Pharmacology Flashcards
Outline the differences between primary and secondary hypertension. Include some of the key risk factors involved in primary hypertension, and how secondary hypertension can be treated.
Primary hypertension is high blood pressure as a result of hereditary and/or lifestyle factors (usually multifactoral), including smoking, age, obesity, lack of exercise, and genetic predisposition. In primary hypertension, pharmacological and lifestyle interventions are designed to reduce blood pressure and alleviate symptoms.
In secondary hypertension (<10% of all cases), the high blood pressure is a result of a specific disease, such as renal hypertension or pheochromocytoma. In these cases, the specific cause is treated, as opposed to interventions to alleviate blood pressure itself.
Explain the mode of effect of beta blockers in the treatment of CVD.
Beta-adrenoreceptor blockers can block the effects of adrenaline on the heart, reducing cardiac output, and thus reduces blood pressure. They also decrease the amount of renin released from the kidneys. These are known as competitive reversible antagonists, meaning that if there is enough of competing substrate, then it will overcome the blocker - therefore, a proportional amount of drug to competing substrate is required.
Propanolol blocks B1 and B2 adrenoreceptors, but more specific drugs, such as atenolol, block B1 specifically.
Adverse effects of B-blockers include exacerbation of asthma, intolerance to exercise, hypoglyaemia, and vivid dreams (they cross the BBB).
Explain the mode of effect of alpha blockers in the treatment of CVD.
Alpha-adrenoreceptor blockers are competitive reversible agonists. They lower blood pressure by lowering the sympathetic tone of arterioles by blocking noradrenalin A1 and 2 receptor.
Phentolamine is an A1 and A1 blocker, doxazosin and prazosin are A1 selective.
Additionally, increased closure of internal sphincter of the bladder can be alleviated by A-blockers, which can treat BPH.
Explain the mode of effect of ACE inhibitors in the treatment of CVD.
Angiotensin converting enzyme (ACE) converts circulating angiotensin I into its active form, angiotensin II. Angiotensin II is a very potent vasoconstrictor. It also stimulates the release of aldosterone, which increases the absorption of sodium and water in the kidneys.
By inhibiting ACE, reduced angiotensin II results in lowered total peripheral resistance, and reduced aldosterone results in lowered absorption of sodium and water (diuretic effect) which lowers circulating fluid volume.
Examples of ACE inhibitors include captopril and enalapril. Adverse effects include a sudden blood pressure drop after the first dose, and a persistent dry cough (due to reduced breakdown of bradykinin, a peptide which activates sensory nerves in lung tissues).
Explain the mode of effect of angiotensin II receptor blockers in the treatment of CVD.
Angiotensin II receptor blockers are a good alternative to ACE inhibitors - they have the same effect but will not cause the same side effects.
The AT2 receptor mediates vasoconstriction and thealdosterone-releasing actions of angiotensin II. Losartan and cendesartan are examples of AT2 blockers.
Explain the mode of effect of calcium channel blockers in the treatment of CVD.
Calcium channel blockers block L-type voltage operated calcium channels (on vascular smooth and cardiac muscle). Blocking these channels reduces calcium entry into vascular smooth muscle and cadiomyocytes, resulting in reduced total peripheral resistance and cardiac output, respectively, by inhibiting the action potentials which cause them to contract.
Some of the drugs operate by blocking open channels (like a cork - e.g. verapamil and diltiazem), whereas others block channels by allosteric modulation (e.g. nifedipine). These drugs can be tissue selective.
Adverse side effects include gum hyperplasia, headache, constipation, and cardiac dysrhythmias.
Explain the mode of effect of diuretics in the treatment of CVD.
Diuretics lower blood pressure by reducing blood circulating volume. They act by reducing renal reabsorption (of sodium, and consequently, water), and may also contribute to lowered peripheral resistance by vasodilation.
They can lead to a reduction in blood plasma potassium ions (and thus, increase liability to cardiac arrhythmia).
An example is bendroflumethiazide.
Define pre-load and after-load.
1) Pre-load is the diastolic pressure that distends the relaxed left ventricle, and is determined by the venous return (which is determined by the dilation of veins).
2) After-load is the force against which the left ventricle contracts, and this is determined by the total peripheral resistance (which is determined by the vascular tone of the resistance arterioles) and circulating blood volume (determined by the level of water reabsorption in the kidneys).
With reference to the Bainbridge reflex, explain how nitrovasodilators can help alleviate symptoms of angina.
The Bainbridge reflex is a sympathetic atrial reflex. When there is an increase in venous return to the atria, the stretch stimulates the baroreceptors of the SA node, increasing sympathetic nerve stimulation, resulting in increased heart rate (similar to the Starling’s reflex). Therefore, reducing venous return (pre-load) will reduce myocardial work.
Nitrovasodilators are a class of drugs which will reduce pre-load by dilating veins. GTN (nitroglycerine) is commonly used as a spray (to prevent first-pass (liver) metabolism). Poppers such as amyl nitrate can be used to treat angina .
These drugs are rapid onset and are short-lived – they can be used prior to exercise, or for rapid relief during anginal attack. These drugs are lipophilic – they readily enter smooth muscle cells and are reduced to nitric oxide (NO) (nitric oxide donors) which mimics the action of endothelium-derived NO. NO activates soluble guanylate cyclase (sGC), a cytoplasmic enzyme, via its haem receptor, activating it. Active sGC converts GTP to cGMP, which causes vasodilation.
Side effects of vasodilation include headache and tolerance to prolonged use .
Outline the four common causes of chronic heart failure,and describe the key symptoms and vicious cycle involved.
Heart failure is a state in which the heart fails to maintain an adequate circulation for the needs of the body despite an adequate venous filling pressure (contractile function is diminished regardless of plenty blood). Common causes of chronic heart failure include:
1) Haemodynamic overload (chronic hypertension or excess blood volume (via obesity or valve regurgitation)).
2) Neurohumoral overload (e.g. toxin overproduction of thyroxine (thyroxicosis)).
3) Tissue damage (e.g. scarring due to myocardial infarction).
4) Genetically determined excessive hypertrophic response to pressure (e.g. familial hypertrophic cardiomyopathy).
Symptoms include fatigue, pulmonary oedema (impaired gas exchange due to increased blood volume in pulmonary circulation), venous distension (build-up of venous blood), and cyanosis (impaired supply of oxygen to peripheral tissues).
Heart failure can arise from a vicious cycle starting with increased central venous pressure, which leads to increased pre-load, increased end-diastolic volume, increased stroke volume, increased cardiac output, increased peripheral vascular resistance, increased diastolic arterial pressure, increased afterload, increased cardiac work, and increased oxygen consumption
Explain the mode of action of HMGCoAR inhibitors in the treatment of high cholesterol.
Hydroxy-methyl-glutaryl-coenzyme-A-reductase inhibitors (HMGCoAR inhibitors, AKA “statins”) are a class of competitive inhibitor drugs which inhibit the rate determining step in cholesterol synthesis within the liver (via the enzyme HMGCoAR). By inhibiting this step, the amount of cholesterol synthesised and stored in the liver decreases, causing the liver to increase expression of LDL receptors, and draw in low-density lipoproteins (e.g. cholesterol) from the circulation, preventing them from invading blood vessels walls, and thus preventing atherosclerosis development.
Describe the autonomic and endocrine control of airway function.
1) Sympathetic (noradrenalinergic) nerves innervate blood vessels and glands. Sympathetic action on glands tends to reduce mucus secretion.
2) Parasympathetic (acetylcholinergic) nerves innervate bronchial smooth muscle and glands. By acting on M3 receptors, the vagus nerve causes increased bronchoconstriction, and parasympathetic action of glands increases mucus secretion.
3) As well as these, there are inhibitory and excitatory non-adrenergic, non-cholinergic (i- and e-NANC) nerves. i-NANC nerves re;ax airway smooth muscle via nitric oxide. e-NANC nerves can cause neuro-inflammation due to tachykinin release.
4) Endocrine system can control respiration - adrenaline from adrenal glands acts on beta-2 airway smooth muscle receptors to constrict them.
Describe the pathology of asthma, and how it can be tested for.
Asthma is an obstructive lung disease – a chronic inflammatory condition with acute exacerbations. Asthma can cause smooth muscle in the airway to thicken (via hypertrophy and hyperplasia) and contract which constricts the airways, as well as mucus hypersecretion. All this can cause epithelial damage and result in infiltration of inflammatory cells, as well as bronchial hyper reactivity.
Asthma symptoms can be triggered by pet dander, dust mites, moulds, pollens, respiratory infections, exercise, cold air, tobacco smoke (and other pollutants), stress, alcohol, and other allergies.
To diagnose asthma, spirometry is used to measure an individual’s forced vital capacity (FVC, maximal expiration following full inspiration), and forced expiratory volume in one second (FEV1, the volume of FVC expelled after one second) to determine peak expiratory flow (FEV1/FVC, less than 80% = asthmatic, generally) . Asthma reduces FEV1, particularly during an acute exacerbation.
Explain the mode of action of bronchodilators in treatment of asthma.
Bronchodilators act as relievers for asthma symptoms (relieve symptoms during an acute exacerbation).
Salbutamol is a common bronchodilator, which acts as a beta-2 agonist (stimulates B2-adrenoreceptors). When B2-adrenoreceptors are stimulated, it leads to the production of cAMP by adenylyl cyclase, which results in the production of PKA, resulting in bronchodilation (signal cascade).
Methylxanthines are also bronchodilators, which act by inhibiting PDE (breaks down cAMP, preventing it from producing PKA).
Other bronchodilators work by blocking constricting parasympathetic cholinergic effects (e.g. ipratropium, a non-selective muscarinic antagonist - M1, 2, 3 receptor blocker).
Explain the mode of action of anti-inflammatory agents in treatment of asthma.
Anti-inflammatory agents act as preventers for asthma symptoms (taken at regular intervals to prevent acute exacerbations).
Glucocorticoids (such as prednisolone) inhibit inflammatory molecules, such as prostanoids, leukotrienes, and cytokines.
Montelukast is a leukotreine receptor antagonist (blocks inflammatory leukotriene receptors).
Sodium cromoglicate is another common preventer, but its specific mechanisms are unknown (interacts with a number of sites/receptors, it is not known what its primary mode is).
