Paracetamol is predominantly metabolized in the liver by three main metabolic pathways:
1. Glucuronidation (45-55%)
2. Sulphate conjugation (30-35%)
3. N-hydroxylation via the hepatic cytochrome P450 enzyme system (10-15%)

Cytochrome P450 enzymes catalyse the oxidation of acetaminophen to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI primarily contributes to the toxic effects of acetaminophen. NAPQI is an intermediate metabolite that is further metabolized by fast conjugation with glutathione. The conjugated metabolite is then excreted in the urine as mercapturic acid. High doses of acetaminophen (overdoses) can lead to hepatic necrosis due to depleting glutathione and high binding levels of reactive metabolite (NAPQI) to important parts of liver cells.

Thoracotomy describes an incision made in the chest wall to access the contents of the thoracic cavity. Thoracotomies typically can be divided into two categories; anterolateral thoracotomies and posterolateral thoracotomies. These can be further subdivided into supra-mammary and infra-mammary and, of course, further divided into the right or left chest. Each type of incision has its utility given certain circumstances.

A scalpel is used to sharply divide the skin along the inframammary crease overlying the fifth rib. Electrocautery is then used to divide the pectoralis major muscle and serratus anterior muscle. Visualization of the proper operative field can be achieved with the division and retraction of the latissimus dorsi. Either the fourth or fifth intercostal space is then entered after the division of intercostal muscles above the rib to ensure the preservation of the neurovascular bundle. Once the patient is properly secured to the operating table, the ipsilateral arm is raised and positioned anteriorly and cephalad to rest above the head. The incision is started along the inframammary crease and extended posterolaterally below the tip of the scapula. It is then extended superiorly between the spine and the edge of the scapula, a short distance. The trapezius muscle and the subcutaneous tissues are divided with electrocautery. The serratus anterior and latissimus dorsi muscles are identified and can be retracted. The intercostal muscles are then divided along the superior border of the ribs, and the thoracic cavity is accessed.

Antidiuretic hormone is synthesised in the hypothalamus and transported to the posterior pituitary within nerve fibres where it is stored in secretory granules. ADH binds V2 receptors on renal principal cells in the late distal tubule and collecting ducts, raising cAMP levels and causing intracellular vesicles to fuse with the apical membrane. In their membrane these vesicles have water channels called aquaporins, which increase the water permeability allowing greater water reabsorption and concentration of urine. Excess levels of ADH results in syndrome of inappropriate ADH secretion (SIADH) characterised by hyponatremia with concomitant hypo-osmolality and high urine osmolality.

Juxtapulmonary or ‘J’ receptors are located on alveolar and bronchial walls close to the capillaries. Their afferents are small unmyelinated C-fibres or myelinated nerves in the vagus nerve. Activation causes depression of somatic and visceral activity by producing apnoea or rapid shallow breathing, a fall in heart rate and blood pressure, laryngeal constriction and relaxation of skeletal muscles via spinal neurones. J receptors are stimulated by increased alveolar wall fluid, pulmonary congestion and oedema, microembolism and inflammatory mediators. J receptors are thought to be involved in the sensation of dyspnoea in lung disease.

Plasma theophylline concentration is usually measured five days after starting oral treatment and three days after each dose adjustment.

A blood sample to check theophylline concentration should usually be taken after 4-6 hours if an IV dose of aminophylline was given.

Dietary fat is chiefly composed of triglycerides. In the duodenum fat is emulsified by bile acids, a process where larger lipid droplets are broken down into much smaller droplets providing a greater surface area for enzymatic digestion. Once inside the epithelial cell, lipid is taken into the smooth endoplasmic reticulum where much of it is re esterified. Dietary and synthesised lipids are then incorporated into chylomicrons in the Golgi body, which are exocytosed from the basolateral membrane to enter lacteals. Chylomicrons consist mainly of triglyceride with small amounts of cholesterol and cholesteryl esters in the centre with a phospholipid coat studded with apolipoproteins. Fat-soluble are absorbed into enterocytes from micelles by simple diffusion together with the products of fat digestion.

Haemophilia A is the most common of the hereditary clotting factor deficiencies. The inheritance is sex-linked but up to one-third of patients have no family history and these cases result from recent mutation. The vast majority of cases are inherited in an X-linked recessive fashion, affecting males born to carrier mothers. Females born to affected fathers can also, rarely, be affected due to homozygosity for the gene, where there is marriage to close relatives.

The defect is an absence or low level of plasma factor VIII. The APTT is prolonged but the PT is normal. Recurrent painful haemarthroses and muscle haematomas dominate the clinical course of severely affected patients and if inadequately treated, lead to progressive joint deformity and disability. Local pressure can cause entrapment neuropathy or ischaemic necrosis. Prolonged bleeding occurs after dental extractions or post-trauma. Spontaneous haematuria and gastrointestinal haemorrhage may occur. The clinical severity of the disease correlates inversely with the factor VIII level. Operative and post-traumatic haemorrhage are life-threatening both in severely and mildly affected patients.

The symptoms of median nerve injury include tingling or numbness in the forearm, thumb, and three adjacent fingers, as well as gripping weakness and the inability to move the thumb across the palm.

Because the thenar muscles and the flexor pollicis longus are paralyzed, flexion, abduction, and opposition of the thumb at the MCPJ and IPJ are gone.

Serious hypokalaemia can occur in severe asthma and the effect can be potentiated by concomitant treatment with theophyllines like aminophylline, corticosteroids, thiazide and loop diuretics, and hypoxia. Plasma-potassium concentration should be monitored in severe asthma.

Spironolactone, a potassium-sparing diuretic, is not likely to have contributed to patients hypokalaemia.

Alteplase is a recombinant tissue-type plasminogen activator (tPA), a naturally occurring fibrin-specific enzyme that has selectivity for activation of fibrin-bound plasminogen. It has a short half-life of 3 – 4  minutes and must be given by continuous intravenous infusion but is not associated with antigenic or hypotensive effects, and can be used in patients when recent streptococcal infections or recent use of streptokinase contraindicates the use of streptokinase.

Noradrenaline (the sympathetic neurotransmitter) is a positive inotrope; it binds to β1-adrenoceptors on the membrane and causes increased Ca2+entry via L-type channels during the AP and thus increases Ca2+release from the SR. Noradrenaline also increases Ca2+sequestration into the SR and thus more Ca2+is available for the next contraction. Cardiac glycosides (e.g. digoxin) slow the removal of Ca2+from the cell by inhibiting the membrane Na+pump which generates the Na+gradient required for driving the export of Ca2+; consequently the removal of Ca2+from the myocyte is slowed and more Ca2+is available for the next contraction. Acidosis is negatively inotropic, largely because H+competes for Ca2+binding sites.

The NICE guidelines for women with lower UTIs who are not pregnant are:
1. Consider prescribing a different antibiotic if symptoms do not improve within 48 hours or worsen at any time
2. If the urine culture and susceptibility test results are available, review the choice of antibiotic according to the results and change the antibiotic accordingly if symptoms are not improving or bacteria is resistant to the prescribed antibiotic

The first choice of antibiotics for non-pregnant women aged 16 years and over is:
1. Nitrofurantoin
100 mg modified-release PO BD for 3 days – if eGFR >45 ml/minute
2. Trimethoprim
200 mg PO BD for three days

The second-choice (no improvement in lower UTI symptoms on first-choice for at least 48 hours, or when first-choice is not suitable) are:
1. Nitrofurantoin
100 mg modified-release PO BD for three days – if eGFR >45 ml/minute
2. Pivmecillinam
400 mg PO initial dose, then 200 mg PO TDS for three days
3. Fosfomycin 3 g single sachet dose

Gentamicin is the aminoglycoside of choice in the UK and is used widely for the treatment of serious infections. It has a broad spectrum but is inactive against anaerobes and has poor activity against haemolytic streptococci and pneumococci. When used for the blind therapy of undiagnosed serious infections it is usually given in conjunction with a penicillin or metronidazole (or both). The main toxic effects are nephrotoxicity and ototoxicity due to damage to the vestibulocochlear nerve (CN VIII).

Gentamicin is contraindicated in myasthenia gravis and should be used with caution in renal disease which may result in accumulation and a greater risk of toxic side effects.

Enoxaparin is a low molecular weight heparin (LMWH) that works in the same way as heparin by binding to and activating the enzyme inhibitor antithrombin III. Antithrombin III inactivates thrombin by forming a 1:1 complex with it. Factor Xa and a few other clotting proteases are also inhibited by the heparin-antithrombin III complex.

Antihistamines e.g. cyclizine, are effective against nausea and vomiting caused by many different conditions, including motion sickness and vertigo. These agents act by inhibiting histamine pathways, and cholinergic pathways involved in transmission from the vestibular apparatus to the vomiting centre. There is no evidence that any one antihistamine is superior to another but their duration of action and incidence of adverse effects differ. Adverse effects include drowsiness and antimuscarinic effects such as blurred vision, dry mouth, urinary retention, constipation and confusion.

Benzodiazepines are gamma-aminobutyric acid (GABA) receptor agonists which enhance inhibitory synaptic transmission throughout the central nervous system, with sedative, hypnotic, anxiolytic, anticonvulsant, amnesic and muscle relaxant properties.

The tidal volume(TV) is the amount of air that moves in and out of the lungs with each respiratory cycle. In a healthy male, the usual volume is 0.5 L (,7 ml/kg body mass).

The vital capacity(VC) is the maximum amount of air that can be exhaled following maximal inspiration. The usual volume in a healthy male is 4.5 L.

The residual volume(RV) is the amount of air remaining in the lungs after maximum expiration. The usual volume in a healthy male is 1.0 L.

The inspiratory reserve volume(IRV) is the maximum amount of air that can be breathed in forcibly after normal inspiration. The usual volume in a healthy male is 3.0 L.

The expiratory reserve volume(ERV) is the volume of air that can be breathed out forcibly after normal expiration. The usual volume in a healthy male is 1.0 L.

Total lung capacity(TLC) is the volume of air the lungs can accommodate. TLC = RV+VC. The usual volume in a healthy male is 5.5 L.

Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the growth stage to the mitosis stage. This leads to continuing cell growth without division, which presents as macrocytosis, with an increase in mean corpuscular volume (MCV). The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency.
Folate is an essential vitamin found in most foods, especially liver, green vegetables and yeast. The normal daily diet contains 200 – 250 μg, of which about 50% is absorbed. Daily adult requirements are about 100 μg. Absorption of folate is principally from the duodenum and jejunum. Stores of folate are normally only adequate for 4 months and so features of deficiency may be apparent after this time.

Antiepileptic medications such as carbamazepine (Tegretol), topiramate (Topamax), and phenytoin (Dilantin) are widely known for reducing the contraceptive effectiveness of OCPs.

PPIs should not be used prior to endoscopic therapy when an early endoscopic examination is performed within 24 hours of admission, according to current recommendations.
High-dose PPI therapy reduces the risk of rebleeding and surgery after endoscopic treatment of severe peptic ulcer bleeding. Both oral and intravenous PPIs produce similar results, and there is no discernible benefit to using the intravenous formulation in patients who can tolerate oral medication.

Tetanus is caused by Clostridium tetani, a bacterium. Tetanus can cause mild spasms to severe whole-body contractions, suffocation, and heart attack.

Gas gangrene and food poisoning are both caused by Clostridium perfringens.

Pseudomembranous colitis is caused by Clostridium difficile.

Urinary tract infections, respiratory infections, dermatitis, soft tissue infections, bacteraemia, bone and joint infections, gastrointestinal infections, and a variety of systemic infections are all caused by Pseudomonas aeruginosa.

Pharyngitis, skin infections, acute rheumatic fever, scarlet fever, poststreptococcal glomerulonephritis, toxic shock–like syndrome, and necrotizing fasciitis can all be caused by Streptococcus pyogenes infection.

Gentamicin, an aminoglycoside antibiotic, acts by binding to the 30S subunit of the bacterial ribosome inhibiting the binding of aminoacyl-tRNA, and thus prevents initiation of protein synthesis.

Gentamicin is given by injection because it is NOT absorbed orally.

It is excreted in the kidneys by glomerular filtration

Gentamicin is not to be used for the treatment of Neisseria meningitidis, Neisseria gonorrhoea, or Legionella pneumophila.There is a risk of patient going into shock from lipid A endotoxin release.

Two of its most notable side effects are hearing loss reversible nephrotoxicity and which are both dose-related and levels should be monitored in patients.

When autonomic reflexes are impaired or intravascular volume is markedly depleted, a significant reduction in blood pressure occurs upon standing, a phenomenon termed Postural Hypotension (orthostatic hypotension). Orthostatic hypotension can cause dizziness, syncope, and even angina or stroke. When autonomic reflexes are impaired, blood pressure falls progressively after standing because the gravitational pooling of blood in the legs cannot be compensated by sympathetic vasoconstriction.

The pectoralis minor, in comparison to the pectoralis major, is much thinner and triangular in shape and resides below the major. It originates from the margins of the third to fifth ribs adjacent to the costochondral junction. The fibres consequently pass upward and laterally to insert into the medial border and superior surface of the coracoid process. It is crucial in the stabilization of the scapula by pulling it downward and anteriorly against the thoracic wall.

Arterial supply to the pectoralis minor also derives from the pectoral branch of the thoracoacromial trunk. Nerve supply of the pectoralis minor is a function of the lateral pectoral nerve and the medial pectoral nerve.

The electron transfer system is responsible for most of the energy produced during respiration. The is a system of hydrogen carriers located in the inner mitochondrial membrane. Hydrogen is transferred to the electron transfer system via the NADH2 molecules produced during glycolysis and the Krebs cycle. As a result, a H+ion gradient is generated across the inner membrane which drives ATP synthase. The final hydrogen acceptor is oxygen and the H+ions and O2 combine to form water.

Myosin is the major constituent of the thick filament.

Actin is the major constituent of the THIN filament.

Thin filaments consist of actin, tropomyosin and troponin in the ratio 7:1:1.

In life-threatening emergencies, oxygen should be started immediately otherwise, it should be prescribed like any other drug. The prescription should include a target saturation range.

Until blood gases can be measured, initial oxygen should be administered using a controlled concentration of 24% or 28%.
The ideal mask is a Venturi mask.

The other mask are not ideal for initial use

Blood transfusion can be a life-saving treatment with significant clinical benefits, but it also comes with a number of risks and potential complications, including:
Immunological side effects
Errors in administration (episodes of ‘wrong blood’)
Viruses and Infections (bacterial, viral, possibly prion)
Immunodilution

A culture of better safety procedures as well as steps to reduce the use of transfusion has emerged as a result of growing awareness of avoidable risk and improved reporting systems. Transfusion errors, on the other hand, continue to occur, and some serious adverse reactions go unreported.

Transfusion-associated graft-vs-host disease (TA-GVHD) is a rare blood transfusion complication that causes fever, rash, and diarrhoea 1-4 weeks after the transfusion. Pancytopenia and liver function abnormalities are common laboratory findings.

TA-GVHD, unlike GVHD following allogeneic marrow transplantation, causes profound marrow aplasia with a mortality rate of >90%. Survival is uncommon, with death occurring within 1-3 weeks of the onset of symptoms.

Because of immunodeficiency, severe immunosuppression, or shared HLA antigens, viable T lymphocytes in blood components are transfused, engraft, and react against the recipient’s tissues, and the recipient is unable to reject the donor lymphocytes.
The following is a list of the most common transfusion reactions and complications:

1) Reaction to a febrile transfusion
The temperature rises by one degree from the baseline. Chills and malaise are also possible symptoms.
The most common response (1 in 8 transfusions).
Cytokines from leukocytes in transfused red cell or platelet components are usually to blame.
Only supportive. The use of paracetamol is beneficial.

2) Acute haemolytic reaction is a type of haemolytic reaction that occurs when the
Fever, chills, pain at the transfusion site, nausea, vomiting, and dark urine are all symptoms of a transfusion reaction.
Early on, many people report a sense of ‘impending doom.’
The most serious reaction. ABO incompatibility is frequently caused by a clerical error.
STOP THE TRANSFUSION OF INFORMATION. IV fluids should be given. It’s possible that diuretics will be required.

3) Haemolytic reaction that is delayed
It usually happens 4 to 8 days after a blood transfusion.
Fever, anaemia, jaundice, and haemoglobinuria are all symptoms that the patient has.
Positive Coombs test for direct antiglobulin.
Because of the low titre antibody, it is difficult to detect in a cross-match, and it is unable to cause lysis at the time of transfusion.
The majority of delayed haemolytic reactions are harmless and do not require treatment.
Anaemia and renal function should be monitored and treated as needed.

4) Reaction to allergens
Foreign plasma proteins are usually to blame, but anti-IgA could also be to blame.
Urticaria, pruritus, and hives are typical allergic reactions. It’s possible that it’s linked to laryngeal oedema or bronchospasm.
Anaphylaxis is a rare occurrence.
Antihistamines can be used to treat allergic reactions symptomatically. It is not necessary to stop transfusions.
If the patient develops anaphylaxis, the transfusion should be stopped and the patient should be given adrenaline and treated according to the ALS protocol.

5) TRALI (Transfusion Related Acute Lung Injury)
Within 6 hours of transfusion, there was a sudden onset of non-cardiogenic pulmonary oedema.
It’s linked to the presence of antibodies to recipient leukocyte antigens in the donor blood.
The most common cause of death from transfusion reactions is this.
STOP THE TRANSFUSION OF INFORMATION. Oxygen should be given to the patient. Around 75% of patients will require aggressive respiratory support.
The use of diuretics should be avoided.

6) TACO (Transfusion Associated Circulatory Overload)
Acute or worsening respiratory distress within 6 hours of a large blood transfusion. Fluid overload and pulmonary and peripheral oedema can be seen. Rapid blood pressure rises are common. BNP is usually 1.5 times higher than it was before the transfusion. It is most common in the elderly and those who have chronic anaemia.

Blood transfusions should be given slowly, over the course of 3-4 hours.

Calcium deficiency (low Ca2+ diet or hypocalcemia) activates 1-alpha-hydroxylase in the cells of the renal proximal tubule which catalyses the conversion of vitamin D to its active form, 1,25-dihydroxycholecalciferol. Increased parathyroid hormone (PTH) and hypophosphatemia also stimulate the enzyme. Chronic renal failure is associated with a constellation of bone diseases, including osteomalacia caused by failure of the diseased renal tissue to produce the active form of vitamin D.

Hyperaemia is the process where the body adjusts blood flow to meet the metabolic needs of different tissues in health and disease. Vasoactive mediators that take part in this process include K+, adenosine, CO2, H+, phosphates and H2O2. Although the mechanism is not clear, all these mediators likely contribute to some extent at different points.

Specific organs are more sensitive to specific metabolites:
K+ and adenosine are the most potent vasodilators in skeletal muscles

CO2 and K+ are the most potent vasodilators in cerebral circulation.