Session 8: Anticoagulants, Antiplatelets, Thrombolytic Therapy and Anaesthetics Flashcards
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
- Hypertension
- 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?
Adverse effects:
- 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?
Initiation
Indication
Personal medical history e.g. peptic ulcer disease, subarachnoid haemorrhage, bleeding disorder
Medications (interactions)
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?
- Interactions
- 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!
Consider:
- Bleeding, INR, indication
- Mechanical valve call cardiologist
Agents:
- 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)
Elective 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
Bleeding/bruising
- Haemorrhage intracranially, at injection sites, at GI sites or epistaxis
Thrombocytopenia
- 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:
Unfractionated heparin:
- Loading dose then IV infusion (to maintain level as half life is quite short) (few hours)
- Monitor APTT
LMWH
- 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.
Describe streptokinase
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.
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 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
Cocaine archetypal
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)
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.
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)
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.
How is MAC determined?
Age (high in infants, lower in elderly)
Hyperthermia (increased); hypothermia (decreased)
Pregnancy (increased)
Alcoholism (increased)
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)
Opioids (decreased)
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
