Tuesday, April 9, 2019

Drugs used in coronary artery disease

Describe how nitrates are used in management of angina

Angina happens when not enough blood gets through to the cardiac muscle. Nitrates dilate resistance vessels, including the coronary arteries supplying the heart, thus increasing the blood supply to the heart. The two main nitrates are glyceryl trinitrate (GTN) and isosorbide dinitrate. They are converted to nitric oxide via organic nitrate ester reductase, and the nitric oxide produced goes onto cause relaxation of vascular smooth muscle.

GTN and isosorbide mononitrate differ in terms of their pharmacokinetics. GTN has very high first-pass metabolism, meaning that if you try to give it orally, it will be broken down by the liver and you won't get much use out of the drug. Therefore, GTN is usually given by sublingual spray or transcutaneous patch, or by IV in severe cases. Isosorbide mononitrate has a lower first-pass clearance and can be given orally.

Another thing to keep in mind with nitrates is that they can lose their effectiveness quickly. If nitrates are used constantly over 24 hours, they lose their effect- a process called "tachyphylaxis." Therefore, if people are using transcutaneous GTN patches, the patches need to be taken off overnight.

Describe how antiplatelet agents, beta adrenoreceptor blockers, thrombolytics and anticoagulants are used in the context of ischaemic heart disease

This lecture basically covered emergency situations ("acute coronary syndromes"), including unstable angina, non-ST elevation acute myocardial infarction, and ST-elevation acute myocardial infarction (STEMI). (ST-elevation refers to a feature of the ECG tracing.)

Antiplatelet agents

Antiplatelet agents are drugs that block various actions of platelets. I've covered them here. Aspirin and clopidogrel (an ADP receptor antagonist) are good for inhibiting platelet aggregation on coronary plaques.

Beta-adrenoceptor blockers

Beta-blockers, as discussed here, reduce the contractility and rate of the heart. In turn, this reduces the heart's demand for oxygen so that it can make do with less oxygen than before. In acute coronary syndromes, beta-blockers help to limit the size of the infarct and reduce pain.

Thrombolytics

Thrombolytics (a.k.a. profibrinolytics) are good when urgent thrombolysis is needed (i.e. you need to get rid of a blood clot NOW, not prevent them from happening in the future). I have discussed them here.

Anticoagulants

Anticoagulants are good for preventing clots from happening in the future. One of the main ones that is used is low molecular weight heparin, which can prevent thrombotic and embolic complications of heart attacks. I have discussed these here.

Monday, April 1, 2019

Drug Management of Heart Failure

Describe the physiology of Na, K and H2O renal excretion, including the renin-angiotensin-aldosterone system


Describe the drug strategies to enhance Na and H2O excretion (ACE inhibitors, aldosterone antagonists)

ACE inhibitors, such as enalapril and captopril, work by inhibiting angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II. Since angiotensin II normally works on the arterioles to cause constriction and on the adrenal cortex to increase the release of aldosterone, inhibiting ACE causes vasodilation (and an increase in blood flow to the kidneys) and an increase in salt and water excretion (via the actions of aldosterone).

Angiotensin II and aldosterone can also be blocked directly. AT1 receptor blockers block the actions of angiotensin II (since AT1 receptors, confusingly enough, are the receptors for angiotensin II). These drugs tend to end with the suffix -sartan, such as irbesartan. Aldosterone antagonists such as spironolactone not only increase salt and water excretion, but also inhibit the myocardial remodelling that occurs during heart failure.

Describe the clinically important beta adrenoreceptor blockers

Beta-1 blockers can also be used to treat heart failure, as they can block cardiac modelling and also decrease the myocardial contractility (which in turn decreases the blood pressure). Furthermore, they can also slow the heart down, allowing more time for the ventricles to fill with blood (which is important in cases of diastolic heart failure). Most beta-blockers end with -olol, and include metoprolol and bisoprolol. Adverse effects of beta-1 blockers are mainly related to off-target activation of beta-2 receptors, and include bronchospasm (which is why beta-blockers tend to be avoided in people with asthma). There are also side-effects from having too much of a good thing, such as excessive slowing of the heart.

Describe the clinically important diuretics

I'll discuss diuretics in a later post, but essentially diuretics act on certain transporters in the tubule to decrease reabsorption and/or increase secretion of salts and water so that you pee more. The main types of diuretics include loop diuretics (e.g. frusemide), thiazides (e.g. hydrochlorothiazide), and aldosterone antagonists (e.g. spironolactone).

Describe how digoxin acts as antiarrhythmic agent and to increase cardiac contractility

Digoxin is an antiarrhythmic that is also used for heart failure. It works by blocking Na+/K+ pumps, thus reducing the gradients of sodium and potassium. Because it blocks the pumping out of sodium, it also has a downstream effect on Na+/Ca2+ exchangers, which bring in sodium to let calcium leave the cell. Because the Na+/Ca2+ exchangers are being affected, there is more intracellular calcium, which leads to more efficient contraction of myocytes and increased cardiac contractility.

Digoxin also has indirect effects on the heart via the vagus nerve. Digoxin stimulates the vagus nerve, causing an increase in parasympathetic stimulation and decreased heart rate. Therefore, digoxin is also good for treating supraventricular tachyarrhythmias (only the supraventricular ones as the ventricles don't get parasympathetic stimulation).

Even though digoxin can reduce heart rate, at toxic doses it can actually increase heart rate. Since digoxin blocks the Na+/K+ pump, there is a smaller potassium gradient and so less potassium leaves the cell during repolarisation. Therefore, the membrane becomes less polarised (i.e. less negative), making it easier to reach threshold during the next heartbeat.

Digoxin toxicity may also present with other symptoms, such as serious arrhythmias, nausea, confusion, and visual problems. Nausea and confusion are most commonly seen in elderly patients. Since digoxin relies a lot on the kidneys for excretion (~70% excretion via the kidneys), it is especially toxic in people with renal impairment. Digoxin is also especially toxic in people who are hypokalaemic, as potassium would ordinarily compete with digoxin for binding to the Na+/K+ ATPase.

Describe how nitrates may be used in heart disease

The actual mechanism of action of nitrates wasn't really discussed in this lecture, other than that they are vasodilators that can help in emergency situations by reducing afterload.

Renal Anatomy

I wasn't sure what to blog about next, so I wrote down all of the fields that we're studying (microbiology, anatomy, physiology, etc.) and let a random number generator pick for me. It picked the number corresponding to Anatomy, so I guess that's what I'll be blogging about now! (Also, I bombed a large proportion of the anatomy questions in the set of formative renal questions that we were given, so I guess I need the extra study...)

Describe the position and functional anatomy of the kidneys and ureters.

The kidneys are located in the abdomen, roughly between T12 and L3. The right kidney is slightly lower than the left kidney because it has been pushed down by the liver. The hilum of each kidney (where the blood vessels etc. join the kidney) is located at around L1-L2. Each kidney is surrounded by a layer of perirenal (or perinephric) fat, which is surrounded by a layer of renal fascia (a.k.a. Gerota's fascia), and then by a layer of pararenal (paranephric) fat.

Demonstrate the topographical relationships of the kidneys and ureters to other abdominal structures.

The kidneys are located laterally to the psoas muscle, and the ureters run along the front of the psoas. As the ureters enter the pelvis, they cross the bifurcation of the iliac arteries.

Describe the blood supply and innervation of the kidneys and ureters.

Blood supply

The kidneys receive blood from the renal arteries. Since both renal arteries arise from the aorta, and the aorta is on the left side of the body, the left renal artery is shorter than the right renal artery. The opposite is true for renal veins: the left renal vein is longer than the right renal vein. The left renal vein also receives blood from the gonads and adrenals (via the left gonadal vein and the left suprarenal vein respectively).

The ureters receive their blood supply from whatever structures are running close to them. The upper part of the ureters tend to receive blood from the renal artery, the middle part of the ureters tend to receive blood from the gonadal arteries and/or the aorta, and the lower part of the ureters tend to receive blood from the vesical arteries.

Innervation

The kidneys receive sympathetic innervation from T10 and T11 nerves (a.k.a. the lesser splanchnic nerves) and parasympathetic innervation from the vagus nerve. Sensory fibres follow the sympathetic fibres back to T10/T11, so kidney pain tends to be felt over those dermatomes. One important point is that nerves are not very important for renal function in general, but for renal blood flow. Aspects of renal function (how much salt and water to absorb, for example) tend to be controlled by hormones.

The ureters receive sympathetic innervation from T12 and L1, and parasympathetic innervation from the vagus and hypogastric (from S234) nerves. Just like with the kidneys, the sensory fibres follow the sympathetic fibres, so pain in the ureters is felt over T12 and L1.

Describe histology (microscopic anatomy) of the renal cortex and medulla including the renal corpuscle, proximal convoluted tubule, Loop of Henle, distal convoluted tubules, and juxtaglomerular apparatus and collecting tubules.

The outer region of the kidney is called the cortex, and is where the renal corpuscles and convoluted tubules are located. (Don't worry, I'll describe what they are and what they do in a bit.) The area deep to the cortex is the medulla, and contains the Loops of Henle and collecting tubules. There is, however, a bit of overlap between these two areas: the columns of the renal medulla contain the structures of the renal cortex, and the medullary rays of the cortex contain structures of the renal medulla.

Renal corpuscle

The renal corpuscle is made out of the glomerulus (a "knot" made out of arteries) and Bowman's space (the first part of the tubular system where urine is formed). Under the microscope, renal corpuscles basically look like a cluster of cells surrounded by a white ring (the Bowman's capsule). The renal corpuscle is the main site where filtration occurs (i.e. the blood gets filtered so that pretty much everything, except for large proteins, is pushed into the Bowman's capsule and the tubular system).

Proximal convoluted tubule

The proximal convoluted tubule is the first lot of tubules. The reabsorption of pretty much all glucose and amino acids occurs here, along with reabsorption of many other substances. Proximal convoluted cells are tall, columnar, and have a brush border to increase their surface area for reabsorption. Since the Na+/K+ pump is critically important for maintaining concentration gradients for reabsorption, proximal convoluted tubule cells have plenty of mitochondria to keep them topped up and ready to go.

Loop of Henle

The loops of Henle have two parts: a thin descending limb and a thick descending limb. The thin descending limb is more permeable to water than salt, whereas the ascending limb is impermeable to water but permeable to salt. The appearance of the Loops of Henle depends on whether you have a cross-section or a longitudinal section of the loop: cross-sections look like little circles, whereas the longitudinal sections look like long white stripes that are lined by cells. (I think. Histology isn't my strong point.)

Distal convoluted tubules and collecting duct

The distal convoluted tubule and collecting duct cells are similar to those of the proximal convoluted tubule, except that cells in the distal convoluted tubule and collecting duct tend to be cuboidal and less metabolically active than those in the proximal convoluted tubule. Both the distal convoluted tubule and the collecting duct are under hormonal control to change the amount of salts and/or water reabsorbed.

Another point of interest is the juxtaglomerular apparatus. The juxtaglomerular apparatus of the distal tubule interacts with the afferent arteriole by secreting hormones etc. to maintain filtration rate (see here).

Describe the histology of the ureter.

Ureters, like many other bodily tubes, have a mucosa, muscularis layers, and an adventitia. (However, unlike many other bodily tubes, they likely do not have a submucosa.) There are two muscularis layers: one is circular, and one is longitudinal. Together, the muscularis layers work to propel urine towards the bladder.

Describe the anatomy of the urinary bladder, its base and ureteric openings and its relationship to the overlying peritoneum.

The bladder is shaped kind of like an upside-down triangular pyramid. The urethra connects to the bladder at the inferior "point." The umbilical ligament, which is a remnant of an embryonic structure called the urachus, joins at the apex, which is the anterior superior "point." The ureters join at the posterolateral points and continue to pass through the wall of the bladder.

One point of interest is the bladder trigone, which is formed from the intermediate mesoderm of the urogenital septum. This is in contrast to the rest of the bladder, which is formed from the anterior part of an embryonic structure called the cloaca. The bladder trigone makes up part of the posterior wall of the bladder. The ureters open into the bladder at the upper lateral corners of the bladder trigone.

Describe the blood supply and innervation of the urinary bladder.

The bladder receives its blood supply from the superior and inferior vesical arteries. The superior vesical artery comes from the patent part of the umbilical artery, which in turn comes from the anterior division of the internal iliac artery. The inferior vesical artery comes directly from the internal iliac artery.

Like the ureters, the bladder receives sympathetic stimulation from T12 and L1. However, its parasympathetic innervation is only from the hypogastric plexus (S234). Both sympathetic and parasympathetic nerves activate muscles, but they activate different muscles: sympathetic stimulation causes the external urethral sphincter to tighten (and stop you from peeing), while parasympathetic stimulation causes the detrusor muscle (i.e. the bladder muscle) to contract, thus making you pee. Sensory information is a bit mixed: pain fibres follow the sympathetic nerves back to T12 and L1, whereas stretch fibres follow the parasympathetic nerves back to S234.

An important reflex to discuss here is the micturition reflex. When the bladder wall is stretched, this information is conveyed back to S234, triggering reflex contraction of the detrusor muscle. When this happens, we feel the urge to pee. However, we can override this reflex through various centres in our brain and through contracting the external urethral sphincter.

Discuss the anatomical reasoning behind differences in referred pain from upper and lower urinary tract infections.

As mentioned, different parts of the urinary tract convey sensory fibres to different parts of the spinal cord. In the kidney, sensory fibres go back to T10/T11, in the ureter they go back to T12/L1, and in the bladder the fibres detecting pain (not stretch) go back to T12/L1. When we feel pain in the urinary tract, we tend to feel it over the dermatomes associated with those sensory nerves: e.g. pain in the kidney is felt over the T10/T11 dermatomes. (However, to my understanding, bladder stones might be felt lower down, like in the S1/S2 dermatomes.)

Describe the anatomy of the urethra; explain the anatomy of its different parts in males and females in relation to continence and catheterisation.

The male urethra is quite long and is divided into three parts (prostatic, intermediate / membranous, and spongy), whereas the female urethra is relatively short and isn't divided into parts. (Some textbooks may consider the pre-prostatic, or intramural, part of the urethra to be a fourth part of the urethra.) Because the female urethra is much shorter, it is easier to catheterise than the male urethra. However, the female urethra is more prone to urinary tract infections than the male urethra. Furthermore, women are more prone to incontinence (though this is also partly because they do crazy stuff like give birth).

An important structure within the male urethra is the verumontanum, also known as the seminal colliculus. The verumontanum is a thickening within the prostatic urethra. It has three orifices: one called the prostatic utricle, and two for the openings of the ejaculatory ducts. The verumontanum is an important marker to look for when removing the prostate via the urethra.

Describe the skeletal and ligamentous components of the pelvis.
Discuss the sexual differences in pelvic skeletal anatomy.
Describe the anatomy and functional importance of the pelvic diaphragm.
Describe the topographical arrangement of anatomical structures within the pelvis.

The pelvis wasn't exactly covered in any of the lectures that we just had (despite pelvic stuff being in the learning outcomes), so I guess it's 2nd year undergrad me to the rescue!