride, organic acid containing many sulphate residues
5000-25000 daltons
Binds to antithrombin III forming thrombin-antithrombin complex. At low dose Factor Xa inhibited. (As dose increases factors 9,11,12 also inhibited)
Given IV/IM/SC
Given negative charge it is highly protein bound and has low lipid solubility
Metabolised by hepatic heparinases and excreted in the urine
Complications of heparin use
Haemorrhage
Thrombocytopaenia (Type 1 and 2)
Hypotension
Osteoporosis
Tell me about LMWH (including advantages)
Formed from the depolymerisation of heparin
2000-8000 Da
Inhibit factor Xa but have little effect at forming thrombin-antithrombin complex
Advantages: Once daily dosing Less impact on platelets Reduced need for monitoring Reduced affinity for VWF
Tell me about protamine
Positively charged molecule that neutralises the anticoagulant effect of heparin
Given intravenously at a dose of 1mg for every 100 units of heparin
Tell me about warfarin
Warfarin is a coumarin derivative that inhibits the reduction of vitamin K which is required to generate active clotting factors 2,7,9,10
Takes ~ 72 hours to take effect
Side effects
- haemorrhage
- teratogenicity
- Drug interactions - Drugs that impair coagulation, displace off protein binding and impair metabolism
Absorption from gut
Highly protein bound
hepatic metabolism
Tell me about the fibrinolytic drugs
Fibrinolytics are used to break down clots usually in cases of acute occlusion where there is appropriate risk-benefit
They work on the plasminogen - plasmin reaction to upregulate the clot break down effect of plasmin
The commonly used include streptokinase, alteplase and urokinase
Streptokinase - from group C beta-haemolytic strep - forms a complex with plasminogen which facilitates its conversion to active plasmin
Complications - haemorrhage, CVS ( arrhythmias post reperfusion) & allergic
Alteplase - a glycoprotein that becomes activated only when it binds to fibrin inducing the conversion from plasminogen to plasmin - means that systemic fibrinolysis occurs to a lesser extent.
Oral anticoagulants (except warfain)
Dabigatran - direct thrombin inhibitor - a prodrug that is converted to active metabolites and then NOT metabolised further - renal excretion therefore caution must be taken in renal failure. Caution with use with phenytoin, ketoconazole, carbamazepine and rifampicin
Rivaroxaban - direct factor Xa inhibitor- oral bioavailability of 80-100%, 70% hepatic metabolism so renal function less important. Caution with CYP3A4 inducers (but less so than dabigatran)
Apixaban - same MoA as rivaroxaban - 50% bioavailability, onset over few hours
Reversal of oral anticoagulants
Warfarin - vitamin K, prothrombin complex concentrate
Dabigatran - idarucizumab or dialysis
Rivaroxaban/apixaban - andexanet alfa
AAGBI recommendations for neuraxial block and oral anticoagulants
Warfarin - INR <1.4
Dabigatran - 48-96 hours
Rivaroxaban - 48 hours
Apixaban - 24-48 hours
Heparin
Unfractionated - 4 hours or normal APTT
Prophylactic LMWH - 12 hours
Treatment dose LMWH - 24 hours
Fondaparinux
Fondaparinux is a synthetic pentasaccharide factor Xa inhibitor. Fondaparinux binds antithrombin and accelerates its inhibition of factor Xa.
Anticoagulation post HIT
Danaparoid and lepirudin which available for use in the UK, whereas argatroban is used in North America
Annoying numbers for Halothane
MW 197 BP 50.2 SVP 32.3 MAC 0.75 B:G 2.4 O:G 224
Annoying numbers for Isoflurane
MW 184 BP 48.5 SVP 33.2 MAC 1.17 B:G 1.4 O:G 98
Annoying numbers for Enflurane
MW 184 BP 56.5 SVP 23.3 MAC 1.68 B:G 1.8 O:G 98
Annoying numbers for Desflurane
MW 168 BP 23.5 SVP 89 MAC 6.6 B:G 0.42 O:G 29
Annoying numbers for Sevoflurane
MW 200 BP 58.5 SVP 22.7 MAC 1.8 B:G 0.7 O:G 80
Annoying numbers for N2O
MW 44 BP -88 SVP 5200 MAC 105 B:G 0.47 O:G 1.4
Annoying numbers for Xenon
MW 131 BP -108 SVP x MAC 71 B:G 0.14 O:G 1.9
Factors that increase MAC
Infancy
Hyperthermia
hyperthyroidism
Catecholamines and sympathomimetics
Chronic opioid
Chronic alcohol use
Acute amphetamines
Hypernatraemia
Factors that decrease MAC
Old age and neonates
Pregnancy Hypotension Hypothermia Hypothyroidms Alpha 2 agonists Sedatives Acute alcohol and opioid Chronic amphetamines Lithium
Pharmacodynamics of sevoflurane
CVS - decreased contractility, SVR and BP
RESP - increased RR, decreased TV and increased PaCO2
CNS - Increased CBF, decreased CMRO, EEG burst suppression
Pharmacodynamics of desflurane
CVS - Increased HR, Decreases SVR and BP (no effect on contractility)
RESP - Increased RR and decreased TV - PaCO2 increased
CNS Increased CBF, decreased CMRO2,
Pharmacodynamics of enflurane
CVS - decreased contractility and SVR, increased HR, decrease BP
RESP Increased RR and decreased TV increased PaCo2
CNS Increased CBF, decreased CMRO, epileptiform activity
Pharmacodynamics of isoflurane
CVS decreased contractility and SVR, increased HR, decreased BP. POSSIBLE CORONARY STEAL
RESP decreased TV, increased RR, decreased PaCO2
CNS Increased CBF, decreased CMRO
Pharmacodynamics of halothane
CVS decreased contractility, HR, SVR and BP. Increased sensitisation to catecholamines
RESP increased RR and decreased TV. Unchanged PaCO2
CNS Increased CBF, decreased CMRO
How do drugs exert their effect?
Many different mechanisms
- physiochemical interaction (antacids/sugamadex)
- Enzymatic interaction (ACEI)
- Voltage gated ion channels (LA)
- Receptros (extra vs intracellular)
Types of receptor
Receptor linked ion channel
Producers of intermediate messengers
Regulators of gene transcription
What is a receptor
A protein containing a region to which a ligand binds specifically to elicit an effect
Usually protein or glycoprote - found at cell membrane, within intracellular organelles or within the nucleus
Examples of receptor linked ion channels
Pentameric:
GABA-A and nACh
Inotropic glutamate:
NMDA (2subunits NR1 and NR)
- stimulation increases calcium permeability and causes CNS excitation
- N2O, Xenon, ketamine inhibit
Receptors with intermediate messengers
G-PROTEIN COUPLED RECEPTORS
- Transmembrane proteins
- Binding of ligand on extracellular side leads to a conformation changes that activates the G-protein
- Galpha-GDP -> Galpha-GTP which dissociates and activates or inactivates effector protein. The alpha-subunit then breaks down the GTP to regenerate the alpha-GDP subunit and rejoins the beta-gamma complex
- Gi (opioid) - inactivates adenylyl cyclase
- Gs (adrenoreceptors) - activates adenylyl cyclase
- Gq - Activate PHOSPHOLIPASE C to form inositol triphosphate and diacylglyercol - causing calcium release from the endoplasmic reticulum and activation of protein kinase C
Tyrosine kinase (insulin and growth factors) - ligands bind to alpha subunits and cause phosphorylation of intracellular tyrosine kinase on beta subunits with subsequent intracellular effects
Guanylyl Cyclase
- Receptors with intrinsic guanylyl cyclase activity
- Stimulation causes increase in intracellular cGMP which phosphorylates intracellular enzymes
Gq receptor sequence
Gq - Activate PHOSPHOLIPASE C to form inositol triphosphate and diacylglyercol - causing calcium release from the endoplasmic reticulum and activation of protein kinase C
What drugs regulate gene transcription
Steroids
Thyroxine
Halothane hepatitis protein
TFAA
Trifluroacetic acid
hapten complex
How do drugs work?
Receptors Ion channels Enzymes Neurotransmitters Hormones transport systems Physiochemical
Classify drug interactions
Physiochemical
- chelation and neutralisation
Pharmacokinetic
- Absorption, distribution, metabolism, excretion
Pharmacodynamic
- Summation
- Synergyism
- Potentiation
- Antagonism
Drugs that undergo extensive 1st pass metabolism
Aspirin Morphine Codeine Diltiazem Propanolol Verapamil Hydralazine
