Sodium-chloride symporter inhibitor.

The thiazide sensitive sodium chloride symporter is inhibited by thiazides at the proximal portion of the distal convoluted tubule leading to increased sodium and water excretion. Increased delivery of sodium to the distal portion of the distal convoluted tubule promotes potassium loss. This is why thiazides are associated with hyponatraemia and hypokalaemia.

Carbonic anhydrase inhibitors are used mainly in the treatment of glaucoma. They act on the proximal convoluted tubule to promote bicarbonate, sodium and potassium loss.

Sodium potassium chloride symporter is inhibited by Loop diuretics.
Epithelial sodium channels are inhibited by Amiloride.
Drugs which lead to nephrogenic diabetes insipidus such as lithium and demeclocycline, are Inhibitors of vasopressin.

The respiratory quotient (RQ) is the proportion of CO2 produced by the body to O2 consumed per unit of time.

CO2 produced / O2 consumed = RQ

CO2 is produced at a rate of 200 mL per minute, while O2 is consumed at a rate of 250 mL per minute. An RQ of around 0.8 is typical for a mixed diet.

The RQ will change depending on the energy substrates consumed in the diet.

Granulated sugar is a refined carbohydrate that contains 99.999 percent carbohydrate and no lipids, proteins, minerals, or vitamins.

Glucose and other hexose sugars – RQ = 1
Fats – RQ = 0.7
Proteins – RQ is 0.9
Ethyl alcohol – RQ = 0.67

The diaphragm has three opening through which different structures pass from the thoracic cavity to the abdominal cavity:

Inferior vena cava passes at the level of T8.

Oesophagus, oesophageal vessels and vagi at T10.

Aorta, thoracic duct and azygous vein through T12.

Sympathetic trunk and pulmonary branches of vagus nerve form a posterior pulmonary plexus at the root of the lung. Fibres continue posteriorly from superficial cardiac plexus to form Anterior pulmonary plexus. It contains vagi nerves and superficial cardiac plexus. These fibres then follow the blood vessel and bronchi into the lungs.

The lower border of the pleura is at the level of:

8th rib in the midclavicular line

10th rib in the lower level of midaxillary line

T12 at its termination.

Both lungs have oblique fissure while right lung has transverse fissure too.

The trachea expands from the lower edge of the cricoid cartilage (at the level of the 6th cervical vertebra) to the carina.

Exposure to anaesthetic hazards is one among the occupational exposures in manipulating toxic agents or inhaling toxic gases during anaesthetic practices.

Toxic gases mainly nitrous oxide, is one of the most gaseous anaesthetic agents that constitutes an important source of pollution. One of the safe and effective technics used in anaesthesia and reducing the amount of pollution is the Total Intravenous Anaesthesia (TIVA) which consists of using opioids in analgesia and propofol for the induction and the maintenance of anaesthesia. It refers to the administration intravenously of an anaesthetic, sedative, and/or tranquilizer. A less polluting but not the best way to get rid of the toxic aesthetic agents is the scavenger system that collects and expels the gas outside the medical environment. Yet, this technique still represents a hazard for the environment and still increase the risk of exposure for the health workers and clinical staff.

Fume cupboards are also not recommended to use because of their high pollution potency, mainly of the air resulting in a great harm for medical workers.

Supraglottic airways as well as the Air Changes per Hour technics could be harmful for both patients and health workers, increasing the risks of transmitted diseases, namely nosocomial infections.

Therefore, the Total Intravenous Anaesthesia technique (TIVA) is most likely to be safe and recommended to use.

The mechanism of action of macrolides is inhibition of bacterial protein synthesis by preventing peptidyltransferase from adding to the growing peptide which is attached to tRNA to the next amino acid.

The drug of choice for the treatment of anaphylaxis is adrenaline. It has an intravenous route of administration. Since the patient already has intravenous access, the intramuscular route is not appropriate.

Second-line pharmacological intervention includes the use of chlorpheniramine 10mg intravenous, Hydrocortisone 200mg.

The basilic vein is one of the primary veins that drain the upper limb, like the cephalic vein. It begins as the dorsal venous arch. The basilic vein originates from the ulnar side of the dorsal arch of the upper limb passes along the posteromedial aspect of the forearm, moving towards the anterior surface of the elbow.

The basilic vein pierces the deep fascia at the elbow and joins the venae commitantes of the brachial vein to form the axillary vein.

The basilic vein passes deep under the muscles as it moves midway up the humerus. At the lower border of the teres major muscle, the anterior and posterior circumflex humeral veins feed into it.

A beta-1 adrenoreceptor agonist is most likely the ligand that causes increased automaticity, increased chronotropy, increased excitability, and increased inotropy on the sino-atrial node. However, alpha-1 adrenoreceptor effects may cause an increase in systemic vascular resistance. Noradrenaline, adrenaline, dopamine, and ephedrine are examples of drugs with mixed alpha and beta effects.

Adrenaline, noradrenaline, dopamine, dopexamine, dobutamine, ephedrine, and isoprenaline are examples of drugs that have some beta-1 activity. The beta-1 receptor is a G protein-coupled metabotropic receptor. When the beta-1 agonist binds to the cell surface membrane, it causes a conformational change in the Gs unit, which triggers a cAMP-dependent pathway and a calcium influx into the cell.

Catecholamines also help to relax the heart muscle (positive lusitropy). Dromotropy is the ability to increase the atrioventricular (AV) node’s conduction velocity.

Inodilators cause an increase in intracellular calcium as a result of phosphodiesterase III (PDIII) inhibition. Milrinone, enoximone, and amrinone are some examples. Positive inotropy is caused by increased calcium entry into the myocytes. Lusitropy is also increased by phosphodiesterase inhibitors. Increased cAMP inhibits myosin light chain kinase, resulting in reduced phosphorylation of vascular smooth muscle myosin, lowering systemic and pulmonary vascular resistance.

The mechanism of action of alpha-1 adrenoreceptor agonists is an increase in intracellular calcium caused by an increase in inositol triphosphate (IP3). IP3 is a second messenger that causes an increase in systemic vascular resistance by stimulating the influx of Ca2+ into smooth muscle cells. Reflex bradycardia can occur as a result of the subsequent increase in blood pressure. Phenylephrine and metaraminol are examples of pure alpha-1 agonists.

Levosimendin is a novel inotrope that makes myocytes more sensitive to intracellular Ca2+. It causes a positive inotropy without changing heart rate or oxygen consumption significantly.

The Na-K-ATPase membrane pump in the myocardium is inhibited by digoxin. This inhibition promotes sodium-calcium exchange, resulting in an increase in intracellular Ca2+ and increased contraction force. The parasympathetic effects of digoxin on the AV node result in bradycardia. Systemic vascular resistance will not be affected by it.

There are 4 different types of globin chains which surround 4 heme molecules in haemoglobin (Hb) – α (alpha), β (beta), γ (gamma), and δ (delta)
α chains are essential.
δ2β2 and β2γ2 are not found in a healthy adult.
97% of the Hb in a healthy adult is made of α2β2 (2 α chains and 2 β chains).
α2δ2 accounts for around 1.5-3% of the adult Hb.
α2γ2 accounts for less than 1%.

With respect to oxygen transport in cells, almost all oxygen is transported within erythrocytes. There is limited solubility and only 1% is carried as solution. Thus, the amount of oxygen transported depends upon haemoglobin concentration and its degree of saturation.

Haemoglobin is a globular protein composed of 4 subunits. Haem is made up of a protoporphyrin ring surrounding an iron atom in its ferrous state. The iron can form two additional bonds – one is with oxygen and the other with a polypeptide chain. There are two alpha and two beta subunits to this polypeptide chain in an adult and together these form globin. Globin cannot bind oxygen but can bind to CO2 and hydrogen ions. The beta chains are able to bind to 2,3 diphosphoglycerate. The oxygenation of haemoglobin is a reversible reaction. The molecular shape of haemoglobin is such that binding of one oxygen molecule facilitates the binding of subsequent molecules.

Such a high rise of end-tidal CO2 (EtCO2) in a patient who is spontaneously breathing is often encountered.

Close observation should occur for further rises in EtCO2 and other signs of malignant hyperthermia. If this were to rise even more, it might be wise to ensure that ventilatory support is available.

A lot would depend on whether surgery was almost completed. At this stage of anaesthesia, it would be inappropriate to administer opioid antagonists or respiratory stimulants.

The blood vessel well is divided into 3 parts, namely:

The tunica intima, which is the deepest layer. It contains endothelial cells separated by gap junctions

The tunica media, primarily consisting of the involuntary smooth muscle fibres, laid out in spiral layers with elastic fibres and connective tissue.

The tunica adventitia, which is the most superficial layer. It consists of the vasa vasorum, fibroblast and collagen.

Using a lean body weight metric encompasses a more scientific approach to weight-based dosing. Lean body weight reflects the weight of all ‘non-fat’ body components, including muscle and vascular organs such as the liver and kidneys. As lean body weight contributes to approximately 99% of a drug’s clearance, it is useful for guiding dosing in obesity.

This metric has undergone a number of transformations. The most commonly cited formula derived by Cheymol is not optimal for dosing across body compositions and can even produce a negative result. A new formula has been developed that appears stable across different body sizes, in particular the obese to morbidly obese.

A practical downfall of the calculation of lean body weight (and other body size descriptors) is the numerical complexity, which may not be palatable to a busy clinician. Often limited time is available for prescribing and an immediate calculation is required. Lean body weight calculators are available online, for example in the Therapeutic Guidelines.

Using total body weight assumes that the pharmacokinetics of the drug are linearly scalable from normal-weight patients to those who are obese. This is inaccurate. For example, we cannot assume that a 150 kg patient eliminates a drug twice as fast as a 75 kg patient and therefore double the dose. Clinicians are alert to toxicities with higher doses, for example nephro- and neurotoxicity with some antibiotics and chemotherapeutics, and bleeding with anticoagulants. Arbitrary dose reductions or ‘caps’ are used to avoid these toxicities, but if too low can result in sub-therapeutic exposure and treatment failure.

Body surface area is traditionally used to dose chemotherapeutics. It is a function of weight and height and has been shown to correlate with cardiac output, blood volume and renal function. However, it is controversial in patients at extremes of size because it does not account for varying body compositions. As a consequence, some older drugs such as cyclophosphamide, paclitaxel and doxorubicin were ‘capped’ (commonly at 2 m^2) potentially resulting in sub-therapeutic treatment. Recent guidelines suggest that unless there is a justifiable reason to reduce the dose (e.g. renal disease), total body weight should be used in the calculation of body surface area, until further research is done. Little research into dosing based on body surface area has been conducted for other medicines.

Ideal body weight was developed for insurance purposes not for drug dosing. It is a function of height and gender only and, like body surface area, does not take into account body composition. Using ideal body weight, all patients of the same height and sex would receive the same dose, which is inadequate and generally results in under-dosing. For example a male who has a total body weight of 150 kg and a height of 170 cm will have the same ideal body weight as a male who is 80 kg and 170 cm tall. Both could potentially receive a mg/kg dose based on 65 kg (ideal body weight).

In statistical terms, correlation is used to denote association between two quantitative variables.

The degree of association is measured by a correlation coefficient, denoted by r. The correlation coefficient is measured on a scale that varies from + 1 through 0 to – 1. Complete correlation between two variables is expressed by either + 1 or -1. When one variable increases as the other increases the correlation is positive; when one decreases as the other increases it is negative. Complete absence of correlation is represented by 0.

The two methods are not synonymous as correlation measures the degree of relationship between two variables whereas regression analysis is about how one variable affects another or what changes it has on the other variable. Both are also shown by a different graphical representation.

After the carotid body, the thyroid gland is the second most richly vascular organ in the body.

The global blood flow to the thyroid gland can be measured using:
1. Colour ultrasound sonography
2. Quantitative perfusion maps using MRI of the thyroid gland using an arterial spin labelling (ASL) method.

This table shows the blood flow to various organs of the body at rest:
Organ Blood Flow(ml/minute/100g)
Hepatoportal 58
Kidney 420
Brain 54
Skin 13
Skeletal muscle 2.7
Heart 87
Carotid body 2000
Thyroid gland 560

Mesenteric ischemia is ischemia of the blood vessels of the intestines. It can be life-threatening, especially if the small intestine is involved.

The inferior mesenteric artery originates 3-4 cm above the bifurcation of the abdominal aorta.
The left colic artery branches off the inferior mesenteric artery to supply the following:
– distal 1/3 of the transverse colon
– descending colon

At approximately the left colic flexure (splenic flexure), a transition occurs in the blood supply of the GI tract. The SMA supplies the proximal part to the flexure, and the IMA supplies the part distal to the flexure. This is why the left colic flexure is a watershed area and is prone to ischemia exacerbated by atherosclerotic changes or hypotension. The dominant arterial supply of the splenic flexure is usually from the left colic artery, but it may also get collaterals from the left branch of the middle colic artery.

The AMA and PMA do not exist.
The splenic artery directly supplies the spleen and has branches that supply the stomach and the pancreas.
The proximal two-thirds of the transverse colon is supplied by the middle colic artery, a branch of the SMA.

Femoral nerve lesion (L2,L3 and L4) is characterised by weakness of the quadriceps femoris muscle. This results in weakness of extension of the knee, loss of sensation over the front of the thigh, and loss of the knee jerk reflex.

The skin over the lateral aspect of the thigh and knee, and the lower lateral quadrant of the buttock is supplied by the lateral cutaneous nerve of the thigh (L1,2).

The adductors of the hip are supplied by the obturator nerve (L2-4). This nerve also supplies sensation to the inner thigh.

The thyroid gland is a gland shaped like a butterfly which lies at the base of the anterior neck. It controls metabolism using hormone secretion.

Iodine is extremely important for the synthesis of hormones within the thyroid. It is internalised into the thyroid follicular cells via the sodium/iodide symporter (NIS).

The parathyroid glands are found posterior to the thyroid gland, with the recurrent laryngeal nerves running posteromedially.

The expected weight of a normal thyroid gland is about 30 grams.

Triiodothyronine (T3) is more potent than thyroxine (T4). It is able to bind to more receptors (90%) compared to T4 (10%), and the onset of action is more immediate (within 12 hours) than T4 (2 days).

Ninety-three percent of thyroid hormones synthesized is T4, and the remaining 7% is T3. The half-life of T3 is shorter (1 day), and its affinity for thyroxine-binding globulin is lower than T4.

Prostacyclin is a strong vasodilator. It is administered as an intravenous infusion for critical ischemia. Commercially, it is available as sodium epoprodtenol.

Atrial Natriuretic peptide (ANP) hormone secreted from the atria, kidney, and neural tissues. It primarily acts on renal vessel to maintain normal blood pressure and reduce plasma volume by: increasing the renal excretion of salt and water, glomerular filtration rate, vasodilation, and by increasing the vascular permeability. It also inhibits the release of renin and aldosterone.

Indoramin is an alpha-adrenoceptor blocking agent. which act selectively on post-synaptic-alpha adrenoreceptor, leading to decease in peripheral resistance.

Angiotensin II is a vasoconstrictor, causing high sodium retention. It also increases the secretion of antidiuretic hormone (ADH) and aldosterone level.

This patient’s limited haematological profile includes mild normocytic anaemia and a normal platelet count.

Iron deficiency is the most common cause of anaemia during pregnancy. It affects 75 to 95 percent of patients. A haemoglobin level of less than 110 g/L in the first trimester and less than 105 g/L in the second and third trimesters is considered anaemia. There will usually be a low mean cell volume (MCV), mean cell haemoglobin (MCH), and mean cell haemoglobin concentration in addition to a low haemoglobin (MCHC). The MCV may be normal in mild cases of iron deficiency or coexisting vitamin B12 and folate deficiency.

To determine whether you have an iron deficiency, you’ll need to take more tests. Low serum ferritin (15 g/L) and less reliable indices like serum iron and total iron binding capacity are among them.

A number of factors contribute to iron deficiency in pregnancy, including:

Insufficient dietary iron to meet the mother’s and foetus’ nutritional needs
Multiple pregnancies
Blood loss, as well as
Absorption of iron from the gut is reduced.

The volume of plasma increases by about 50% during pregnancy, but the mass of red blood cells (RBCs) increases by only 30%. Dilutional anaemia is the result of this situation. From the first trimester to delivery, the RBC mass increases linearly, while the plasma volume plateaus, stabilises, or falls slightly near term. As a result, between 28 and 34 weeks of pregnancy, haemoglobin concentrations are at their lowest. The effects of haemodilution will be negated in this patient because she is 37 weeks pregnant.

Vitamin B12 and folate deficiency are less common causes of anaemia in pregnancy. The diagnosis could be ruled out if the MVC is normal.

During pregnancy, the platelet count drops, especially in the third trimester. Gestational thrombocytopenia is the medical term for this condition. It’s due to a combination of factors, including haemodilution and increased platelet activation and clearance. Pre-eclampsia and HELLP syndrome are common causes of thrombocytopenia. Pre-eclampsia isn’t the only cause of anaemia during pregnancy.

A typical blood picture of a haemoglobinopathy like sickle cell disease shows quantitative and qualitative defects, with the former leading to a severe anaemia exacerbated by haemodilution and other factors that contribute to iron deficiency. Microcytic cells are the most common type.

Among the types of muscles, cardiac muscles have the greatest number if mitochondria due to the heart energy requirements.

Approximately 35% of the cardiac muscle volume is due to the mitochondria. While in skeletal and smooth muscles, it comprises 3-8% of the muscle volume.

Type I muscle fibre has a slow contraction velocity, with a red fibre colour, and predominantly uses oxidative phosphorylation to produce a sustained contraction. It contains more mitochondria and myoglobin than type II, and is often used for endurance training.

Type II muscle fibre has a fast contraction velocity, a white fibre colour, and predominantly uses anaerobic glycolysis. It has fewer mitochondria and myoglobin, and is often used for weight or resistance training and sprinting.

Coronary perfusion pressure(CPP), the difference between aortic diastolic pressure (Pdiastolic) and the left ventricular end-diastolic pressure (LVEDP), is mainly determined by the formula:

CPP = Pdiastolic -LVEDP
where
Pdiastolic is the lowest pressure in the aorta before left ventricular ejection and
LVEDP is measured directly during a cardiac catheterisation or indirectly using a pulmonary artery catheter. The pulmonary artery occlusion or wedge pressure approximates best with LVEDP.

Using this patient’s haemodynamic data:

CPP = Pdiastolic – MPAWP
COO = 70 – 12 = 58mmHg

Second messengers relay signals to target molecules in the cytoplasm or nucleus when an agonist interacts with a receptor on the cell surface. They also amplify the strength of the signal. The most ubiquitous and abundant second messenger is calcium and it regulates multiple cellular functions in the body.

These include:
Muscle contraction (skeletal, smooth and cardiac)
Exocytosis (neurotransmitter release at synapses and insulin secretion)
Apoptosis
Cell adhesion to the extracellular matrix
Lymphocyte activation
Biochemical changes mediated by protein kinase C.

cAMP is either inhibited or stimulated by G proteins.

The receptors in the body that stimulate G proteins and increase cAMP include:

Beta (?1, ?2, and ?3)
Dopamine (D1 and D5)
Histamine (H2)
Glucagon
Vasopressin (V2).

The second messenger for the action of nitric oxide (NO) and atrial natriuretic peptide (ANP) is cGMP.

The second messengers for angiotensin and thyroid stimulating hormone are inositol triphosphate (IP3) and diacylglycerol (DAG).

Gabapentin is an amino acid-like molecules that was originally synthesized as an analogue of GABA but is now known not to act through GABA mechanisms. It is used in the treatment of focal seizures and various nonepilepsy indications, such as neuropathic pain, restless legs syndrome, and anxiety disorders.

Despite its close structural resemblance to GABA, gabapentin does not act through effects on GABA receptors or any other mechanism related to GABA-mediated neurotransmission. Rather gabapentin binds avidly to ?2?, a protein that serves as an auxiliary subunit of voltage-gated calcium channels. Moreover, it binds to NMDA receptor to modulate its transmission.

Closing capacity refers to volume of gas within the lungs at which the conducting small airways begin to close, that is, the point during expiration when small airways close.

It is calculated mathematically as:

Closing capacity = Closing volume (CV) + Residual volume (RV)

Functional residual capacity (FRC) is the volume of gas still present within the lungs post expiration.

Closing capacity is lower than the functional residual capacity in younger adults, but begins to rise to eventually equal, and then exceed it with increasing age (at about middle age), increasing intrabdominal pressure, decreasing blood flow in the pulmonary system and parenchymal disease within the pulmonary system.

The standard error of the mean (SEM) is a measure of the spread expected for the mean of the observations – i.e. how ‘accurate’ the calculated sample mean is from the true population mean. The relationship between the standard error of the mean and the standard deviation is such that, for a given sample size, the standard error of the mean equals the standard deviation divided by the square root of the sample size.

SEM = SD / square root (n)

where SD = standard deviation and n = sample size

Therefore, the SEM gets smaller as the sample size (n) increases.

If we want to depict how widely scattered some measurements are, we use the standard deviation. For indicating the uncertainty around the estimate of the mean, we use the standard error of the mean. The standard error is most useful as a means of calculating a confidence interval. For a large sample, a 95% confidence interval is obtained as the values 1.96×SE either side of the mean.

A 95% confidence interval:

lower limit = mean – (1.96 * SEM)

upper limit = mean + (1.96 * SEM)

Results such as mean value are often presented along with a confidence interval. For example, in a study the mean height in a sample taken from a population is 183cm. You know that the standard error (SE) (the standard deviation of the mean) is 2cm. This gives a 95% confidence interval of 179-187cm (+/- 2 SE).

Hence, it would be wrong to say that confidence levels do not apply to standard error of the mean.

The basilar artery is a large vessel that is formed by the union of the vertebral arteries at the junction of the medulla and pons. It lies in the pontine cistern and follows a shallow groove on the ventral pontine surface, extending to the upper border of the pons.

The basilar artery then bifurcates into the two posterior cerebral arteries that form part of the Circle of Willis.