BMD225 revision cards for week 5 -7

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What effects does the gonadotropin releasing hormone have on the anterior pituitary?
It has a positive feedback effect and is released in a pulsatile manner
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What are the hormones involved in the maturation within the ovary?
The FSH and LH both have a positive effect on ovary maturation. The FSH positive effect is on the Graafian follicle which develops and then involutes to form the corpeus luteum after the ovum has been released. LH has a positive effect on the CL.
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What hormone does the GF produce and what effect does it have on the anterior pituitary?
Oestrogen and it has a negative feedback
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What hormone does the CL produce and what effect does it have on the anterior pituitary?
It produces oestrogen and progesterone. Progesterone has a negative feedback on anterior pituitary and the hypothalamus.
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What are the uses of oestrogens?
1. Hormone replacement therapy - hypo-ovarian conditions, menopause. 2. Contraception. 3. Menstrual disorders.
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What are the uses of progestogens?
1. Hormone replacement therapy. 2. Contraception. 3. Endometriosis. 4. Endometrial Cancer
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What are the uses of androgens?
1. Male contraception. 2. Androgen replacement therapy?
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What are the endogenous forms of oestrogens?
Oestradiol, Oestrone, Oestriol.
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What are the synthetic forms of oestrogens?
Ethinyloestradiol, Mestranol, Diethylstilboestrol.
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What are the endogenous forms of progestogens?
Progesterone, Hydroxyprogesterone, Medroxyprogesterone
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What are the testosterone derivatives of progestogens?
Norethisterone, Norgesterol, Gestodene
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What is the preparation of androgens?
Testosterone
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What are anti-oestrogens, give an example and its use?
They are competitive antagonists/partial agonists. An example is clomiphene used to induce ovulation. They compete with natural eostrogens for receptors in target organs
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What is clomiphene?
A non-steroidal oestrogen receptor antagonist, administered during early part of cycle, ovulation rates greater than pregnancy rates, blocks -ve feedback to hypothalamus and pituitary
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Give examples of progestogens?
Progesterone, 19-Nortestosterone, Norethindrone, Norgestimate, Levonorgestrel, Desogestrel, Gestodene.
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Give examples of oestrogens?
Estradiol, Estrone, Estrio, 17alpha-Ethinylestradoil
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What is the aim of contraceptive mechanisms of progestogens and oestrogens?
The main aim is to suppress mid cycle FSH and prevent LH surge.
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In the cervical mucus what contraceptive mechanisms occurs?
Progestogen causes secretion of thick viscid mucus hostile to sperm penetration
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In the endometrium what contraceptive mechanism cocurs?
Sustained levels of eostrogen or progestogen cause asynchronous (not existing/occuring at the same time) development less receptive to implantation.
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In the ovary what contraceptive mechanism occurs?
Estrogen inhibits ovulation by blocking Gn surge, progestogen much weaker but has same effect
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In the fallopian tube what contraceptive mechanism occurs?
Progestogen inhibits motility: estrogen enhances motility causing abnormal rates of ovum transport?
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What are the main effects of the combined oral contraceptive pill?
Oestrogen inhibits secretion of FSH via negative feedback on the AP suppressing development of the ovarian follicle. Progestogen inhibits secretion of LH and prevents ovulation. Both act to alter the endometrium to discourage implantation
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Which biphasic/triphasic preparation affect estrogen levels?
Triphasil
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Which biphasic/triphasic preparation affect progestin levels?
ortho-novum 7/7/7 increases it across time. tri-norinyl increases then decreases it. Triphasil increases it across time.
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What is the role of biphasic and triphasic preparations?
They can effectively reduce overall sex hormone exposure
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What are the benefits of the combined oral contraceptive pill?
Reduction in ovarian/endometrial cancer risk. Improves the HDL/LDL oestrogen ratio in favour of HDL. It normalises dysfunctional uterine bleeding.
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What are the disadvantages of the combined oral contraceptive pill?
May have a breast/cervical cancer risk, Thromboembolism, Ischaemic heart disease/stroke, Hypertension, HDL/LDL (progestogens), Androgenic effects (Progestogens). Mood
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What is the role of the progestogen only pill?
It hinders implantation through its effect on the endometrium and on the motility and secretions of the fallopian tubes.
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Give some examples of the progestogen/progestin only pill?
Norethisterone, levonorgestrol and ethynodiol
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How is the PoP taken?
Daily without interruption with no placebo/pill-free interval - no variation in pill formulation. Mode of action is primarily on the cervical mucus which is made inhospitable to sperm.
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How reliable is the PoP compared to the combined pill? Give some statistics.
less reliable. 12 month pregnancy rates 1-13%. Typical use failure rates 8-9%
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What are some alternative methods of contraceptive delivery?
Injection, Patch, Vaginal Ring.
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What is the mechanism of sustained release contraceptions?
Progesterone can be contained in some non-biodegradable strips/capsules subcutaneously that provide a constant supply releasing their hormone slowly over 5 years. Eg: levonorgesterol. This route avoids 1st pass metabolism
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How does male contraception work?
Conception is prevented by diverting/suppressing sperm output and/or inhibiting the sperm fertilizing capacity. By reducing the number of fertile sperm in the ejaculate to levels that prevent fertilisation.
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Via male contraception why is there no fertilisation?
In the testes the Leydig cells and Sertoli cells do not produce testosterone and spermatogenesis respectively. Testosterone does not activate the SC so is broken down into DHT and estradiol = androgen effects, no fertility.
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What is sildenafil and what is it's role?
A phosphodiesterase type V inhibitor used to treat erectile dysfunction, potentiates the action of NO, inhibits breakdown of cGMP
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What does NO activate?
Guanylyl cyclase
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What are the three different classifications of angina?
Stable, Unstable, Prinzmetal's (variant)
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What is the pharmacotherapy of angina aimed at?
Increasing blood flow or decreasing oxygen demand - prophylactically/during acute attack
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What are the different ways that angina pharmacotherapy is achieved?
Organic Nitrates, Potassium Channel Activators, Beta-adrenoreceptor antagonists, Calcium channel antagonists
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what happens with a decreased oxygen supply?
decreased coronary blood flow, decreased vessel calibre, increased heart rate, decreased perfusion pressure, increased ventricular wall tension
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What does an increased oxygen demand cause?
increased heart rate, increased myocardial contractility, increased ventricular wall tension, increased filling pressure (preload), increased resistance to ejection (afterload)
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What are some examples of organic nitrates?
Glyceryl Trinitrate, Isosorbide mononitrate, Dipyridamole
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what do organic nitrates do?
Relax vascular smooth muscle by mimicking the effects of nitrous oxide on: venous capacitance vessels, large muscular arteries, coronary arteries (particularly collateral blood vessels), Arterial Resistance vessels.
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What occurs when guanylyl cyclase is activated?
cGMP is formed, this activates protein kinase G which decreases calcium ion influx into the cell but increases its storage in the sarcoplasmic reticulum and increases myosin light-chain dephosphorylation?
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How are organic nitrates administered?
Sublingual, buccal, transdermal (glyceryl trinitrate), oral (isosorbide mononitrate)
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What are some unwanted effects of organic nitrates?
Venodilation causes postural hypotension, reflex tachycardia, syncope, dizziness. Arterial dilation causes throbbing headaches, flushing. Tolerance to thesse effects develops.
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What do organic nitrates cause?
Increased blood flow and reduced oxygen demand
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What are the benefits of nitrates
They dilate the colalteral vessel thus allowing more blood through to the underperfused region.
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In a patient taken no drug with CAD what is to be expected?
The atheromatous plaque in itself already causes dilated arterioles, blood flow to the normal area slightly increases whereas bloodflow to the ischaemic area decreases. The collateral is normal.
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In a patient taken dipyradamole what is the effect?
IT dilates arterioles, increasing flow through the normal area at the expense of the ischaemic area (BF reduced)
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Give an example of potassium channel activators?
Nicorandil - used in patients who are symptomatic with other treatments
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What do PCA's cause?
increased blood flow and reduced oxygen demand and generates NO affecting arterial and venous dilation
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What mechanism do PCA's employ?
Increased K permeability with K extrusion from cell, Vascular SM hyperpolarisation, Closure of L type voltage dependent Ca channel/ Inhbition of intracellular Ca release, Reduced free intracellular Ca, Quiescence, hypoxia protection/Vasodilation
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What do beta adrenoreceptor antagonists cause?
Reduced oxygen demand
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Give some examples of beta adrenoreceptor antagonists?
Propranolol, atenolol, pinolol, labetolol
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What is the role of beta adrenoceptor antagonists?
Blockade of B1 receptors acts to reduce heart rate, reduce force of contraction and lower blood pressure by reducing cardiac output
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Which B adrenoceptor antagonist is cardioselective?
Atenolol
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What are the pharmacokinetics of B adrenoceptor antagonists?
Lipophilic (propranolol), Hydrophilic (atenolol).
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What are the unwanted effects of B adrenoceptor antagonists?
Precipitation of heart failure/ impairment of blood supply to peripheral tissues, lowering of HDLs, sleep disturbance, sudden withdrawal syndrome
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What do Calcium channel antagonists cause?
Increased blood flow and reduced oxygen demand.
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What are the three classes of calcium antagonists and their compounds?
Phenylalkylamines (verapamil), Dihydropyridines (nifedipine, amlodipine), Benzothiazepines (diltiazem)
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What is the role of calcium channel antagonists?
Blocks cellular entry of Ca through L-type channels, this results in arteriolar/arterial dilation and a reduction in heart rate and cardiac contractility
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What are the pharmacokinetics of calcium channel antagonists?
They're mostly lipophilic and well absorbed with variable first pass metabolism and short half lives. Some have active metabolites.
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What are the side effects of calcium channel antagonists?
Arterioral dilation - headache, flushing, dizziness and ankle oedema. Reduced cardiac contractility can precipitate heart failure, and there's altered gut motility (verapamil). Heartburn and nausea (nifedipine).
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Describe the actions of different calcium channel antagonists?
Nifedipine causes reflex tachycardia, causes a rapid fall in bp triggering that reflex. Diltiazem and Verapamil slow heart rate. Nifedipine causes arterial resistance decrease.
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Which fibrinolytic drugs promote plasminogen activation?
Streptokinase, Alteplase rt-PA, Tenectaplase/Reteplase
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Which antifibrinolytic drugs inhibits plasminogen activation?
Tranexamic acid/ Aprotinin
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For myocardial infarction what does secondary prophylaxis include?
Stop smoking, exercise more. Low dose aspirin/warfarin. Beta adrenoreceptor antagonists. ACE inhibitors. Calcium channel blockers. Statins to lower cholesterol.
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Why does heart failure occur and what are some causes?
Because the cardiac output of the heart is insufficient to meet the demands of the body. Causes: coronary artery disease, hypertension, valve disease, arrhythmia
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What are the symptoms of heart failure?
Breathlessness, peripheral oedema, fatigue
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What is the aim of heart failure therapy?
To increase myocardial contractility, reduce oedema, inhibit renin-angiotensin-aldosterone system
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What occurs when there is reduced cardiac output?
Decreased renal blood flow, renin release, formation of angiotensin 2, release of aldosterone, na/water retention, oedema, increased central venous pressure, increased preload, decreased cardiac output.
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Give an example of a cardiac glycoside and its role?
Digoxin, increases intracellular sodium by inhibiting the na/k atpase, this reduces the na gradient for the passive export of calcium resulting in increased intracellular calcium and enhanced contractile responses. It has a very low therapeutic index
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what are examples of loop diuretics?
furosemide, bumetanide, torasemide
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What are loop diuretics clinically used for?
In treatment of salt and water overload associated with acute pulmonary oedema, chronic heart failure, ascites, nephrotic syndrome, renal failure. Also used in treatment of hypertension and acute treatment of hypercalcaemia
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Where do loop diuretics work in tubular reabsorption and diuretic action?
Ascending limb of henle loop, it is the most potent (15-25% of filtered na is excreted)
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What are examples of thiazides and related drugs?
Thiazides: bendrochlorothiazide, hydrochlorothiazide. Other drugs: chloralidone, indapamide, metolazone.
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Where do thiazides and related drugs take their effect on?
The distal tubule.
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What mechanism do thiazide and related drugs involve?
Inhibiting the Na-Cl cotransporter, thus reducing na reabsorption
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In the control of gastric acid secretion what compounds inhibit secretion of HCL?
GIP, somatostatin
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In the control of gastric acid secretion what inhibits the release of gastrin?
Somatostatin and secretion of HCL via negative feedback.
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Give examples of gastric acid secretions.
HCL, pepsinogen, mucus and bicarbonate ions.
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Which cells maintain the acidic environment in the stomach?
The action of parietal cells.
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Is hydrogen secreted in gastric secretions along/against a concentration gradient?
Against
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How do peptic ulcers arrive?
When the protective layer is disrupted.
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What causes peptic ulcers?
Stress, NSAIDS, diet, alcohol, bacterial, Zollinger-Ellison syndrome.
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Which two scientists received a nobel prize for their work on Helicobacter pylori?
Barry Marshall and Robin Warren.
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What are the therapeutic approaches for peptic ulcers and dysepsia based on?
Manipulation of the gastrin, enterochromaffin-like parietal cell axis .
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What do therapeutic approaches also test for?
presence of Helicobacter pylori.
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What are the roles of antacids?
Buffer. Neutralise acid and raise pH, promote healing over time.
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Give examples of antacids and what they do?
Magnesium and aluminium salts : Mg produces diarrhoea, and AL produce constipation so are used together. Sodium bicarbonate. Alginates, simeticone - affect viscosity of mucus.
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When were histamine receptor subtypes identified?
In the early 1970s.
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What is the effect of histamine H2 receptor antagonists?
They have an effect on both basal and stimulated acid and pepsinogen secretion, can promote healing. There is also a reduction in volume of gastric juice and both basal and food stimulated acid secretion is decreased by 90% or more.
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What are some examples of h2 receptor antagonists?
Cimetidine (inhibits P450), Ranitidine.
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What is common with H2 receptor antagonists?
Ulcer relapse.
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What are proton pump inhibitors?
irreversible inhibtors of h/k atpase. Long term action over 2-3 days, maximum effectiveness reached after 5 days. They reduce basal and stimulated gastric acid secretion.
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What are the benefits of proton pump inhibitors?
They produce fastest rate of healing, generally better tolerated and cheaper than other drugs.
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What is the disadvantage of proton pump inhibitors?
Some association with increased risk of infection, most notably PNEUMONIA AND C.DIFFICILE and originally thought that ecl hyperplasia was problematic.
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Give an example of a proton pump inhibitor and how are they usually administered?
Omeprazole - now accounts for over 90% of prescription for dyspepsia. usually administered in enteric coating.
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How useful is therapy for H.pylori?
80% vs 20% re-ocurrence when eradicated, very useful as this is probably the most important step in healing of peptic ulcers.
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What is involved in H.pylori therapy?
Triple therapy with antibiotics: 2 from amoxicillin/metronidazole/clarithromycin and a proton pump inhibitor. Bismuth chelate is also used in resistant cases..
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What can occur with elimination of H.pylori?
Long-term remission of ulcers, reinfection with the organism.
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What compounds are involved in the protection of the mucosa?
Bismuth chelate, sucralfate, misoprostol - prostaglandin E1 analogue.
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What are the properties of bismuth chelate?
Toxic to H.pylori and prevents adherance, coats ulcer base - adsorbs pepsin - stimulates PG synthesis and bicarbonate secretion, minimally absorbed and normally fully excreted.
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What are the properties of sucralfate?
Aluminium hydroxide and sulfrated sucrose, forms complex gels with mucus - inhibits pepsin - stimulates secretion of mucus, PGs and bicarbonates, requires acidic environment and blocks absorption of some other drugs, may cause constipation.
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What are the properties of misoprostol?
given orally, used for healing of ulcers and prevention of gastric damage from NSAIDs, exerts a direct action on the ECL cell and parietal cell, inhibits the basal secretion of gastric acid and stimulation of production seen in response to food
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Is control of emesis central/local?
Both.
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Where is the primary action of many emetic and antiemtic drugs?
CTZ - chemoreceptor trigger zone that reveives input from the labyrinth through the vestibular nuclei.
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In the control of emesis what compounds inhibit the vestibular nuclei input?
H1 receptor antagonists, muscarinic receptor antagonists.
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In the control of emesis what compounds inhibit the visceral afferents input?
5-HT3 antagonists
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In the control of emesis what compounds directly inhibit the CTZ?
Dopamine antagonists,aprepitant, 5-HT3 antagonists
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In the control of emesis what compounds inhibit the nucleus of the solitary tract?
H1 receptor antagonists and muscarinic receptor antagonists.
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In the control of emesis what compounds inhibit the vomiting centre?
Muscarinic receptor antagonists.
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What are the main antiemetics?
H1 receptor antagonists, muscarinic antagonists.
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What are the antiametics used for postoperative nausea and with cancer chemotherapy?
Selective 5-Ht3 receptor antagonists, antipsychotic, benzodiazepines, D2 receptor antagonists.
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What are some other antiemetics?
Cannabinoids, Glucocorticoids, Neurokinin-1-antagonists.
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Give examples of H1 receptor antagonists and what is their role.
Effective against motion sickness and morning sickness in pregnancy. Cinnazine, Cyclizine, Promethazine.
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What are some side effects of H1 receptor antagonists?
Drowsiness and sedation.
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Give examples of muscarinic antagonists and what is their role
Common motion sickness, prophylaxis. Hyoscine (scopolamine)
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What are some side effects of muscarinic antagonists?
Dry mouth and blurred vision, less drowsiness than antihistamines.
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Give examples of selective 5-HT3 receptor antagonists and side effects?
GI effects and ehadaches, relatively uncommon. Ondansetron, Palonosetron.
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Give examples of antipsychotics and side effects?
Frequently: drowsiness, hypotension, motor disorders. Chlorpromazine.
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What is the role of benzodiazepines?
Adjunct therapy in circumstances where anxiety is a factor.
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Give examples of D2 receptor antagonists, their other role, and side effects?
Metoclopramide, Domperidone. Also increase GI motility. Metoclopramide may have serious CNS side effects.
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Give examples of cannabinoids, their role, and side effects?
Nabilone, sometimes effective when other drugs have failed, decrease vomiting caused by agents that stimulate the CTZ. Side effects: drowsiness, dizziness, dry mouth, mood changes.
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Give examples of glucocorticoids, their role, and side effects?
Dexamethasone, control emesis especially when caused by cytotoxic drugs, involved in inflammatory processes
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Give examples of neurokinin-1 antagonists, their role, and side effects?
Aprepitant, inhibits action of substance P; inhibtor of P450
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How many phases does asthma have and what are they?
2; early and late.
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What is asthma characterised by?
Airway inflammation, bronchial hyperreactivity, reversible airways obstruction.
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How can the degree of obstruction in asthma be measured?
By spirometry; FEV1, FVC, FEV/FVC, PEFR.
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In the immediate phase what are the eliciting agents?
Allergen/ Non-specific stimulus.
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Briefly, what is the process that occurs in the immediate phase resulting in bronchospasm?
Mast cells, mononuclear cells get activated forming spasmogens/chemotaxins/chemokines, this activates bronchospasm.
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How can bronchospasm be reversed?
B2 adrenoceptor antagonists, CysLT-receptor antagonists and theophyline.
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In the late phase what are the eliciting agents?
Inhalation of cytokine releasing Th2 cells, and monocytes, and activation of inflammatory cells; eosinophils.
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What is the mechanims that occurs in the late phase that leads to airway inflammation, hyperreactivity and bronchospasm, wheezing, coughing?
The eliciting agents produce mediatiors and EMBP/ECP. EMBP/ECP activates epithelial damage which activates airway hyper-reactivity and therefore bronchospasm. Meanwhile, the mediators activate all three.
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How can all three reactions be inhibited?
By glucocorticoids.
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In genetically susceptible individuals what does allergen interact with?
Dendritic cells and CD4 T cells, leading to the development of Th0 lymphocytes which give rise to a clone of Th2 lymphocytes.
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What is the therapy given for changes that occur in the bronchioles?
Bronchodilators and anti-inflammatories.
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What are some of the changes that occur in the bronchioles during severe chronic asthma?
dilated blood vessels, thickened basement membrane, epitelial cell loss, mucus plug with eosinophils and desquamated epithelial cells, hypertrophied smooth muscle, infiltration of inflammatory cells.
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To treat asthma what are the first 4 steps physicians would take?
1. very mild disease controlled with short acting BRONCHODILATORS. 2. Addition of a regular inhaled corticosteroid. 3. Addition of a long acting bronchodilator. 4. Addition of one or the other: Theophylline/Monteleukast OR increase IC.
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To treat asthma what is the last step physicians would take?
Addition of a regular oral corticosteroid.
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What is the role of B2-adrenoceptor agonists?
To dilate the bronchi, increase cAMP generation, inhibiton of mast cell mediator release, enhance mucociliary clearance.
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Give examples of short acting B2-adrenoceptor agonists, when are they given and what are their roles?
Salbutamol, Terbutaline, given as needed. Role: prevent/treat wheeze in patients with reversible obstructive airways disease.
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Give examples of long acting B2-adrenoceptor agonists, when are they given and what are their roles?
Salmeterol, Formoterol (enters lipid bilayer), given as adjunct to other treatments/prophylactically. Role: prevent bronchospasm in patients needing long term therapy.
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What are some properties of B2 adrenoceptor agonists?
Usually administered by inhalation, selectivety is dose related, structure [prevents uptake and metabolism by COMT, duration of action prolonged by incorporation of lipophilic side chain.
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Are there other methods that short acting B2 adrenoceptor agonists can be delivered by?
Orally, subcutaneously and intravenously.
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What are some unwanted affects from B2-adrenoceptor agonists?
Desensitisation/tolerance to effects, tremor (most common), tachycardia/arrhythmia (particularly with high dose), acute metabolic responses, paradoxical bronchospasm, heada
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Why does hyperpolarisation occur in the mechanism of B2-adrenoceptor agonist?
It occurs due to an opening of K channels as K moves out of the cell down the concentration gradient, this then decreases the voltage and causes closure, this causes intracellular calcium ion levels to fall meaning so a contraction is less likely.
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What is the role of corticosteroids?
They inhibit the allergen-induced influx of eosinophils into the lung, they are the mainstay of therapy because they are the only asthma drugs that potently inhibit T cell activation + thus the inflammatory response in the asthmatic airways and inhi
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Give some examples of corticosteroids?
Beclometasone, Budesonide, Fluticasone, Mometasone, Ciclesonide, Prednisolone.
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What are some other actions of corticosteroids?
Inhibit production of leukotrienes, upregulate B2-adrenoceptors, decrease microvascular permeability
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What are some unwanted effects from corticosteroids?
Limited by route of administration, oropharyngeal thrush, sore throat, adrenal suppression
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How are corticosteroids introduced?
When using bronchodilator more than once daily.
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What are the 3 types of muscarinic receptors associated with airway functions and their roles?
M1-facilitate parasympathetic ganglia transmission, M2 - presynaptic inhibtory autoreceptors, M3 - postsynaptic, mediating bronchoconstriction and mucus secretion via generation of cGMP
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How are antimuscarinic compounds introduced?
By inhalational route, non selectivity may inhibit effect
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Give examples of antimuscarinic compounds?
Ipratopium (short acting) and tiotropium (medium)
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What are antimuscarinic compounds used for ?
To reduce secretions/increased clearance - can be used in conjunction with drugs like salbutamol.
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What are some unwanted effects of antimuscarinic compounds?
Dry mouth, constipation, can contribute to glaucoma.
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What is the role of methylxanthenes?
They have a negative effect on contraction bringing about dilation
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Give an example of a methylxanthene?
Theophylline and related derivative AMINOPHYLLINE
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What are the actions that methylxanthenes take?
Phosphodiesterase III, IV, V inhibtion which elevates cGMP and CAMP, increased contraction of diaphragm, adenosine receptor antagonism, activation of histone deacetylases, administered with steroids and also iv in severe asthma
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What are some unwanted effects of methylxanthenes?
hypotension, CNS and GI disturbance, potential for drug interaction as metabolised by CYP3A4 and has low TI
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What are leukotriene receptor antagonists?
Oral agents with additive effects when given with corticosteroids, well tolerated antagonists of CysLT1 receptors only.
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What do leukotrine receptor antagonists do?
Inhibit early and late stage bronchoconstriction, Reduce acute reactions to aspirin in sensitive patients, they inhibit exercise-induced asthma, relax the airways in mild asthma
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Five an example of a leukotriene receptor antagonist?
Monteluklast
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What is status asthmaticus?
A severe form of asthma needing hospitalisation/medical emergency requiring prompt attention
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What methods are used to treat status asthmaticus?
high concentration oxygen, use of nebuliser to deliver salbutamol, iv corticosteroid, oral prednisolone, may require supplementation with other drugs, monitored with spirometry and blood gas
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What did Meyer commence about general anaesthetics?
When any chemically indifferent substance has attained a certain molar concentration in the lipids of the cell
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List in order of anaesthetics decreasing oil:gas partition coefficient and increasing MAC (atm)?
Methoxylflurane, Chloroform, Halothane, Ether, Fluroxane, Cyclopropane, Xenon, Nitrous oxide, Sulfur hexafluoride, Carbon tetrafluoride
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What is the receptor mediated mechanism of action of general anaesthetics?
Potentiation of GABAa and glycine. Inhibition of NAChR, 5HT3 and NMDA.
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What are the effects that general anaesthetics have on the nervous system?
Enhancement of tonic inhibition, unconsciousness, loss of reflexes, analgesia, amnesia due to interference with hippocampal function, high concentrations affect whole CNS
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Whatis the description of each stage of anaesthesia ?
1 - Analgesia. 2 - Excitation. 3 - Surgical Anaesthesia. 4 - Medullary depression.
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Give some examples of intravenous anaesthetics?
Propofol, Thiopental, Etomidate, KEtamine, Midazolam
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Give some examples of inhalational anaesthetics?
Nitrous oxide, Isoflurane, Desflurane, Sevoflurane, Halothane, Enflurane, Ether.
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Give some examples of local anaesthetics?
Procaine, Cocaine, Lidocaine, Mepivacaine, Tetracaine, Bupivacaine, Priiocaine, Articaine.
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What are the factors affecting rate of induction and recovery and how do they affect it?
Solubility in blood - Blood:gas partition coefficient -- Induction/recovery quicker with low blood solubility as equilibrium is reached sooner. Solubility in fat-oil:gas coefficient -- Determines potency, if too high recovery is delayed
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what are the properties of local anaesthetics?
all effective compounds are weak bases existing in both ionised and unionised form at physiological pH - important as otherwise have no penetration of axonal membrane. Act by use-dependent block of neuronal Na channels.
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Why are pain pathways more sensitive to the effect of local anaesthetics?
A resting nerve has less sensitivity to a local anaesthetic than a naive nerve that is repeatedly stimulated.
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What are some properties of the ideal anaesthetic?
Inherently stable, analgesic, non-toxic, inexpensive, non-irritant to the airways
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In reality how are anaesthetics used?
Except for simple surgery, in combination: sedative, iv anaesthetic, one/two inhalational anaesthetics, neuromuscular blocker, an antiemetic, an antimuscarinic and an analgesic.
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What kind of system controls blood pressure?
An integrated system.
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What are the prime contributors in the integrated system that controls blood pressure?
Cardiac output - stroke volume, heart rate .Total peripheral resistance
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What are some key things that increase cardiac output and BP?
Increased cardiac stimulation, increased arterial constriction, venous constriction and therefore increased venous return.
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What are some key things that decrease cardiac output and BP?
decreased baroreceptor afferent input, increased sympathetic vasomotor center activity
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What occurs when decreased cardiac output leads to decreased BP?
Renin is released
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For the treatment of hypertension in the vasomotor centre what drugs can be used?
alpha2 adrenoceptor agonists, imidazoline receptor agonists.
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For the treatment of hypertension in the sympathetic nerve terminals, what drugs can be used?
adrenergic neuron antagonists
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For the treatment of hypertension in the sympathetic ganglia what drugs can be used?
ganglion blockers
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For the treatment of hypertension in the heart what drugs can be used?
Beta-adrenoceptor antagonists
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For the treatment of hypertension on the vessels what drugs can be used?
Angiotensin receptors - ACE inhibitors and AT1 receptor antagonists. Alpha-adrenoceptors - a1 antagonists
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For the treatment of hypertension on the vascular smooth muscle what drugs can be used?
Diuretics, vasodilators, nitrovasodilators, calcium channel antagonists, potassium channel openers.
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For the treatment of hypertension in the kidney tubules what drugs can be used?
Diuretics, ACE inhibitors
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For the treatment of hypertension in the juxtaglomerular cells that release renin, what drugs can be used?
Beta-adrenoceptor antagonists
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For the treatment of hypertension in the adrenal cortex what drugs can be used?
ACE inhibitors of angiotensin 2 formation, AT1 receptor antagonists
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Give some examples of Beta-adrenoceptor antagonists used in controlling blood pressure?
Atenolol, propranolol, pindolol
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What are the actions that beta- adrenoceptor antagonists use in controlling blood pressure?
B1 receptor blockade - decreased CO and HR, reduced renin secretion
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Do beta-adrenoceptor antagonists ever get aid?
Yes, in some cases, by vasodilation of blood vessels supplying skeletal muscle
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What are some problems with beta-adrenoceptor antagonists?
Some show rapid 1st pass metabolism, hence poor bioavailability
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Give some examples of alpha-adrenoceptor antagonists used in controlling blood pressure?
Prazosin, Doxazosin - a1 selective. Phenoxybenzamines - non selective.
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What are the actions that alpha- adrenoceptor antagonists use in controlling blood pressure?
Reduction of arteriolar resistance and dilation of venous capacitance vessels.
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What else can alpha- adrenoceptor antagonists do?
Induce a reflex tachycardia that may be marked with non selective compounds, can increase HDLs,
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Between the compounds of alpha-adrenoceptor agonists used what are their different therapeutic half lives?
Prazosin - short acting, Doxazosin - Long acting
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What are some side effects of alpha-adrenoceptor antagonists?
Postural hypotension (venous pooling), lethargy and palpitations.
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Give examples of ACE inhibitors?
Captopril, enalapril.
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What are the mechanisms that ACE inhibitors use to get a therapeutic effect?
Hypotensive effect without reflex tachycardia, Reduced aldosterone release, Reversal of left ventricular hypertrophy, prevention of vascular change by inhibition of cellular growth, reduced degradation of vasodilator kinins (side effect of cough link
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Give some examples of Angiotensin receptor antagonists?
Losartan, Valsartan
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What are some properties of Angiotensin receptor antagonists?
selective for the At1 receptor, AT antagonists are better absorbed but much 1st pass metabolism (although active metabolite formed), better tolerated than ACE inhibitors but may cause headache and lethargy
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Give examples of directly acting vasodilators?
Calcium channel antagonists, potassium channel activators (minoxidil). Hydralazine
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What are the side effects of minoxidil?
Flushing, headache, reflex tachycardia and palpitations, salt and water retention, hirsutism
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How do potassium channel antagonists work?
By antagonising the action of intracellular ATP on these channels, opening the channel hyperpolarises the cells and switches off voltage dependent calcium channels
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How does Hydralazine work?
It produces relaxation by mechanism similar to organic nitrates, it interferes with the action of inositol triphosphate on calcium release from the sarcoplasmic reticulum
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What are the side effects of hydralazine?
Reflex sympathetic activation and an SLE like syndrom
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In the management of hypertension when are you more likely to treat borderline hypertension?
If patient has renal impairment, ischaemic heart disease, diabetes or previous stroke.
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For the young, what type of drug treatments for hypertension are to be expected?
Beta-adrenoceptor antagonists/ ACE inhibitors
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For the elderly, what type of drug treatments for hypertension are to be expected?
Calcium channel antagonists/ Diuretics
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In pregnancy what type of drug hypertension is to be expected?
Methyldopa
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Via the British hypertension society in the overall mechanism for expected drugs given to the young vs elderly what is stage 4?
Resistant hypertension
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What is advised in Stage 4?
Add either alpha-adrenoceptor antagonist/ spironolactone/ other diuretic.
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What are the simplified steps of atherosclerosis?
Plaque formation, plaque rupture, thrombus formation, death and disability caused by heart attack (myocardial infarction) and stroke
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In lipid processing, what is the importance of cholesterol?
Important for constituent of cell membrane and precursor of important steroids (bile salts, steroid hormones)(
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In lipid processing, where is cholesterol made?
By the liver by HMG-CoA reductase and excess released complexed with VLDLs which generates LDLs
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How are LDLs taken up?
By the liver (receptor mediated) or into peripheral tissues (non receptor mediated)
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What do HDLs promote?
transport from peripheral tissues to liver
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In the endogenous pathway what do statins decrease?
synthesis of cholesterol
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In the endogenous pathway what do statins, renins and fibrates increase?
Uptake of LDL
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In the endogenous pathway what do fibrates decrease?
Secretion of cholesterol
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Where do fibrates enhance?
conversion of vldl to ldl -endogenous. conversion of chylomicrons to chylomicron remnant - exogenous
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Where do resins bind in the exogenous pathway?
Bile acids
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Can dyslipidaemia be either a primary or secondary form, or must it be one specifically?
Either.
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What do primary/secondary dyslipidaemia result from?
Inherited disorder, dietary factors, diseases affecting lipid metabolism
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What is the name of the classification of hyperlipoproteinaemia?
Fredrickson, defines 6 groups based on which lipoprotein is elevated
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Which groups, out of the 6 are at most risk of atheroma?
Groups 2a and 2b
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Give examples of statins?
Simvastatin, lovostatin, pravastatin, atorvastatin
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What are the roles of statins?
Inhibit HMG-CoA reductase reducing cholesterol, upregulates LDL receptors, reduce VLDL and increase HDL production, should be considered for patients at risk of cardiovascular disease.
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Are statins well absorbed, and where are they excreted?
Yes, from the gut. They are excreted by the liver
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What are the non lipid effects of statins?
Restored function to damaged endothelium, stabilisation of atherosclerotic plaques, altered haemostasis, reduced inflammatory cell infiltration into plaques.
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Give some examples of fibrates and when are they of benefit?
Bezafibrate, Gemfibrozil, Ciprofibrate. Of benefit in the treatment of mixed dyslipidamia due to action on triglycerides.
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What is the mechanism that fibrates use?
They are agonists at PPARalpha nuclear receptors. Once activated the ppre/target genes then cause an increase in ldl particle size, hdl synthesis and reverse cholesterol transport. And a decrease in triglycerides and inflammation.
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