What could lead to the formation of arterial and venous clots?
Disorders of haemostasis are common e.g. thrombosis, embolism
Arterial (white clot): Cerebrovascular Accident, Myocardial Infarction; Antiplatelets and Thrombolysis
Venous (red clot): Deep Vein Thrombosis, Pulmonary Embolism; Anti-Coagulation
Other uses: pro-thrombotic state and primary prevention
Describe Virchow's Triad
In normal thrombosis, a thrombus forms from activation of any of Virchow’s Triad (abnormality in vessel wall, abnormality to blood constituents, abnormality to blood flow).
Changes in blood composition => hypercoagulability
- Genetic: Protein C & S deficiency, Factor V Leiden
- Acquired: Antiphospholipid Syndrome (autoimmune hypercoagulable condition caused by antiphospholipid antibodies), oral contraceptive pill, smoking, malignancy, prosthetic heart valves
Changes in blood vessel wall => endothelial damage
- Atheroma => MI, CVA
- Toxins – cigarettes, homocysteine
- Arterial clot is formed
Changes in blood flow => stasis
- Immobility – ill health, post-op, economy class (long flights)
- Immobility factors tend to cause venous clots
- Cardiac abnormality – atrial fibrillation, congestive cardiac failure, mitral valve disease and post-MI
- Cardiac abnormalities tend to cause arterial clots
Describe the formation of arterial thrombosis?
Rupture of atherosclerotic plaque in artery leads to (adhesion, activation and aggregation of platelets), (in vivo pathway – tissue factor and factor VIIa activation) and (contact pathway factors - XII and XI activation).
Platelet reaction: Adhesion, activation and aggregation of platelets => secretion of preformed mediators e.g. ADP and synthesis of mediators e.g. TXA2, PAF => Further aggregation of platelets -> Thrombus
Describe the common end pathway of blood coagulation
Blood coagulation: Intrinsic and extrinsic pathways have a common end pathway = both lead to Factor Xa => Factor II (Prothrombin) -> II (Thrombin) => Fibrinogen -> Fibrin -> Thrombus
Both anticoagulants and anti-platelets will target this physiology to prevent thrombus formation.
What are the types of anticoagulant drugs?
Anticoagulant drugs include Vitamin K antagonists and Heparin.
Antiplatelet agents include Thromboxane A2 inhibitors e.g. Aspirin, Dipyridamole; Platelet ADP Receptor Antagonists e.g. Clopidogrel, Ticlopidine; and GpIIb/IIIa inhibitors
Process of Clot
Role of coagulation system
- Anticoagulation: prevention and treatment of thromboembolism (venous and arterial)
- Fibrinolysis: breakdown of existing clot (separate lecture)
Role of platelets
- Antiplatelet agents – treatment of patients with vascular disease (mainly arterial) e.g. ischemic heart disease, cerebrovascular disease
Describe the mechanism of action of warfarin
Anticoagulant drugs can be used in the treatment and prophylaxis of disorders resulting from intravascular clotting
Vitamin K antagonist
Mechanism of action:
- Vitamin K promotes synthesis of prothrombin and Factors II, VII, IX, X (also Proteins C & S). Vitamin K normally acts to carboxylate gla residues on certain clotting factors and in turn is itself oxidised and so must be reduced to be reused again.
- Competitively antagonised (inhibited) by coumarin derivatives e.g. Warfarin – Warfarin acts by competitively antagonising this reduction of the oxidised vitamin K, meaning these clotting factors cannot be produced.
- Warfarin stops conversion of Vit K to its active form
- Inhibits II (Prothrombin), VII, IX, X (extrinsic pathway) – leads to synthesis of non-functional coagulation factors
- Onset: LONG - days due to turnover of clotting factors (activated clotting factors need to be depleted before effect is seen)
As it is a competitive antagonist, Warfarin can be displaced by excessive Vitamin K to limit its effects.
As a result of its mechanism of action, Warfarin can be used effectively as an anti-coagulant drug for deep-vein thrombosis, pulmonary embolism, atrial fibrillation and mechanical prosthetic heart valves (to prevent emboli developing on the valves); heparin is usually preferred for the prophylaxis of venous thromboembolism in patients undergoing surgery.
What are the practical pharmacokinetics of warfarin?
Good GI absorption – (PO) oral dosing – preferred choice for long-term anticoagulation.
Causes dose dependent reduction in Vit K dependent factors but:
Slow, gradual onset of action and slow offset (persisting anticoagulant action on cessation of treatment – needs to be stopped 3 days prior to any surgery allowing time for synthesis of new clotting factors).
- Need heparin cover – initially heparin is required to block clotting factors straightaway
Heavily protein bound so can be displaced to have greater effect.
Why is it affected by enzyme inducers and inhibitors?
Its metabolism is via CYP450 metabolic pathway so levels will be affected by enzyme inducers and inhibitors (numerous drug interactions resulting in altered anticoagulant effect – majority increase anticoagulant effect but some decrease effect). Further care must be taken when co-administering aspirin or heparin.
Caution with liver disease
INTERACTIONS WITH WARFARIN ARE HIGHLY SIGNIFICANT
Drugs potentiating warfarin: 3 ways are clinically significant
- Inhibit hepatic metabolism => increased [warfarin] in plasma: Amiodarone, Quinolone, Metronidazole, Cimetidine, ingesting alcohol
- Inhibiting platelet function (can potentiate bleeding): Aspirin
- Reduce Vitamin K synthesis from gut bacteria: broad-spectrum antibiotics such as Cephalosporin antibiotics.
Albumin displacement (NSAIDS) and drugs that decrease GI absorption of Vit K have lesser effect – tend to be temporary rather than prolonged.
INR will increase if you start one de novo.
Drugs inhibiting Warfarin:
- Antiepileptics (except Na valproate), Rifampicin, St Johns Wort
- Most work by inducing hepatic enzymes thereby increasing metabolism of warfarin (so effects are potentially inhibited) => decreased INR.
How would you monitor warfarin? What are target INRS
Monitoring warfarin involves extrinsic pathway factors. The prothombin time is the citrated plasma clotting time after adding calcium and thromboplastins.
Dose levels should be monitored via the INR value (Internationalised Normalised Ratio is time taken for blood to clot compared to average for specific age and gender, so high INR means poor blood clotting). INR allows a standard value between labs – corrected for different lab thromboplastins reagents.
Target INRs with Warfarin use are:
- INR of 2.0-3.0 for DVT (3-6 months), PE (6 months), AF (until risk > benefit)
- INR of 2.5-4.5 (NB: high INR associated with increased risk of bleeding) for mechanical prosthetic valves (high risk), patients with recurrent thromboses on Warfarin or thrombosis associated with inherited thrombophilia conditions.
Regular monitoring is required
Other uses of warfarin include cardiac thrombus, CVA especially with AF, cardiomyopathy.
Extreme variation in individual dose requirement
Differing degrees of anticoagulation, depending upon condition
What are the adverse effects of warfarin and describe reversal of therapy?
- Excessive bleeding/bruising/purpura especially GI haemorrhages yet can also result in epistaxis, at injection site and intracranial haemorrhage. Patient can present with anaemia.
- In pregnancy, it can cross the placenta – teratogenicity - if administered during first trimester.
- Do not give in 3rd trimester - risk of brain haemorrhage in baby during birth
- If female patient on warfarin, advise regarding pregnancy
- With any haemorrhage that does occur, variations in treatments occur depending on INR value and level of bleeding.
Reversal of therapy:
Antagonism of therapy by administration of Vitamin K – Vitamin K can outcompete the action of Warfarin. Parenteral (i.e. IV) vitamin K is slow.
Fresh frozen plasma is fast.
What practical considerations do you need to consider with prescribing warfarin? What do you need to discuss with the patient?
Personal medical history e.g. peptic ulcer disease, subarachnoid haemorrhage, bleeding disorder
Age, mobility (blood tests and clinics), falls risk score
Review blood tests (LFT, platelet count, INR)
Consider Loading Dose and Heparin cover (so that when effects of warfarin kick in, take heparin off)
Prescribe (when to start)
DVT: start warfarin the same day as heparin (including LMWH)
PE: start warfarin 48 hours after heparin
Discuss with patient
- Side effects
- Bleeding and when to consult a doctor
- Young and female?
- Other medication (starting or stopping)
- Over the counter drugs
- Alcohol (inducer) and cranberry/grapefruit juice (inhibitors)
- INR monitoring (1-4 weeks)
- Give patient Anticoagulant card
How would you go about reversal of warfarin?
Common Sense: stop warfarin!
- Bleeding, INR, indication
- Mechanical valve call cardiologist
- IV Vit K (be careful when giving large doses as Vit K is a pro-coagulant and affects re-warfarinisation for 6 weeks)
- Prothrombin Complex Concentrate
- Fresh Frozen Plasma
Source of bleeding (OGD, surgery)
Describe the mechanism of action of heparin
Mechanism of action:
Linear mucopolysaccharide chains (glycosaminoglycans) of variable length and molecular weight (range 12000-15000 Daltons)
- Glucose backbone
- One of 5 different groups on each glucose, some with sulphate. Produced by mast cells
Active site is a unique pentasaccharide sequence – activates Anti-Thrombin III.
Markedly increases antithrombin-mediated inhibition of predominantly Thrombin and Xa, (but also Factors IXa, VIIa, XIa, XIIa)
Give the differences between standard and lmw heparin
Heparin can be subdivided into unfractionated (or ‘standard’) heparin or low-molecular weight heparin (LMWH) and have slightly different mechanisms of action and pharmacokinetics.
Unfractionated heparin (about 45 saccharide units, MW 13,500) binds to ATIII via its unique pentasaccharide sequence, leading to conformational change and increased ATIII activity. ATIII inactivates thrombin (IIa) and factor Xa but also has effects on V, VII, IX and XI.
- Intravenous, continuous, occasionally, subcutaneous for prophylaxis 20 kDa
- Mix of variable long length heparin chains of variable lengths (12-15 kDaltons).
LMW heparins (about 15 saccharide units, MW 4,500) binds to Antithrombin III but not to thrombin (poorly inactivates thrombin – no effect). It binds to ATIII via pentasaccharide (sufficient to inactivate Xa).
- Subcutaneous 3-4 kDa
- To catalyse inhibition of IIa by AT III, heparin needs to bind simultaneously to IIa and AT III. Unfractionated heparin is large enough for this but not LMW heparin.
- Xa inhibition by AT III needs only heparin to bind to AT III so both low and unfractionated heparin can act here
- LMW heparins have smaller chains.
- Like unfractionated heparin, LMW heparin has a unique sequence to bind to ATIII. Affects Factor Xa specifically.
What other anticoagulants are more specific
Other anticoagulants can act specifically as factor Xa inhibitors, such as Fondaparinux, Idaparinux, Rivaroxaban, Apixaban and Edoxaban or as direct thrombin inhibitors (which do not involve ATIII and have no effect on Xa) such as Bivalirubin or Desirubin.
In both unfractionated and LMW heparins, the heparin-ATIII complex will also act on factors IXa, XIa and XIIa.
What are the pharmacokinetics of heparin? How would you monitor it?
Poor GI absorption – therefore administered IV/SC (parentally)
Rapid onset/offset of anticoagulant activity
Variable bioavailability due to binding of plasma proteins
Standard heparin shows a non-linear dose response and its bioavailability is variable (unpredictable binding to cells and proteins). Its action is variable thus monitor with APTT. Administration via IV. Bolus is required for initiation then IV.
LMW heparin shows a predictable dose response and predictable bioavailability (does not bind to macrophages, endothelial cells and plasma proteins). No monitoring is required – little affect on APTT. Administration via SC (not IM!), once daily/twice daily. It is absorbed more uniformly, high bioavailability (>90%) and has a long biological half-life. It is cleared by the kidneys so caution in renal failure.
Dose/effect monitored by APTT (activated partial thromboplastin time). APTT measures the efficacy of the coagulation pathways.
What are indications for use of heparin/
LMWHs are usually preferred over unfractionated heparin in the prophylaxis of venous thromboembolism because they are as effective and they have a lower risk of heparin-induced thrombocytopenia.
LMWHs are also used in the treatment of deep-vein thrombosis and pulmonary emboli (administered prior to Warfarin to cover whilst warfarin loading is achieved), myocardial infarction and unstable coronary artery disease. LMWH is often used unless fine control is required.
Heparin is used instead of Warfarin during surgery (as Warfarin is stopped 3 days prior to the surgery) as its quick offset allows its cessation if haemorrhage occurs.
Prevention of Thromboembolism
- Peri-operative: LMWH low dose
- Immobility: congestive cardiac failure, frail or unwell patient
- Used to cover for risk of thrombosis around times of operation in those normally on warfarin but who have stopped it for the surgery, as quick offset time allows its cessation if bleeding.
Heparin is also used in Acute Coronary Syndromes (reduces recurrence/extension of coronary artery thrombosis) e.g. in MI, unstable angina
It can be used cautiously in pregnancy in place of warfarin.
Describe the adverse effects of heparin
- Haemorrhage intracranially, at injection sites, at GI sites or epistaxis
- Autoimmune condition where heparin binds to PF4 on platelet surface and stimulates immunogenic response.
- Usually 1-2 weeks of treatment
- May bleed or get serious thromboses
- Heparin and PF4 on platelet surface are immunogenic – immune complexes activate more platelets, release more PF4, forms more IgG and complexes, leads to depletion of platelets, thrombosis
- Platelets <100 (or a 50% reduction)
- Lab assay for these antibodies
- Stop heparin, add hirudin (anti-thrombin)
Osteoporosis (long term administration - uncommon)
Describe the reversal of heparin therapy and practical considerations
Reversal of therapy
- Any reversal of therapy involves administration of Protamine sulphate – causes dissociation of Heparin/Antithrombin III complex and binds irreversibly to heparin. Consequently, any haemorrhage involves administration of protamine, stopping heparin therapy and monitoring the APTT (if unfractionated).
Practical Info for Heparin:
- Loading dose then IV infusion (to maintain level as half life is quite short) (few hours)
- Monitor APTT
- Give according to body weight
- No monitoring (occasionally may need Xa assay – if side effects/adverse effects)
Describe anticoagulants and the clotting cascade
Intrinsic pathway: exposed collagen kallikrein
Extrinsic pathway: tissue damage, thromboplastin, platelet PL (platelet lysate)
What can antiplatelet agents be used for? Give examples of thromboxane A2 inhibitors
Antiplatelet agents can be used in the treatment and prophylaxis of disorders resulting from intravascular clotting (especially that with predominant platelet aggregation e.g. arterial disease)
Plaque fissure/rupture => platelet adhesion => platelet activation => platelet aggregation => thrombotic occlusion
Thromboxane A2 inhibitors include Aspirin and Dipyridamole
Thromboxane A2 liberated from activated platelets – causes platelet aggregation/vasoconstriction
Describe Aspirin and Dipyridamole
Aspirin: irreversibly inhibits cyclooxygenase (COX1) through covalent acetylation of serine and therefore platelet thromboxane A2 production. It also attenuates the protective effect of gastric mucosal prostaglandins (through cyclooxygenase inhibition) => gastric erosions/ulcers may occur. It prevents platelet aggregation.
- Known as a ‘hit and run’ drug because the effect can only be reversed by cell turnover and new platelets. So effects of aspirin lasts severe days.
Dipyridamole: inhibits platelet phosphodiesterase – rising platelet 128eli levels inhibit Thromboxane A2 production
- Positive inotrope and vasodilatory effects (flushes and headaches)
- Secondary prevention of stroke (in combination with aspirin).
What do platelet ADP receptor antagonists do? Give examples
Platelet ADP receptor antagonists include Clopidogrel and Ticlopidine
- ADP/ADP-receptor interaction – one of many stimuli for platelet aggregation
Inhibit ADP dependant aggregation by inhibiting the ADP-receptor.
They block the P2Y12 receptors which decreases cAMP via Gi
*Prostacyclin, a member of the prostaglandin family increases cAMP – reduces aggregation
Ticlodipine (original drug) is now outdated due to side effects (particularly bone marrow suppression).
Cardiac indications include Acute Coronary Syndromes, PCI (do NOT stop)
Used in combination with Aspirin
- More serious bleeds but same rate of life threatening
- Not for long term use if possible
- E.g. use for 1 year after NSTEMI (then carry on with aspirin)
Describe GpIIb/IIIa inhibitors
GpIIb/IIIa inhibitors such as Abciximab, tirofiban and eptifibaide inhibit final common pathway of platelet aggregation – decrease platelet crosslinking by fibrinogen (fibrinogen normally binds these receptors which causes platelet aggregation) – 3 classes:
Monoclonal antibodies to GpIIb/IIIa receptors (Abciximab)
Peptide antagonists to GpIIb/IIIa receptors (eptifibatide, tirofiban)
‘Non-peptide’ small molecule antagonists of GpIIb/IIIa receptors
Uses in high risk Acute Coronary Syndromes and post PCI (increases bleeding complications but decreases acute thrombosis and re-stenosis).
Describe the normal clearance of thrombi and what fibrolytic drugs do
The normal clearance mechanism for thrombi is by plasmin, a trypsin-like enzyme which cleaves fibrin (and fibrinogen and several other coagulation factors including II, V and VIII).
Plasmin is formed from the circulating precursor plasminogen, which binds to fibrin strands within a thrombus. The conversion of plasminogen to plasmin is achieved by a number of plasminogen activation e.g. tissue plasminogen activators (tPA), urokinase-type plasminogen activator (uPA) and others. These activate plasminogen bound to fibrin.
The fibrinolytic system is itself regulated by circulating inhibitors such as PAI-1.
Following endothelial damage, tPAs are released to allow production of plasmin.
Plasmin is an active protease and works by being “brought together” with tPA to the fibrin surface, and breaks down the fibrin to form the fibrin degradation products.
Fibrinolytic drugs generate plasmin either themselves (e.g. tPA, approved name alteplase) or by binding to and activating endogenous plasminogen (e.g. the bacterial product streptokinase).
The former mechanism works preferentially in the presence of fibrin and is therefore described as ‘clot-specific’, whereas streptokinase causes a degree of fibrinolytic activity in the general circulation. The practical significance of this difference is uncertain.
Streptokinase is a bacterial protein derived from Beta-haemolytic streptococci and therefore antigenic (immunogenic).
It will produce an immune response in the body after initially given.
Streptokinase acts by binding to plasminogen and inducing a conformational change to plasmin, thereby becomes a surplus of plasmin and can induce a systemic lytic state.
It can cause allergic reactions (major in about 0.1% of treated patients) and cannot be used twice since it invariably generates blocking antibodies which persist for many years.
Streptokinase is given via IV infusion and has a half life of around 15 mintues.
Streptokinase also commonly causes transient hypotension when being infused; the blood pressure usually comes up again if the infusion is slowed.
Describe recombinant tPAs
Recombinant tPAs (r-tPAs) are produced using recombinant DNA technology and hence are non-immunogenic.
Examples include Alteplase, Reteplase and Tenecteplase.
They work by the same mechanism as natural tPAs. They are given by IV bolus and infusion and have a half life of around 3-17 minutes.
Compare streptokinase to tPAs and describe indications for their use
In large randomised trials, streptokinase and alteplase have been of very similar efficacy in acute myocardial infarction (ISIS-3 and GISSI studies); alteplase achieved a very slightly greater mortality reduction (vetter survival rates) partly offset by an increased risk of haemorrhagic stroke – increased risk of intracranial haemorrhage (GUSTO study).
The main reasons why r-tPAs are used fully clinically instead of streptokinase is that r-tPAs can be repeatedly administered and are easier to administer, yet are more expensive.
Fibrinolytic therapy within the first 1-2 hours of onset of myocardial infarction will prevent up to 60 deaths per thousand patients treated. Newer genetically engineered agents (reteplase, duteplase) have less extensive trials evidence but have simpler administration regimens.
Urokinase is produced from cultured human embryonic kidney cells but is not licensed for use in myocardial infarction.
What are the main conditions in which thrombolytics are used?
In carefully selected patients, fibrinolytic drugs are used for the following indications:
- Acute myocardia infarction (<12 hours in duration and without any contra-indications (yet coronary angioplasty has better prognosis than tPAs)).
- Pulmonary embolism
- Major venous thrombosis
Trials have also examined the use of fibrinolytic agents in ischaemic acute stroke (where a haemorrhagic mechanism has been excluded by CT or MRI scan), but their use in this indication is not routine because of the associated risk of induced cerebral haemorrhage and narrow time-window of potential benefit.
In each case, early treatment is essential before the consequences of vascular occlusion becomes irreversible. Furthermore, as they age, thrombi become more resistant to lysis. The potential benefit of treatment declines continuously over time, whereas the risks remain constant.
The window of opportunity is within approximately 12 hours for coronary occlusion, rather longer for venous thrombo-embolism but only about 3 hours for ischaemic stroke.
Less common indications include clearance of thrombosed shunts and intraocular thromboses.
What are the adverse effects of thrombolytics? Describe their indications and contraindications
- All fibrinolytic agents carry the risk of causing haemorrhage, most seriously into the brain (haemorrhagic stroke, in 0.1-0.2% of patients) or into the gastrointestinal tract (major in about 0.5-1.0%).
- Careful patient selection is important to ensure that the potential benefit outweighs these risks and informed consent should be sought from the patient.
Indications and contra-indications
Myocardial infarction: clear evidence from the history and ECG of acute myocardial infarction <12 hours duration, without contra-indications. It is essential that fibrinolytic treatment (plus aspirin) is started as quickly as possible after diagnosis, to minimise myocardial necrosis.
Pulmonary embolism: a clear diagnosis, evidence of significant haemodynamic compromise and absence of major contraindications are criteria for fibrinolytic therapy.
Major contra-indications include active peptic ulcer or other potential bleeding source, recent trauma or surgery, history of cerebral haemorrhage/haemorrhagic stroke or stroke of uncertain aetiology, CNS neoplasm, aortic dissection, uncontrolled hypertension and coagulation defect (known bleeding disorder).
Age per se is not a contraindication.
Streptokinase should not be given to a patient who has received it in the past.
How would you treat the thrombolytic effects of contraindications?
Hypotension is common with streptokinase and corrected by slowing or briefly stopping the infusion.
Allergic reactions to streptokinase require that the treatment be stopped and a non-immunogenic alternative given instead.
Severe allergy or anaphylaxis is treated with adrenaline, oxygen, intravenous fluids, an antihistamine and hydrocortisone as required.
Any cerebrovascular event occurring after fibrinolytic therapy requires a CT or MRI diagnosis to establish whether the cause is haemorrhagic (treatment related) or ischaemic (i.e. probably embolic from the heart). The two are equally likely after fibrinolytic treatment of myocardial infarction.
Serious bleeding after fibrinolytic treatment may require transfusion of blood or volume expanders, inhibition of further fibrinolysis with tranexamic acid (competitively inhibits the activation of plasminogen to plasmin) or aprotinin, specific recombinant or pooled clotting factors.
Recognise the names of example inhalational and IV anaesthetics
Inhalational agents: Nitrous Oxide (N2O); Isoflurane; Desflurane; Sevoflurane. These three are closely related halogen compounds with similar anaesthetic actions.
Intravenous agents: Propofol; Ketamine
Describe the range of anaesthesia techniques and anaesthesia from a practical viewpoint? How safe is anaesthesia?
Anaesthetic techniques are not mutually exclusive and can be combined.
Conscious sedation: use of small amounts of anaesthetic or benzodiazepines to produce a ‘sleepy-like’ state (maintain verbal contact but feel comfortable).
Anaesthesia from a practical view point:
- Premedication (Hypnotic – benzodiazepine).
- Induction (usually intravenous but may be inhalational).
- Intraoperative analgesia (usually an opioid).
- Muscle paralysis – facilitate intubation/ventilation/stillness
- Maintenance (intravenous and/or inhalational).
- Reversal of muscle paralysis and recovery which includes post-operative analgesia (opioid/NSAID/paracetamol).
- Provision for post-operative nausea and vomiting (PONV) – give anti-emetic.
- So during anaesthesia, many interacting pharmacological agents “on board” (e.g. around 9, sometimes more) requiring excellent pharmacological knowledge and skill to manage.
- Despite polypharmacology, anaesthesia is very safe (deaths caused are very rare – in UK ~5/1,000,000 anaesthetics given).
Describe the pharmacology of general anaesthetics? What are the sites of action? What is an important feature in determining potency?
At the level of the CNS, mixed anatomical sites of action are involved
Different sites in the CNS appear to be involved with mediating effects of anaesthetic and the level of anaesthetic depth.
Immobilisation in response to surgical incision, is due to action at the level of the spinal cord.
For inhalational anaesthetics, the thalamus and the hippocampus appear to be involved for mediating unconsciousness and amnesia respectively
Lipid solubility is an important feature predicting potency
For virtually all anaesthetic agents, lipid solubility, and hence their ability to dissolve and enter cell membranes, predicts potency. Remember, potency is the concentration of a drug needed to attain a half or 50% of its maximal therapeutic effect.
For some time, it was thought that this anaesthetic effect was due to a disruptive effect on neuronal (i.e. ‘excitable’ membranes). This has now been superseded by experimental work that shows anaesthetic effects are likely to be mediated in large part by action on a range of ligand gated ion channels – or LGICs. However, lipid solubility is still very important for the majority of inhalation and intravenous anaesthetic agents in determining how they gain access to their target sites situated in lipid membranes.
What are the reversible effects of anaesthesia?
Anaesthesia has a long clinical history going back to the late 18th century. Originally, surgical anaesthesia was performed using single gaseous agents delivered by inhalation such as ether or choloroform. Intravenous anaesthetic agents such as thiopental were developed from the 1930s onwards.
The reversible effects of anaesthesia include: sedation up to unconsciousness; amnesia; muscular relaxation; reflex suppression and immobilisation; anxiolysis; analgesia. No single agent is able to produce all these effects. Consequently, since the 1930s, a range of adjuvant drugs were developed to significantly augment the anaesthetic state in surgery.
Nowadays the broad term anaesthesia is often used with regards to the integration of CNS effects by using a principle anaesthetic agent and a range of adjuvant drugs.
Describe General and Regional Anaesthesia
General anaesthesia: affects the whole body and typically involves uses of intravenous and inhalational anaesthetics with adjuvants. They act reversibly to inhibit sensory, motor and sympathetic nerve transmission in the CNS to produce unconsciousness and absence of sensation.
Regional anaesthesia: this involves rendering larger specific regions of the body insensate. The region is determined by transmission block between that part of the body and the spinal cord. Both spinal and epidural anaesthesia can achieve this. The patient remains conscious, but may also be administered adjuvants depending on the procedure.
- Uses local anaesthetic and/or an opioid
- Upper extremity (e.g.): interscaleene, supraclavicular, infraclavicular, axillary
- Lower extremity (e.g.): femoral, sciatic, popliteal, saphenous
- Extradural/intrathecal/combined (labour)
Describe Local and Dissociative Anaesthesia
Local anaesthesia: involves a more defined peripheral nerve block with injection of a local anaesthetic. Used for tooth extraction (dentistry), or for example, procedures on the hand and fingers, foot or big toe, or internally in the urethra (obstetrics) when performing cystoscopy, regional surgery (patient awake), post-op (wound pain) and chronic pain management (postherpetic neuralgia).
Dissociative anaesthesia: uses agents such as ketamine that inhibit transmission of nerve impulses between higher and lower centres of the brain. Mainly used in children and the elderly for short procedures, as they appear to be less susceptible to its postoperative hallucinogenic effects.
Describe the characteristics of Local anaesthetics including Bupivacaine infiltration for wound analgesia
Local anaesthetics include Lidocaine, Bupivacaine, Ropivacaine and Procaine
- Characteristics include lipid solubility – potency (higher greater potency)
- Dissociation constant (pKa) – time of onset. Lower pKA, faster onset.
- Chemical link – metabolism (esters are short-acting, amides are long-acting)
- Protein binding – duration (greater protein binding, longer duration)
- Basic anaesthetic structure: aromatic ring – link (ester/amide) - amine
Bupivacaine infiltration for wound analgesia
Block is USE dependent
Block small myelinated (afferent) nerves in preference hence nociceptive and sympathetic block
Adrenaline (vasoconstriction) increases duration
Bupivacaine is an amide so more stable – longer lasting. Slow onset (pKa 8.2)
Compared to Procaine, Bupivacaine is more potent with a longer duration of action (greater protein binding). Procaine is esterase metabolised – exceptionally Bupivacaine has slightly faster onset (smaller pKa)
How does experimental evidence propose anaesthetics mediate their effects? Describe the nature of the interactions
Experimentally, there is a lot of evidence to show that anaesthetics mediate their effects by affecting postsynaptic transmission of both inhibitory and excitatory ligand gated ion channels or LGICs.
Importantly, for inhalational agents, the interactions at these sites are very weak and easily reversed – an essential feature of anaesthesia. One very interesting feature of their action is they need to reach high concentrations in the cell membranes. This is in the millimolar range (10^-3 M). This compares with active concentrations of many other non-anaesthetic drugs in the 1-100 micromolar (10^-4 – 10^-6 M) range.
Describe Inhibitory LGICs 1: GABA(A) activated Chloride Channels
Many inhalational and intravenous anaesthetics appear to have a primary effect on GABA(A) LGICs. Once bound, they act by increasing sensitivity to GABA and increasing Chloride currents, thereby hyperpolarising the neurone and decreasing its excitability.
GABA is a major inhibitory neurotransmitter. Anaesthetics potentiate GABA activity => anxiolysis, sedation and anaesthesia.
With the exception of Xe, Nitrous Oxide and ketamine all anaesthetics potentiate GABA(A) mediated Cl- conductance to depress CNS activity (behave as agonists).
Depending on the specific anaesthetic, there appear to be one or more binding sites external to the GABA(A) Chloride Ion pore. These effects on GABA(A) at differing anatomical sites, would contribute to a number of specific aspects of the anaesthetic state described earlier. Propofol is considered to exert its main sedative effect on this channel.
Describe: Inhibitory LGICs 2: Glycine activated Chloride Channels
Inhibitory LGICs 2: Glycine activated Chloride Channels
Experimentally, Glycine activated Chloride Channels have also been shown to be sensitive to some inhalational and intravenous anaesthetic agents. Interestingly, these LGICs are structurally closely related to the GABA(A) LGIC, which likely explains their shared sensitivity.
Once the anaesthetic is bound, they again act by increasing sensitivity to glycine to increase Chloride currents. This hyperpolarises the neurone and decreases its excitability.
Glycine LGICs are especially important in signalling inhibitory neurotransmission in the spinal cord and brainstem and act to reduce the response to noxious stimuli.
Describe Excitatory LGICs 1: Neuronal Nicotinic (N) ACh Receptors
Excitatory LGICs 1: Neuronal Nicotinic (N) ACh Receptors
Some inhalational anaesthetics also appear to inhibit some subtypes of neuronal N ACh receptors.
Pharmacologically this inhibition will act to reduce excitatory Na+ currents caused by ACh binding.
In terms of anaesthetic effect, this action on N ACh receptors is considered to likely contribute to analgesia and amnesia rather than sedation.
What is the Molecular-Cellular Target specifically? What is meant by Systems Target: Brain Circuitry?
Molecular-Cellular Target: in the brain consciousness is (simplistically) a balance between excitation (Glutamate) and inhibition (GABA). Anaesthetics modulate this balance.
Systems Target: Brain Circuitry
- Reticular formation (hindbrain, midbrain and thalamus) depressed (connectivity lost).
- Reticular system often called “activating system” due to ability to increase arousal.
- Thalamus transmits and modifies sensory information.
- Hippocampus depressed (memory).
- Brainstem depressed (respiratory and some CVS)
- Spinal cord – depress dorsal horn (analgesia) and motor neural activity (MAC)
Why is it difficult to classify general anaesthetic structures? Why is the pharmacokinetics of anaesthetics so complicated?
The PKs of anaesthetics can be highly complicated due to their widely differing kinetics across body compartments. Additionally, giving inhalational and intravenous agents in combination adds further layers of pharmacokinetic complexity. This is why anaesthetists are needed to literally ‘fine-tune’ and customise delivery for each patient to match their personal compartmental distribution.
General anaesthetics are difficult to classify due to the vast range of structures so are broadly categorised as gases (delivered via lungs) and intravenous.
Describe Administration of inhalational anaesthetics.
All inhalational “volatile” agents require careful titration using specialist equipment to vaporise the modern inhalational fluranes which exist as volatile liquids at room temperature.
The principle anaesthetic agent is then mixed with a carrier of oxygen, air and often with Nitrous Oxide. This is then fed to the respiratory system by mask under spontaneous or controlled respiration.
What is MAC? When is it reduced?
As End point is concentration dependent, we can use MAC to describe potency for volatiles: Minimal Alveolar Concentration:
The specialised equipment allows close control of the relative proportion of each of the gases reaching the alveolar space.
The percentage of inhaled anaesthetic (alveolar concentration at 1atm) that abolishes response to surgical incision results in 50% of patients is the Minimal Alveolar Concentration or MAC.
- Concentration dependent curves are very steep – indicates a “switch” between awake and asleep
The lower the MAC value, the more potent the inhaled anaesthetic is as the MAC closely related to its lipid solubility.
- Potency is the concentration dose range in which the drug produces its therapeutic effect.
At equilibrium [alveolar] = [spinal cord]
MAC, MAC-BAR (autonomic response – cardiovascular response – normally 1.5 MAC), MACawake (normally 0.25 MAC)
Anatomical substrate for MAC is spinal cord, not the brain
- In animal models if section cord (ie. remove connection to the brain), MAC is unchanged
Anaesthetic potency correlates with lipid solubility and activation of GABA(A) (GABA(A) interaction)
For the modern fluranes, MACs falls between 1-6% by volume of the inspired gas mixture. In anaesthetic practice, the MAC forms a standardise unit of delivery, for example 1 MAC or 2 MACs for any inhalational anaesthetic. The MAC shows relatively little variation between individuals and for most inhalational anaesthetics, surgical depth is typically achieved within 1.2-1.5 MAC. This again underlines the need for the very precise control of their delivery.
The MAC for individual agents can be significantly reduced when given in combination with other agents such as nitrous oxide, or the potent opiate fentanyl. Physiological states such as reduced cardiac output, ventilation rate and depth or shock can significantly affect management of anaesthesia.
What are the factors affecting induction and recovery?
Factors affecting induction and recovery: Partition coefficients (solubility)
Blood:Gas partition (in the blood) – solubility in blood
- Low value fast induction and recovery e.g. desflurane
Oil:Gas partition (in fat) – solubility in fat
- Determines potency and slow accumulation due to partition into fat (e.g. halothane) – the fat becomes a reservoir => increased potency, low MAC
How is MAC determined?
Age (high in infants, lower in elderly)
Hyperthermia (increased); hypothermia (decreased)
Central stimulants (increased)
Other anaesthetics and sedatives (decreased). Nitrous oxide is very often added to other volatile agents (reduced dosing and reduced side effect profile)
Describe how absorption is determined by the Blood:Gas Coefficient
Absorption is determined by the Blood:Gas Coefficient
The inhaled agent very readily passes down its concentration from the alveoli into the bloodstream.
Whilst the intervening pharmacokinetics are quire complications, put simply: the concentration of inhalational agents in the alveoli directly determine the concentration they reach at the target sites in the CNS.
The degree of absorption across the alveoli and into the blood is defined by the blood:gas coefficient. The blood:gas coefficient describes the volume of gas in litres that can dissolve in one litre of blood. For isoflurane, this is 1.4 so a litre of blood could dissolve 1.4 litres of isoflurane.
The higher the blood:gas coefficient, the more readily it will enter the blood.
Describe how anaesthetic distribution is dependent on relative blood supply to organs? Describe how anaesthetic partitioning varies by tissue type
Anaesthetic distribution is dependent on relative blood supply to organs
- Once the gas is dissolved in the blood, it is then distributed by the vascular system to all tissues. However, the distribution around the body varies depending on two major factors; the relative blood supply to each organ or tissue and the specific tissue uptake capacity for the anaesthetic.
- In broad terms, the gradient of relative blood supply at rest is: (brain, liver, kidneys) 75% > (muscle) 18% > (fat) 5%.
Tissue:Blood Coefficients – Anaesthetic partitioning varies by tissue type
- The specific tissue:blood partition coefficients then determine the relative uptake from blood. This describes how readily the anaesthetic will move from blood to a specific tissue type, normalised for tissue volume.
- For isoflurane entry into the CNS, the brain:blood coefficients is 1.6 so this means for an equivalent volume of brain to blood, the brain will take up 1.6x as much anaesthetic.
- Somewhat counter intuitively for isoflurane, partitioning into muscle the muscle:blood coefficient is 2.9. So at equilibrium, the muscle tissue compartment takes up proportionately nearly twice the amount of isoflurane than the brain does.
- The fat:blood partition coefficient is even greater at 45, meaning that nearly 30 times the amount of isoflurane is absorbed by the fat than by the brain. This is a very large reservoir of anaesthetic that can redistribute during the recovery phase.
- Taken together, these factors affecting distribution to other compartments outside the CNS will act to affect the rate of induction by inhalation. Plasma protein binding with fluranes does occur but the interaction is relatively weak and with rapid dissociation.
Describe the metabolism and elimination of inhalational anaesthetics
Metabolism of Inhalational Anaesthetics
- Modern fluranes undergo little transformation by hepatic metabolism and does not contribute significantly to their elimination.
Elimination of Inhalational Anaesthetics
- In effect, elimination is the reverse of distribution and absorption. As surgery is finished the anaesthetic carries out a controlled withdrawal of anaesthesia ensuring adequate oxygenation in the latter stages of surgical procedure.
- As the concentration in the blood drops the anaesthetic moves out of the cell membranes into the venous blood supply back to the alveolus to be eliminated unchanged.
- The rate of recovery is similar to the rate of induction for inhalational agents. This is led by movement by well perfused tissues (brain, liver, kidney) followed by muscle and then finally fat.
- Importantly, fully recovery from anaesthesia can take some hours to days. As described above, the larger capacitance for the gases in the larger muscle and fat compartments, allied with a lower perfusion rate, means drug will move out back into the venous supply more gradually.
- This will be removed from the lungs in a first order manner, but it is also free to redistribute around the body during circulation and gain entry back into the CNS.
- The levels achieved during this recovery phase can still very markedly affect conscious function. The duration of recovery is directly related to the length of procedure and the degree of loading of the muscle and fat compartments with anaesthetic agent.
Describe Main Intravenous Anaesthetics
Propofol (rapid), Barbiturates (rapid), Ketamine (slower).
Given intravenously for ‘induction’.
- Can be used as sole anaesthetic in TIVA (Total IntraVenous Anaesthesia). TIVA uses a defined PK based algorithm to infuse at a rate to maintain set point. Pre-ceded by a bolus.
Target sites as for inhalational
With exception of Ketamine (NMDA), all potentiate GABA(A).
Systems target as for inhalational
Intravenous anaesthetic potency is described as the plasma concentration to achieve a specific end point (loss of eyelash reflex or a bispectral index (BIS) value etc).
For induction in mixed anaesthesia – bolus to end point then switch to volatile.
Induction of anaesthetic depth sufficient for surgery with inhalational agents alone would take a number of minutes. In contrast, use of an intravenous agent, most commonly propofol, can result in sufficient anaesthetic depth within 20 seconds. This also bypasses the confusion of ‘excitement/aggression’ during stage II of anaesthetic depth.
However, use of IV agents requires further vigilance as their dose related effects are not easily reversed once administered. Their use is further complicated by a two stage distribution profile as the drugs move between tissue compartments served by different rates of vascular supply.
Describe the ADME of Propofol
Propofol: administration (absorption) and distribution
- An IV bolus in the arm results in rapid distribution to the well supplied CNS with proportionately lower distribution to the muscle and fat compartments. In contrast, with fluranes, protein binding is very high at 98%. Therefore its free plasma levels may be affected by other drugs that compete for the same binding sites.
- Propofol redistributes rapidly from the CNS to the other compartments
- With single dosing for induction, surgical anaesthesia is maintained for about 5 minutes. The depth then diminishes as drug in the CNS compartment begins to redistribute throughout the circulation into the muscle and fat compartments that have a much larger capacity for lipophilic drugs described earlier.
- Further supplementary dosing by bolus or infusion may be given if the anaesthetist is using propofol as an adjunct in order to lower the flurane MAC. It can also be used alone for surgical procedures of short duration of about 20-30 minutes.
Metabolism and elimination
- Unlike the fluranes, propofol is unusual in that it undergoes hepatic and extrahepatic conjugation. These results in a half-life of about 2 hours. This elimination means it does not contribute to a prolonged post procedural ‘hangover’ during recovery.
Describe the pharmacodynamics of Inhibitory LGIC
Inhibitory LGIC Pharmacodynamics – Increased Ligand Potency and Efficacy
Experimentally, these anaesthetics potentiating the effects of GABA and Glycine, appear to act in a similar fashion at their respective LGIC sites. When plotted on a graph, they act to decrease the concentration of the EC50 which measures potency.
This means a lower level of GABA or Glycine is needed to produce the same effect. Therefore the anaesthetic acts to increase the potency of GABA or Glycine.
They also act to increase the relative efficacy of GABA or Glycine, so that binding at any one channel, more Chloride current is allowed to flow. This may reflect a stabilising effect of the anaesthetic on the ‘open’ state of the channel.
Pharmacodynamically, this effect is known as Positive Allosteric Modulation.
Allosteric means it acts at a separate site to the main receptor ligand sites – in this case GABA and Glycine. It is positive because it increases the efficacy of the neurotransmitter.
Describe the pharmacodynamics of Excitatory LGICs
Excitatory LGIC Pharmacodynamics: Unchanged Potency and Decreased Efficacy
In contrast, the experimental evidence for pharmacodynamics action at Excitatory LGICs such as N Ach and NMDA is that the EC50 or potency, stays unchanged.
However, efficacy of the excitatory ligand decreases – this is typical of non-competitive allosteric antagonists.
The non-competitive effect means that once bound by the anaesthetic antagonist, it inactivates the receptor. The reduced pool of bound anaesthetic receptors results in reduced efficacy but the ligand binding affinity of the remaining unbound receptors is unchanged.
This means that the overall effect of the anaesthetics at these receptors is to reduce inward movement of excitatory currents.
What is meant by Synergistic Interactions? When would you typically use Benzodiazepines?
- In much surgery, especially over an extended period, a number of adjuvant drugs are required to produce an effective and balanced anaesthesia. Individual agents usually have a specific effect on CNS function related to their group.
- These are normally given as adjuvants with one of the fluranes acting as the principal inhalational anaesthetic producing unconsciousness.
Benzodiazepines for inducing anxiolysis and amnesia
- Midazolam is an example from this group that exerts their agonistic effect on GABA(A) receptors.
- The anaesthetist may judge their use appropriate to produce anxiolysis and amnesia.
- They can be given about a hour or so IV prior to surgery as a ‘premed’.
- At acute doses used in surgery, there is normally only a low risk of cardiovascular or respiratory depression. At higher dose levels they produce adequate sedation for short procedures.
When would you use Propofol and Nitrous Oxide?
Propofol for rapid induction of deep initial sedation:
- Propofol is the agent of choice for rapid IV induction of anaesthesia.
- It is often compared to the barbiturates it replaced, but is not chemically related to them.
Nitrous Oxide for analgesia and reducing main inhalational agent MAC
- Nitrous Oxide does not produce sufficient anaesthetic depth on its own but contributes significantly to analgesia via its likely primary action on NMDA receptors.
- Even though much less potent than the fluranes, at alveolar concentrations of 50-70% in combination, it allows for significant reduction in the effective MAC of the flurane.
- Its rapid controlled pulmonary elimination is also highly advantageous in minimising recovery time.
When would you use opioids and neuromuscular blocking agents?
Opioids for analgesia
- Morphine and fentanyl are two opiates commonly used to produce analgesia during surgery. Compared to morphine fentanyl is much more potent (x100) including analgesia almost immediately and acts over 30-60 minutes.
- This allows for finer control of analgesic effect relative to morphine during surgery.
Neuromuscular blocking agents to abolish reflexes and induce muscle relaxation
- These act as either competitive N ACh receptor antagonists such as tubocurarine or pancuronium, or as N ACh receptor depolarising agonists such as succinylcholine.
- These act to abolish normal muscular reflex responses that occur with significantly invasive procedures, which would otherwise dangerously interfere with surgery.
- Via their CNS action fluranes also potentiate neuromuscular relaxation.
What is meant by balanced anaesthesia?
Balanced Anaesthesia is enabled by using agents in combination
The use of a diverse range of agents especially in theatre requires careful monitoring. However, the pharmacological ‘division of labour’ between the drugs mean finer control of anaesthetic depth is available than would be available with just one drug alone.
For example, neuromuscular blockade and pain control can be affected without having to change the MAC and risking more serious side effects by increasing anaesthetic depth.
In addition, it is very useful for the anaesthetist to have inhalational agents whose combined effect is calculated from an additive MAC scale
For example, 50% alveolar Nitrous Oxide is approximately 0.5 MAC, which can be added to the 0.5 MAC of approximately 0.6% alveolar isoflurane. Isoflurane has a MAC approximately 1.2%.
The use of opiates also allows for an additional reduction in MAC as it reduces pain and further reduces risk of cardiovascular depression of the flurane.
What are adverse drug reactions (particularly re general anaesthesia)
There are a wide range of ADRs with anaesthesia, especially when balancing drugs in combination (polypharmacology)
The anaesthetist has a primary aim of minimising these whilst achieving sufficient anaesthetic depth.
The most serious ADR is death, due to CNS depression, although death rates directly attributable to anaesthesia are less than 1 in 100,000 as distinct from the complications from surgery or pre-existing morbidity.
- Post-operative nausea and vomiting (due to opioids)
- CVS – hypotension (common)
- PCOD (cognitive dysfunction) – duration of symptoms increases with increasing age (quite common)
- Chest infection – due to paralysis and immobility.
Local and regional
Depends on the agent used and usually result from systemic spread (locals are Na+ channel blockers so cardiovascular toxicity).
Increased general concern regarding allergic reactions/anaphylaxis
What are the ADRs of Fluranes/
Inhalational anaesthetics - Fluranes
Cardiovascular and respiratory depression arises via decreased neuronal activity in the medullary control centres.
Arrhthymia may also occur along with hypotension due to reduced vascular resistance from a direct effect of anaesthetic on arteriolar smooth muscle, although with normal cardiac output maintained.
Cerebral blood flow increases due to decreased vascular resistance – can lead to increased intracranial pressure.
Bronchodilation is seen with fluranes (which is not an ADR). However, isoflurane and desflurane can act as airway irritants during induction causing coughing and larynogospasm. Malignant hyperthermia (muscle tetany due to massive flurane induced sarcoplasmic Ca2+ release) occurs in a small number of susceptible individuals.
What are the ADRs of Nitrous Oxide?
The different side effects profile of Nitrous Oxide to the fluranes further justifies its use as a major adjunct. These include expansion of airway cavities e.g. sinuses and the middle ear are common or where there is bowel obstruction. This is because as a gas, it enters the alveolar space much faster than Nitrogen. This is dangerous in patients with a pneumothorax, with intracranial air or where vascular air emboli are present.
In recovery, Nitrous Oxide again diffuses very rapidly out of the blood into the alveoli, decreasing alveolar oxygen concentration. This is known as diffusion hypoxia and can be important in patients with compromised respiratory function. This is offset by increasing the partial pressure of inspired oxygen at the onset of recovery when surgery is completed.
What are the ADRs of propofol, benzodiazepines, opioids and non-anaesthetic adverse drug-drug interactions?
Intravenous Anaesthetics - Propofol
- Cardiovascular and respiratory depression via action on medullary control centres.
Benzodiazepines and Opioids
- Respiratory depression
Anaesthesia – Non-Anaesthetic Adverse Drug-Drug Interactions
- There is a very wide range of adverse interactions with many non-anaesthtic therapeutic agents that include markedly enhanced hypotension.
What is meant by Pre-Surgical Review and Peri-Surgical Monitoring?
The anaesthetist is directly responsible for patient assessment before surgery and for monitoring during the operation and over recovery.
Pre-surgical review would include direct assessment of the patient including: their age; BMI; prior medical and surgical history; current medication; history of drug abuse; fasting time; airway assessment.
Peri-Surgical Monitoring: Anaesthetic and adjuvant delivery
Direct control and monitoring of gaseous mixture calculation for % partial pressures of:
The rate of mechanical ventilation is also under anaesthetist control.
Peri-Surgical Monitoring: Systemic Physiological Monitoring
Comprehensive systemic physiological monitoring is carried out for cardiovascular, respiratory and thermoregulatory function.
This includes ECG, BP and pulse oximetry to monitor SpO2 and risk of hypoxaemia.
Expired CO2 is used to assess ventilation state, especially the risk of hypoventilation.
Core temperature drop will occur with prolonged anaesthesia.
It is therefore essential for the anaesthetist to be aware of any fever due to infection and to be able to detect malignant hyperthermia as soon as possible.
EEG monitoring may be used as a further measure of CNS activity and anaesthetic depth. This reduces the risk of under/overdosing and is a further monitor of the efficacy of adjuvant synergy and interaction.
What are the three main stages of anaesthesia?
The 3 main stages of anaesthesia that the anaesthetist oversees are induction, maintenance and recovery.
With induction, propofol is normally administered at the beginning of inhalational delivery.
Adjuvants will also be administered IV.
During maintenance, the anaesthetist keeps the adjuvants in balance to maintain adequate anaesthetic depth. This is likely to oscillate over a time scale of minutes during the operation thus needs regular adjustment to keep the depth within the therapeutic window.
For recovery, the agents are withdrawn and physiological function monitored closely to make sure it can be maintained without support. Antidotes may be given as necessary to facilitate this.
How is anaesthetic depth divided into 4 main stages?
Anaesthetic depth is also divided into 4 main stages.
The first two stages of depth, analgesia and excitement, usually correspond to the induction, the initial stage of management. Analgesia occurs due to early effects on transmission in the spinothalamic tract.
In Stage 2, or ‘excitement’, delirium and aggressive behaviour are experienced. This is now uncommon as induction occurs so rapidly with propofol.
In Stage 3: surgical anaesthesia is attained with profound CNS depression. Skeletal muscles are fully relaxed. Breathing may need to be assisted and cardiac function affected. This is attained with as described with an effective integrated MAC between 1.2-1.5.
The Therapeutic Window for Stage III for the vast majority of individuals is about 1.2-2.2 MAC for isoflurane
Once above this, there is an increasing risk of Stage 4, with severe medullary depression leading to respiratory and cardiac arrest and death. The Therapeutic Index of 4 for specifically for cardiac arrest does not fully convey the individual risk of cardiac or other adverse events. In practice, the anaesthetist must keep within the therapeutic window as far as possible to maintain the low death rate of 1 in 100000 associated with anaesthesia.
What are Guedel's Signs?
Stage 1: analgesia and consciousness, feeling slightly sleepy, breathing normal, muscle tone normal, eye movement slight
Stage 2: unconscious, breathing erratic but delirium could occur leading to excitement phase – muscle tone is normal to markedly increased, moderate eye movement
Stage 3: surgical anaesthesia, with four levels describing increasing depth until breathing weak
Stage 4: respiratory paralysis and death
What is anaesthesia a combination of?
Hypnosis (loss of consciousness)
Depression of spinal reflexes
Muscle relaxation (insensibility and immobility).