Treatments & Drugs

After a differential diagnosis, medical intervention is necessary in most cases; this is to aid the body in regaining optimal, or at least close to optimal, health and allowing for homeostatic mechanisms to efficiently be resumed, thus keeping the patient alive and well. Courses of treatment vary in nature, intensity, and timespan according to the diagnosis and prognosis of a patient. Sometimes, chronic health conditions are managed by simply providing palliative care - for example, when a patient presents with an inoperable, malignant tumor. Though medical advancement has been exponential, there are still several diseases and disorders that have no cure, thus requiring only symptomatic treatment.

This page aims to investigate the many courses of treatment - pharmacotherapy, surgical, radiation, and movement therapy - for a wide spectrum of diseases and disorders. It is noteworthy that a lot of these treatments are not used in isolation. The information is derived from secondary sources, as well as anecdotal experience which allows further insight into certain procedures. Having the opportunity to shadow surgeons allows for great practical learning, and this page compiles that very gathered knowledge.

The explained treatments and drugs are of all kinds - ranging from the action of paracetamol tablets to open-heart surgery, so scroll to whichever you find the most interesting (and not overwhelming, of course).

CABG - Coronary Artery Bypass Graft

A Beating Heart Surgery

This surgical procedure, described as the 'bread and butter of a cardiac surgeon', refers to the redirection of blood within the coronary arteries of the heart. The coronary arteries are responsible for providing the heart with a supply of oxygenated blood and nutrients to ensure it continues its pumping function with as much accuracy as possible.

The coronary arteries consist of - the right coronary artery and the right acute marginal artery towards the right side of the heart, and the left coronary artery, the circumflex artery, the left obtuse marginal artery, the left anterior descending artery which then branches into the diagonal arteries (D1 and D2). The names parallel the arteries' placement, which makes them considerably easy to differentiate. A greater number of arteries are present towards the left as it is larger and more muscular than the right, and also pumps blood with great pressure to the rest of the body. A diagram of the same is provided in Image 1.

The surgical procedure - an off-pump coronary artery bypass graft - as the name suggests, clears the path of blocked / partially blocked arteries and ensures oxygen-rich blood reaches all the parts of the heart - especially its primary pumping chamber; the left ventricle that is supplied by the main left coronary artery. 'Off-pump' means that a heart-lung / cardiopulmonary machine is not used, thus the heart can continuing beating and providing blood to the body, with its circulation function remaining intact rather than being passed onto a machine. This 'off-pump' approach is comparatively new as traditional open-heart procedures lay preference to using the heart-lung machine that takes over the heart-lung function. As the heart continues beating, a stabilization system is used during the operation. This consists of a heart positioner and tissue stabilizer. "The heart positioner guides and holds the heart in a position that provides the best access to the blocked arteries. The tissue stabilizer holds a small area of the heart still while a surgeon works on it."

A surgical procedure is often the last resort of severe CHD - Coronary Heart Disease when oral medication, lifestyle changes. or angioplasty cannot solve the problem. This is a potentially fatal condition where the heart's coronary arteries collect plaque (solids made of an accumulation of calcium, fat, cholesterol, fibrin and, other cellular wastes). This collection of arterial plaque in the arteries (not just the coronary arteries) is known as atherosclerosis, i.e. the hardening of the arteries.

The surgery begins with giving the patient general anesthesia and applying a coat of Betadine (an iodine-based antiseptic) over the patient's chest. Then a midline incision over the sternum is created with a scalpel. "The skin incision should extend from just below the sternal notch to a few centimeters below the xiphoid process", labeled in Image 3. Then the subcutaneous tissue and pectoral fascia are cauterized, using a surgical cautery through the vertical center of the sternum. The cautery ensures no excessive bleeding as potential bleeders (the capillaries) are closed off due to the intense heat. The next part refers to a bone saw being used to crack the sternum; the procedure is called an osteotomy. Here, the anesthesiologist stops ventilation so the pleura does not accidentally open. Lastly, a cellulose towel (degradable within the body) is placed between the sternal edges and the pericardium to reduce bleeding. The sum of these steps is known as a midline sternotomy. This provides the surgeon with a wide view of the thoracic cavity and access to both pleural spaces.

The vein/artery graft is being prepared in the meantime. The most common vein grafts are derived from the saphenous vein in the leg. The most common artery grafts are from the inside of the chest wall, known as the internal mammary arteries; if not, the radial arteries in the arms are used. These vessels are seen in Image 4. These grafts are harvested, simply put, by - the application of Betadine, a few inches long cut using a scalpel (varies on the type of graft), and cauterization of subcutaneous tissue and nearby capillaries to the main graft vessel. In places where cauterization does not work, vascular clips tie off bleeders; this is known as blood vessel ligation. The graft vessel (for example, the saphenous vessel seen in Image 5) is carefully detached from each connecting vessel and put in a saline solution.

Vein and artery grafts are connected to different parts of the heart in accordance with the coronary artery impacted by CHD. This is further explained in Image 6 below.

The bypass procedure is then conducted as the anesthesiologists keep a check on the patient's breathing, blood pressure, heart rate, electrolytes, and other vital signs. A sternal retractor, as seen in Image 7, ensures enough space and visibility for the surgery to be performed. The grafted vein/artery is sewed onto the cardiac muscle and an anastomosis is created. Such technique requires great care, patience, and dexterity. 'Most anastomotic techniques for CABG surgery are continuous sutures using polypropylene monofilaments. For bypass grafting to small coronary arteries, it may be difficult to achieve patency with continuous sutures in anastomotic sites of the target coronary artery and graft. Three stitches anchoring the graft at each end of the coronary arteriotomy can guarantee patency of the proximal and distal coronary arterial lumens.' This states that graft will stay in place and can take over, i.e. bypass, the function of the blocked coronary artery/arteries. The graft's patency is checked by releasing the clamp tying off the graft from supplying the heart and then pumping saline through it to ensure no leaks. In all simplicity, this means the anastomosis is holding and the bypass, barring further complications, is successful.

The closure of the thoracic cavity is a series of steps that begins with the insertion of chest tubes (mediastinal and pleural), via stab incisions, to drain excess fluid and/or air in the chest cavity; this is so that further complications do not occur (for example, the lungs collapsing due to excess fluid/air in the pleural space). Closing off the chest cavity is performed as 'four to eight stainless steel wires are used for closure (either singular or figure of eight). The wires can either be placed parasternally or through the sternal bone.' The needle passes equidistantly and perpendicularly through the sternum with each byte which results in its closure. The remaining wires can be placed through the corpus or the intercostal spaces, though a riskier approach. The towels are removed and a saline rinse in the mediastinum is conducted to check for bleeders. The wires are pulled out of the thoracic cavity (at the surface of the skin), not with too much pressure to avoid horizontal fractures. 'If the patient is too spastic, the anaesthetist can be asked for another dose of muscle relaxant.' The wires used are then cut and twisted in a manner that is most beneficial for the healing of the sternum and chest cavity; a careful reapproximation is required. This brings the procedure to an end. The incision post surgery is seen in Image 8.

The recovery period in a hospital is approximately 7 days, where the wound and vital signs are closely monitored. Normal walking can be regained in up to 5 days. The surgery has several variants (minimally invasive, traditional with a cardiopulmonary pump), and the steps above refer only to one such potential alternative.


Citations:

https://www.medtronic.com/us-en/patients/treatments-therapies/heart-surgery-cad/beating-heart-bypass-surgery-what-is-it.html

https://pubmed.ncbi.nlm.nih.gov/20715430/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147479/

https://mmcts.org/tutorial/80


Image 2 - 'Off-pump' stabilization system with a heart positioner and tissue stabilizer. From:https://www.annalsthoracicsurgery.org/article/S0003-4975(98)00477-9/fulltext


Image 3 - Anatomy of the skeletal thoracic cage.From:https://courses.lumenlearning.com/ap1/chapter/the-thoracic-cage/
Image 4 - Potential grafts for a CABG surgery. From:https://www.nhs.uk/conditions/coronary-artery-bypass-graft-cabg/what-happens/


Image 7 - A Sternal Retractor holding open a Thoracic Cavity post a Midline Sternotomy. From:https://www.researchgate.net/figure/Sternal-protection-device-in-situ-with-a-sternal-retractor_fig1_330109940

Antidepressants

Antidepressants are a class of drugs that aim to change the balance of amines in the synaptic clefts found in the brain. Amines are organic chemical compounds distinguished by the presence of a nitrogen atom with a lone pair of electrons. Amines are formed when organic groups replace the hydrogen atoms in an ammonia molecule, they are thus further categorized into primary, secondary and tertiary amines. The synaptic cleft is the gap between 2 neurons, also known as the synapse where neurotransmission occurs.

Image 1 - Prozac tablets, with the drug Fluoxetine From : https://www.indiamart.com/proddetail/prozac-20877338833.htmlImage 2 - Schematic Diagram of the Mechanism of SSRIs in the Synaptic Cleft. From: https://www.researchgate.net/figure/Schematic-diagram-showing-mechanism-of-action-of-SSRIs-These-agents-block-the-reuptake_fig1_7730046

SSRIs - Selective Serotonin Reuptake Inhibitors

SSRIs are a type of antidepressant drug that, as the name suggests, reduce the amount of serotonin absorbed by receptors on a neuron. Serotonin is both a neurotransmitter and hormone that has been associated with elevating mood, and is known to relay information within the CNS. It is widely found in the brain, blood platelets, and bowels. Empirical evidence has found that increased concentrations of serotonin in the synaptic cleft helps in the alleviation of symptoms of MDD (Major Depressive Disorder).

SSRIs are very commonly prescribed and widely available today as they target only serotonin receptors and have a highly specialized function, thus reducing adverse side effects that may occur by the administration of other antidepressants.

The Pharmacokinetics of SSRIs

The word pharmacokinetics is the 'study of the time course of drug absorption, distribution, metabolism, and excretion.' Clinical pharmacokinetics today helps establish the efficacy of a drug in an individual patient and follows its biological pathway in the body. Serotonin is a monoamine neurotransmitter, chemically known as 5-hydroxytryptamine / 5-HT. SSRIs are taken orally and focus reducing the reabsorption of only 5-HT from the synaptic cleft in the brain - this is unlike other nonspecific antidepressants such as monoamine oxidase inhibitors that reduce the reuptake of several amines, i.e., dopamine, norepinephrine, histamine, muscarine, and serotonin. The specificity of SSRIs is perhaps what makes them the most commonly prescribed antidepressants today alongside their efficacy.

Clinical trials have revealed that different SSRIs have different pharmacokinetics and efficacy, however, the given list names the SSRIs approved by the FDA (Food and Drug Administration) to treat depression:

  • Citalopram (Celexa)

  • Escitalopram (Lexapro)

  • Fluoxetine (Prozac)

  • Paroxetine (Paxil, Pexeva)

  • Sertraline (Zoloft)

'Fluoxetine and citalopram are available as racemic mixtures, the isomers of fluoxetine having almost equal affinity to the 5-HT reuptake carrier, while the reuptake inhibitor properties of citalopram reside almost exclusively in the (+)-isomer.' Raecimic mixtures are made of 2 equal amounts of chiral enantiomers; enantiomers are molecules that are identical in every aspect, except that they are mirror images of each other, thus are non-superimposable. This also means that a racemic mixture is optically inactive, meaning it undergoes no net rotation in a plane of polarized light; this is important in pharmacokinetics as the angle of rotation for both unsymmetrical enantiomers has to be exactly the same - one with a positive plane of rotation and the other with a negative - only then does the net rotation equal 0 as the effect of both enantiomers are canceled out. These properties stand true in fluoxetine that equally divides the primary reuptake inhibitor properties into both the positive and negative sides of the racemic mixture, but not citalopram which has these very properties on its positive enantiomer. The positive enantiomer of citalopram is called escitalopram and is the functional and most stereoselective part of the drug; it has a 1:2 ratio to the negative enantiomer, effectively making 2/3rd of the drug inactive. It is noteworthy that escitalopram is highly selective and is also metabolized quickly, meaning chances of inter-drug interactions in the body are reduced. Further studies into using only the positive, active stereoisomer as an antidepressant to increase efficacy are being conducted.

Gastrointestinal absorption of SSRIs generally peaks after 4-6 hours of oral administration; this is true of both fluoxetine and citalopram, however their binding to plasma proteins varies with fluoxetine being 95% or above and citalopram being hardly 50%. Despite these differences, the potency of both drugs remains paralleled with their highly selective inhibition properties. The excretion of these drugs occurs in the liver after they undergo a metabolic breakdown. 'Metabolites of fluvoxamine and fluoxetine are predominantly excreted in urine' whereas larger quantities of other metabolites from different antidepressants (paroxetine and sertraline) are excreted in faeces. Most antidepressants have an average half-life of 1 day, whereas fluoxetine has that of 2 days (though after multiple doses over a minimum of 6 days). 'The elimination half-life of a drug is a pharmacokinetic parameter that is defined as the time it takes for the concentration of the drug in the plasma or the total amount in the body to be reduced by 50%. In other words, after one half-life, the concentration of the drug in the body will be half of the starting dose.'

Antidepressants, despite their efficacy, have adverse side effects like insomnia, dry mouth, headaches, decreased libido, nausea, dizziness, restlessness, and changes in appetite amongst others. They may also interfere with other drugs - especially blood thinners - resulting in increased risks of bleeding, and blood not clotting, again, amongst others. Though the general "amine hypothesis" and "serotonin hypothesis" are popular today, antidepressants may sometimes not be the best course of treatment for MDD. Antidepressants are not known to be addictive, however, sudden breaks or alterations in medication may leave one feeling withdrawal-like symptoms. Antidepressants cannot be used excessively or in certain cases - during pregnancy, with children - and must be prescribed by a physician.

Citations :

https://www.ashp.org/-/media/store%20files/p2418-sample-chapter-1.pdf

https://www.news-medical.net/health/What-is-the-Half-Life-of-a-Drug.aspx

https://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825

https://pubmed.ncbi.nlm.nih.gov/8384945/

Reference from: https://medcraveonline.com/JABB/antidepressants-mechanism-of-action-toxicity-and-possible-amelioration.html