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PA20321 Retake > Pharmacology Last time > Flashcards

Pharmacology Last time Flashcards

1
Q

What is the hypothalamo-pituitary axis?

A

The hypothalamus is part of the brain that monitors many aspects of the state of the body systems, integrating a large amount of information from many sensory pathways. With regards to the endocrine system it is recognised as being closely linked with the pituitary gland, a small gland hanging from underneath the hypothalamus.There are two parts to the pituitary gland, an anterior part (the adenohypophysis) and a posterior part (the neurohypophysis).

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2
Q

What can pituitary disease cause?

A
  • Over- or underactivity of each of the hypothalamic-pituitary-end-organ axes- Benign pituitary tumours (adenomas) are the most common cause (90%)- Vision loss due to compression of the optic chiasm is a common comorbidity
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3
Q

What is Hypopituitarism?

A
  • Diminished hormone secretion by the pituitary gland, causing dwarfism in children and premature ageing in adults- Rare- Managed by replacement therapy with the appropriate hormone
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4
Q

Explain different types of thyroid hormones

A
  • Triiodothyroxine (T3) and Thyroxine (T4: 90% of total)- T4 regarded as a prohormone for T3: has a lower affinity: T4 is convereted to T3 in peripheral tissues by Type I and Type II deiodinases: Half-life of T3 (1day) is shorter than T4 (6days)- Thyroid hormones circulate bound to plasma proteins (>99%): thyroxine-binding globulin (TBG), transthyretin (TTR) and thyroxine binding prealbumin- Thyroid hormones regulate BMR and enhance actions of cathecholamines
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5
Q

What is Pendrin and how does it contribute to thyroid hormone synthesis?

A
  • Pendrin is a sodium-independent chloride/iodide transporter and acts as an antiporter anion exchanger protein- Pendrin presents at the apical (luminal) membrane of follicular cells in the thyroid gland, where it transports iodide from cytoplasm to follicle lumen. Its activity is necessary for production of thyroid hormone
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6
Q

What are Thyroid Oxidase (TO) and Thyroid peroxidase (TPO) responble of?

A
  • iodination of tyrosyl residues in TG (thyroglobulin) and coupling reactions
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7
Q

What are the physiological effects of thyroid hormone in the following targets?1. Cardiovascular system2. Bone3. Respiratory system4. GI system5. Blood6. Neuromuscular function7. Carbohydrate metabolism8. Lipid metabolism9. Sympathetic nervous system

A
  1. Cardiovascular system- Increases HR and Cardiac Output2. Bone- Increases bone turnover and resorption3. Respiratory system- Maintains normal hypoxic and hypercapnic drive in respiratory centre4. GI system- Increases gut motility5. Blood- Increases RBC 2, 3-BPG faciliating oxygen release to tissues6. Neuromuscular function- Increases speed of muscle contraction and relaxation and muscle protein turnover7. Carbohydrate metabolism- Increases hepatic gluconeogenesis/ glycolysis and intestinal glucose absorption8. Lipid metabolism- Increases lipolysis and cholesterol synthesis and degradation9. Sympathetic nervous system- Increases catecholamine sensitivity and b-adrenergic receptor numbers in heart, skeletal muscle, adpose cells and lymphocytes- Decreases cardiac a-adrenergic receptors
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8
Q

What is Hypothyroidism?

A
  • Abnormally low activity of the thyroid gland, resulting in retardation of growth and mental development in children and adults.- One of the most common endocrine disorders- Usually primary (disease of thyroid) but can be secondary (decreased TSH)- Most common form is atrophic (autoimmune) hypothyrodism
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9
Q

What are clinical features of hypothyroidism?

A
  • Tiredness- Weight gain- Cold intolerance- Goitre (swelling in neck)- Mental Slowness- Dry skin and hair- Bradycardia- Slow-relaxing reflexes
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10
Q

What is diagnosis and management of Hypothyroidism

A

Diagnosis- Serum TSH ( increased level confirms primary hypothyroidism): low free T4 confirms the diagnosis and excludes TSH deficiency (secondary hypothyroidism)Management- Replacement therapy with levothyroxine (lifelong)

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11
Q

What is Hyperthyroidism?

A
  • Over-activity of the thyroid gland, resulting in a rapid heartbeat and an increased rate of metabolism
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12
Q

What is diagnosis and management of Hyperthyroidism

A

Diagnosis- Serum TSH (↓< 0.05 mU/L): raised T3 (more sensitive) or T4 confirms the diagnosis- TSHR-Ab usually present (80%) but not routinely measured- Thyroid peroxidate (TPO) and thyroglobulin antibodies usually presentManagement1. Antithyroid drugs e.g Carbimazole2. Radioiodine 3. Surgery

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13
Q

What are the hormones secreted by endocrine pancreas?

A

Beta cells- produce and release insulin- stimulates glucose utilisation and uptakeAlpha-cells- produce and release glucagon-increases breakdown of glycogen and glucose release

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14
Q

What features does insulin have regarding plasma levels?

A
  • Decrease glucose- Decrease amino acids- Decrease FFAs- is Anabolic
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15
Q

What features does glucagon have regarding plasma levels?

A
  • Increases glucose- Increase ketones- is Catabolic
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16
Q

What are the issues associated with untreated high BP.

A

Atherosclerosis (Endothelial damage)Internal organ damage (Kidney, eyes and nerves..)Strain on heartPulmonary oedema (left ventricular hypertrophy)Peripheral oedema (congestive heart failure)

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17
Q

Give the cardiovascular risk factors.

A

SmokingHigh salt intakeSystemic hypertensionAlcohol (greater than 21 units in men, and greater than 14 in women)Lack of exerciseObesityDyslipidaemiaDiabetesGeneticsAgeLifestyle

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18
Q

What are some causes of systemic hypertension.

A

Majority of the time, there is no apparent cause…Endocrine gland disordersKidney diseaseDrug inducedWhite-coat hypertension

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19
Q

Describe when stage 1, 2, and 3 hypertension is diagnosed.

A

Stage 1 = greater or equal to 140/90mmHg in the clinic, and greater than 135/85mmHg when measured at homeStage 2 = greater or equal to 160/100mmHg in the clinic, and greater than 150/95mmH when measured at homeStage 3 = greater or equal to 180/110

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20
Q

When is hypertension treated?

A

Stage 1 hypertension = lifestyle changesStage 1 + one of the following…Target organ damageEstablished CVDRenal diseaseDiabetes10-year CV risk greater or equal to 20%Stages 2 and 3

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21
Q

What are the different types of anti-hypertensives available.

A

Drugs that act on RAAS (Renin angiotensin aldosterone system)-ACEi-ARBs-Renin inhibitors-Aldosterone antagonistsKidneys-DiureticsDirectly acting vasodilators-CCB-Potassium channel openers-others..Drugs that act on the sympathetic nervous system-Beta blockers-Alpha 1 adrenoceptor antagonists (targets blood vessels)

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22
Q

What is the first line treatment of hypertension.

A

Under the age of 55-ACEi or angiotensin II receptor blocker (ARB)Over aged 55 or black person of african or caribbean family origin (any age)-CCB

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23
Q

How is the secretion of renin regulated. What is the purpose of it.

A

Drop in blood pressureSympathetic stimulation of beta 1 adrenaline receptorsLow blood volumeIncreases in PGE2/PGI2Loss of NA+Renin is released from the juxtaglomerular cells in the kidney and rapidly enters the bloodstreamCleaves angiotensinogen (inactive) which is produced in the liver and is constantly circulating the blood –> Angiotensin I (inactive)Angiotensin converting enzyme is abundantly present on endothelial cells surfaces to produce angiotensin II,

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24
Q

Describe how angiotensin II elicits its effects.

A

Angiotensin II binds to AT1 receptors (Angiotensin II type 1 receptors)This causes 3 main things..Vascular growth-Hyperplasia (increase in number of cells)-Hypertrophy (increase in size of cells)Vasoconstriction-Directly acts on blood vessels and causes sympathetic NA releaseSalt retention-Increases aldosterone -Increases Na+ reabsorption

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25
Q

How do ACEi work?What is a common side effect?

A

ACEi prevent angiotensin II from being produced from angiotensin I – via inhibition of the angiotensin converting enzyme.This reduces vasoconstriction and reduce the amount of aldosterone produced – less salt is retained, and so there is less water entering the blood to increase the blood pressure via osmosis.ACE breaks down bradykinin. The inhibition of it therefore results in increased bradykinin levels.Increased bradykinin increases the vasodilating effects, but also causes a cough. –pril drugs

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26
Q

How do ARBs work?

A

Angiotensin receptor blockers prevent angiotensin II from binding to AT1 receptors. This, like ACEi, reduce the levels of aldosterone and vasoconstriction.–> reduced blood pressureHowever, because ARBs are specific to AT1 receptors, this does not block the breakdown of bradykinin from ACE.Hence, angioedema and coughs are prevented–sartan drugs

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27
Q

What is the triple whammy effect with respect to the use of NSAIDs, ACEi and diuretic.

A

Dangerously low GFR and potential for renal failure.The blood volume is decreased due to the diuretic. This causes the GFR to decrease. RAAS is stimulated in order to increase the blood volume and hence increase the GFR.However, ACEi impairs the function of RAAS. This prevents effective constriction of the efferent arterioles resulting in a greater reduction of the GFR.The afferent arteriole cannot relax more due to the NSAID blocking COX-2. Further reducing GFR.–>Renal failure?

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28
Q

What are the common side effects of ACEi

A

-Hypotension-Taste disturbances (Captopril)-Dry cough-Angioedema-Hyperkalaemia (reduced excretion of potassium due to aldosterone reduction)-Reversible renal failure in patients (reversed if ACEi is stopped)

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29
Q

What is Type 1 diabetes mellitus?

A
  • Body unable to produce any insulin- Usually appears in childhood and before the age of 40- Sudden onset- Accounts for between 5-15% of all people with diabetes
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30
Q

What are the symptoms of T1DM?

A
  • Increased thirst - Increased urination- Weight loss- Fatigue- Nausea, Vomitting- Coma- Patients often diagnosed in an emergency setting as symptoms develop over a short period of time
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31
Q

What type of disease is T1DM?

A
  • Autoimmune disease- Characterised by immune-mediated destruction of the insulin-secreting beta-cells of the pancreas- Auto-antibodies to insulin (IAA), glutamic acid decarboxylase (GADA), islet cell cytoplasm, zinc transporter and protein tyrosine phosphate have all been identified
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32
Q

What causes T1DM?

A
  • Genetic risk factors (HLA)- Environmental factorse.g viral infection
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33
Q

What are the risk and benefits of the islet cell transplantation for T1DM?

A

Risk- Transplantation surgery risk- Immunosuppresants drugs side effects- Need 2-3x transplantsBenefits- Live without insulin injections- Improved blood glucose control

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34
Q

What is Type 2 Diabetes Mellitus?

A
  • Body cannot produce enough insulin OR the body cannot respond to insulin = ‘insulin resistance’- Used to appear in people >40yrs of age but younger poeple are increasingly diagnosed- Can go undiagnosed for a long time- Accounts for between 85-95% of all patients with diabetes
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35
Q

What are the symptoms of T2DM?

A
  • Increased thirst- Increased urination- Increased appetite- Fatigue- Blurred vision- Slow-healing infections- Slower onset than T1DM, symptoms develop over a long period of time and may go unnoticed
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36
Q

What are the risk factors of T2DM?

A
  • Parent, brother, sister with diabetes- Obesity- Age greater than 45 yrs- Some ethnic groups- Gestational diabetes or delivery a baby >9lbs- High blood pressure- High cholesterol level
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37
Q

what is Gestational diabetes?

A
  • Associated with pregnancy and usually transient- Body cannot product enough insulin- Serious risk to mother and baby
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38
Q

What testings are there for diabetes?

A
  1. Glycosylated haemoglobin (HbA1c)- when glucose attaches to proteins they become glycated- measures glycated haemogloblin2. Fasting plasma glucose test (FPG)- Fast for 8h, blood sample taken3. Oral glucose tolerance test (OGTT)- Fast for 8h, blood sample taken, drink sugary drink, 2h later blood sample taken4. Urine analysis- Glycosuria- Ketone bodies
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39
Q

What are the metabolic complications of diabetes?

A
  • Hypoglycaemia/Hyperglycaemia- Diabetic ketoacidosis (DKA)- Hyperosmolar hyperglycaemic state (HHS)
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40
Q

What are the microvasuclar complications of diabetes?

A
  • Damage to small blood vessels (arterioles, capillaries, venules): retina (retinopathy): kidney (nephropathy): nerves (neuropathy)
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41
Q

What are the macrovascular complications of diabetes?

A
  • Damage to larger arteries: brain (stroke): heart (coronary heart disease): legs & feet (peripheral vascular disease)
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42
Q

How are hypoglycaemia and hyperglycaemia induced?

A

Hypoglycaemia- not eating enough carbohydrates- taking too much insulin- exercising too muchHyperglycaemia- eating too much sugary food- drinking alcohol- not taking medication- not exercising

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43
Q

How is diabetic ketoacidosis in T1DM induced?

A
  • when glucose not available for energy generation- body uses fat where ketones are a by-product of fat metabolism, lowers plasma pH
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44
Q

How is hyperosmolar hyperglycaemic state (HSS) induced?

A
  • High blood sugar results in high osmolarity without significant ketoacidosis
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45
Q

How does diabetic retinopathy occur? What are the stages?

A

Background retinopathy- Tiny bulges develop in the blood vessels, which may bleed slightly but don’t usually affect visionPre-proliferative retinopathy- More severe and widespread changes affect the blood vessels, including more significant bleeding in the eyeProliferative retinopathy- Scar tissue and new blood vessels, which are weak and bleed easily, develop on the retina

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46
Q

How does diabetic nephropathy occur?

A
  • Damage to the capillaries in the glomerulus leads to breakdown of filtration barrier and more protein collected in the urine- Exacerbated by hypertension, a common prioblem in DM- Develops very slowly and over time, decline in kidney function leads to chronic kidney failure
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47
Q

How does diabetic neuropathy occur?

A
  • Peripheral nerve dysfunction- Capillary damage can lead to nerve damage and loss of sensation- Loss of sensation and circulation problems leads to increased risk of infection, ulcer and gangrene
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48
Q

What is the major mechanism underlying macrovascular complications in diabetes mellitus?

A

Atherosclerosis- results from chronic inflammation and injury to the arterial wall in the peripheral or coronary vascular system

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49
Q

Give examples of cardiovascular regulation by the ANS

A
  • Control of heart rate- Contraction & relaxation of smooth muscle in blood vessels & organs- Regulation of glandular secretion- Metabolism
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50
Q

Why are drugs that affect RAAS not used in specific patient groups.

A

Elderly patients’ RAAS system is less effective. (55 yrs+)Patients of african/caribbean origin have a lower activity of RAASThere is potential for teratogenic effects in pregnant women.

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51
Q

How are CCB effective in treatment of hypertension.

A

They block L-type voltage gated ion channels – reduces calcium entering the smooth muscle cells.-> Causing arterial dilation and venodilation-> Decrease in TPR & cardiac after load and reduces venous pressure and cardiac preload respectively.Good alternate treatment in the elderly, pregnant and caribbean/african population.-dipine drugs

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52
Q

What are the common side effects associated with CCB

A

Postural hypotensionTachycardiaHypotensionAnkle oedemaHeadaches and flushesMyocardial ischaemiaConstipationAV block, bradycaridaNegative inotropic effect – do not use the drug in heart failure

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53
Q

How can potassium channel activators be used in the treatment of hypertension.

A

ATP-sensitive potassium channels are activated in the vascular smooth muscles.This causes membrane hyperpolarisationL-type voltage gated calcium channels are closedThere is less calcium influxVasodilation occurs

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54
Q

Give an example of a potassium channel activator, and name some common side effects.

A

MinoxidilReflex tachycardiaFluid retentionDiabetes mellites (by inhibiting insulin release from beta pancreatic cells Hisutism (hair growth)

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55
Q

What is hydralazine? In what patient groups is it indicated for? What are the side effects?

A

A direct actin vasodilatorCauses systemic dilation of arteries and arteriolesDecreases TPR & cardiac afterloadIndicated for severe hypertension in pregnancy (with diuretic and beta blockers)Heart failure in those of african-caribbean origin. (with nitrates)Side effects:-Lupus syndrome-Tachycardia & palpitations-Hypotension and peripheral oedema

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56
Q

Give examples of drug classes for hypertension that act on the sympathetic NS.

A

Beta blockersAlpha 1 receptor antagonistsAlpha 2 receptor agonistsImidazoline receptor agonistsGanglion blockersAdrenergic neuron blockers

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57
Q

How do beta-blockers work?

A

Block beta-1 receptors in the heart – responsible for increasing of heart rate.Reduces reflex tachycardia Reduces renin release and activation of RAASReduces central sympathetic activity-olol drugs

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58
Q

When are beta-blockers used? What are the side effects commonly associated with drug

A

Resistant hypertensionSevere hypertension in pregnancy (only labetalol)Bronchoconstriction (asthma???)Hypoglycaemia and reduced awareness of itBradycardiaNegative inotropic effectFatigueCold extremitiesErectile dysfunction

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59
Q

Receptors in noradrenergic transmission: alpha and beta can be further subdivided intoalpha - alpha1, alpha 2beta- beta1, beta2, beta3What does this subdivision induce?

A
  • Receptor subtypes mediate different responses by coupling to different second messenger systems
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60
Q

When would alpha 1 adrencoceptor antagonists be used.What are the side effects of the drug.

A

Severe hypertension in addition to first line treatment drugs & diureticsFirst dose hypotensionDizzinessFatigue

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61
Q

What are the therapeutic applications of: 1.) Moxonidine2.) Alpha Methyldopa3.) Clonidine

A

Moxonidine = resistant hypertensionAlpha methyldopa = severe hypertension in pregnancyClonidine is usually used in migraine, insomnia and opioid detoxification – rarely used as a antihypertensive.

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62
Q

Give the adverse effects of central acting drugs

A

Rebound hypertension upon withdrawalDry mouthSedation and drowsinessRespiratory depressionImmune haemolytic reactionsLiver toxicity

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63
Q

How does trimetaphan work.

A

Competitive nicotinic acetylcholine receptor antagonist at the autonomic gangliaActs on both sympathetic and parasympathetic ganglia

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64
Q

Give 2 examples of ganglion blocking drugs

A
  1. Hexamethonium- Non depolarising nicotinic antagonist- No clinical use2. Local anaesthetics- Sympathetic ganglion block- Blocks sympathetically-mediated pain pathways
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65
Q

How is a transmitter synthesised?

A
  • Postganglionic fibres send axons to target organ- Enzymes involved in transmitter synthesis made in cell body- Synthetic enzymes transported to nerve terminus- Transmitters made at terminal varicosities
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66
Q

Describe synthesis of noradrenaline at nerve terminal

A
  1. L-tyrosine, under influence of Tyrosine hydroxylase, forms DOPA2. DOPA, under influence of DOPA decarboxylase, forms Dopamine3. Dopamine, under influence of dopamine beta-hydroxylase, forms Noradrenaline
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67
Q

Drugs affecting synthesis of noradrenaline

A
  1. The initial enzyme in formation of NA (L-tyrosine to DOPA) is tyrosine hydroxylase- inhibited by alpha-methy-p-tyrosine (Metirosine)2. Second stage of synthesis (DOPA to Dopamine) by DOPA decarboxylase- inhibited by Carbidopa3. Dopamine beta-hydroxylase inhibited by Nepicastat but is not clinically useful
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68
Q

How is nor-adrenergic release regulated?

A
  • Depolarisation of nerve ending opens calcium channel- Leads to vesicle exocytosis- NA released- Released NA activates presynaptic receptors that inhibit adenylyl cyclase- This prevents calcium channel opening and limits further release of NA
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69
Q

Describe termination of Noradrenergic transmission

A
  1. NA rapidly removed from synaptic cleft by Neuronal Epinephrine Transporter (NET) - Uptake 12. Uptake into vesicles by Vesicular Monoamine Transporter (VMAT)3. Free concentration of NA low in neuron cytoplasm due to monoamine oxidase (MAO) activity4. Extraneuronal Monoamine Transporter (EMT) - Uptake 2
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70
Q

Which drugs inhibit release of noradrenaline?

A
  1. Methyldopa- metabolised to methyl-NA- false precursor molecule- alpha2 agonist- Peripheral and central effects on BP- Also inhibits DOPA decarboxylase2. Guanethidine- substrate for NET- blocks depolarisation at nerve terminal- also substrate for VMAT- overall effect: block of adrenergic neurons3. Reserpine- inhibits VMAT- prevents transport of NA into vesicles- vesicular level falls- antihypertensive
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71
Q

What are the unwanted effects of inhibiting NA synthesis/release?

A
  1. General anti-sympathetic effects: hypotension: bradycardia: digestive disorder: nasal congestion: sexual dysfunction2. Central effects common: sedation: mood disturbance
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72
Q

Which enzymes metabolise Noradrenaline?

A
  1. Monoamine oxidase (MAO)- found mainly in neurones, also liver & GI tract- NA → DOMA2. Catechol-o-methyl transferase- neuronal and non-neuronal tissue- also metabolises DOMA produced from MAO
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73
Q

Receptors in noradrenergic transmission: alpha and beta can be further subdivided intoalpha - alpha1, alpha 2beta- beta1, beta2, beta3What does this subdivision induce?

A
  • Receptor subtypes mediate different responses by coupling to different second messenger systems
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74
Q

What is atherosclerosis

A

A progressive disease of large and medium sized muscular arteries.It is characterised by inflammation and dysfunction of the lining of the blood vessel, and results in the build up of cholesterol, lipids and cellular debris.This forms an atheroma that obstructs good blood flow, and results in poorer oxygen supply to target organs.Largely asymptomatic

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75
Q

What are the complications relating to atherosclerosis

A

CHDLeading anginaACS & MICerebrovascular atherosclerotic disease

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76
Q

What are the risk factors associated with atherosclerosis

A

HypertensionUncontrolled diabetes mellitusSmokingExcessive alcohol consumptionHigh fat dietLack of exerciseObesityGenderAgeGenetics

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77
Q

What are some of the plasma markers that can indicate atherosclerosis

A

CRPHomocysteineCoagulation factorsLipoprotein(a)

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78
Q

Describe the 2 types of cholesterol

A

LDL -Single apolipoprotein – B-100 – important for recognition of the lipoprotein by the receptors-Small size-Low protein to cholesterol ratioHDL-Recycles unused cholesterol back to the hepatocytes to be reused.-Main lipoproteins are A-I and A-II-Small size-High protein to cholesterol ratio

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79
Q

What are some ways in which cholesterol and lipoproteins are transported

A

Chylomicrons: They transport triglycerides and esterified cholesterol into the bloodstream from the intestines. (EXOGENOUS CHOLESTEROL)VLDL (very low density lipoprotein): Cholesterol esters and newly synthesised triglycerides (ENDOGENOUS CHOLESTEROL)IDL (Intermediate density lipoprotein): Cholesterol

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80
Q

Describe the movement of dietary cholesterol.(10 marks)

A

Dietary cholesterol is transported into intestinal cells via the Niemann-Pick C1-Like 1 transporter alongside with triglycerides.The cholesterol is then modified and transported into a vesicle with fatty acids (triglycerides) and produces a chylomicron vesicle using MTTP.This is then absorbed into the intestine lumen and is enriched with other apolipoproteins.The chylomicron can then enter the bloodstream via hepatic and lymphatic pathways.The lipoprotein lipase on the surface of endothelial cells can remove triglycerides from the chylomicron to produce chylomicron remnants - uptake by hepatocytes possible via LDL receptors (recognises apolipoprotein B) or by LRP1. Adipocytes can take up the cleaved triglycerides and convert it into fat reserves.The uptaken chylomicron remnants can then be repacked with newly synthesised triglycerides to form VLDL. The product can then be secreted into the bloodstream.Surface lipoprotein lipases on cells can then cleave off the fatty acid on the VLDL to produce IDL and energy.Hepatic lipases can then strip off the other proteins on IDL to produce LDL.This can then be taken up again into hepatocytes via LDL receptors. Hepatocytes recycle the cholesterol. Cells can also take up the cholesterol to restructure the cell membrane, or produce lipid metabolising mediators.Unused non-esterified cholesterol can be transported out of the cell via ABCA1 and ABCG1 into the plasma back to the liver in the form of HDL. It is then taken up by the hepatocytes via SRB1The cholesterol can also be esterified using LCAT. The esterified cholesterol can be transferred into LDL/VLDL using CETP

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81
Q

Describe selectivity of adrenoceptors

A
  • Adrenoceptors are relatively unselective (similar affinity) for two neurotransmitters : Adrenaline (A): Noradrenaline (NA)- Both NA and A activate alpha and beta adrenoceptors: A more potent at alpha 2 & beta 2: NA more potent at alpha 1 & beta 2
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82
Q

What are adrenoceptors agonists?

A
  • Agents that bind to a receptor and elicit a response- Agonists of sympathetic alpha and beta receptors (adrenoceptors) may be termed: sympathetic agonist: adrenergic agonist: sympathomimetic agonist- Agonists can act either directly/indirectly on the receptor
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83
Q

Give examples of direct sympathomimetics and their effects & uses

A
  1. Phenylephrine- selective alpha 1 - vasoconstrictor- can treat acute hypotension, glaucoma, adjunct to local anaesthetic2. Clonidine- selective alpha 2- prevent NA release and reduce BP- primary action in medulla to inhibit sympathetic outflow3. Beta-agonists- increase cardiac output- adrenaline in analphylactic shock- dobutamine used to treat cardiogenic shock
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84
Q

Give examples of indirectly acting sympathomimetics

A

Structures similar to NA but do not activate receptors1. Amphetamines- substate for NET and VMAT- prevent NA accumulation in vesicle- inhibit MAO- promotes NA export via NET- increase cytosol NA- increase NA outflow into synapse2. Ephedrine, Pseudoephedrine- reverse NET3. Cocaine- inhibits NET- increase NA in synapse by inhibiting reuptake

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85
Q

What are the receptors and indications for the following direct-acting sympathetic agonists?1. Isoprenaline2. Dobutamine3. Salbutamol4. Phenylephrine5. Clonidine

A
  1. Isoprenaline- beta- Asthma (obsolete)2. Dobutamine- beta1- Cardiogenic shock3. Salbutamol- beta2- Asthma4. Phenylephrine- alpha1- Acute hypotension- Nasal decongestant5. Clonidine- alpha2- hypertension
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86
Q

What are the actions and uses for the following indirect-acting sympathetic agonists?1. Tyramine2. Amphetamine3. Ephedrine4. Cocaine

A
  1. Tyramine- NA release- No clinical use2. Amphetamine- NA release from vesicles- CNS stimulant3. Ephedrine- NA release- Decongestant4. Cocaine- Blocks NET: synaptic NA increased- Abuse
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87
Q

Describe functions of different adrenoceptors

A

alpha1 agonists- constrict most smooth muscle- except GI where they relaxalpha2 agonists- mediate presynaptic inhibition of neurotransmitter release- sympathetic and parasympatheticbeta1 agonists- increase heart rate and force of contractionbeta2 agonists- dilate/relax smooth musclebeta3 agonists- stimulate thermogenesis in skeletal muscle

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88
Q

Describe action of beta-adrenoceptor receptor activation in the heart

A

Heart- increase in cardiac myocyte Ca2+- increase in pacemaker activity in SA node- increase rate and force

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89
Q

Describe actions of adrenoceptors antagonists

A
  • Bind to receptor but elicit no response: prevents binding of an agonist- Can be selective for alpha or beta receptors- NA activity can also be indirectly antagonised by interfering with its synthesis
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90
Q

What does alpha-adrenoceptor antagonists(non-selective) do?

A
  • Cause hypotension, postural hypotension: alpha1 blockade- Increase cardiac output and cause tachycardia: reflex due to hypotension: alpha2 blockade leads to increased sympathetic output
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91
Q

What does alpha1-antagonist (selective) ‘-azosin’ do ?

A
  • Block direct action of NA ana A on vascular smooth muscle- Cause vasodilation and fall in arterial pressure: hypertensive drugs- Relax bladder neck smooth muscle and prostate capsule
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92
Q

What does alpha2-antagonists (selective) do?

A
  • Limited clinical use- Yohimbine mainly experimental- Yohimbine has vasodilator and stimulants effects
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93
Q

What is action of the beta-antagonists (beta-blockers)?

A
  • Most important desired effects on cardiovascular system- Decreases arterial pressure: reduction of cardiac output (CO): reduction of renin release: CNS - reduce sympathetic output- Prevent tremor : skeletal muscle beta-receptor
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94
Q

What are the unwanted effects of beta-antagonists?

A
  • Bronchoconstriction - Cardiac failure- Bradycardia (low HR)- Hypoglycaemia- Fatigue- Cold extremities
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95
Q

What is the clinical use of beta-antagonists?

A

Cardiovascular- hypertension- angina- cardiac dysrhythmiasOther uses include- glaucoma- Hyperthyroid disease- anxiety- tremor- migraine

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96
Q

GIve 2 examples of Mixed alpha/beta antagonists and their Actions & Uses

A
  1. Labetalol- alpha/beta antagonist- Hypertension in pregnancy2. Carvedilol- alpha/beta antagonist- Heart failure
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97
Q

Clues in the nameDrugs name ending in ‘azocin’ are alpha1-antagonistsDrugs name ending in ‘-olol’ are beta-antagonists

A

ga yau ga yau

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98
Q

What is metabolic syndrome and what are the constituent conditions?

A
  • Abnormal carbohydrate and lipid metabolism- It puts you at greater risk of getting coronary heart disease, stroke and other conditions that affect the blood vesselsCombination of- insulin resistance- elevated fasting blood glucose- hypertension- Dyslipidaemia
99
Q

What are the risk factors of metabolic syndrome?

A
  • Visceral obesity- Age- Weight- Race (higher in afro-carribean, asian)- Non-alcoholic fatty liver- History of gestational diabetes- polycystic ovary syndrome
100
Q

What does lipid overflow-ectopic fat represent?

A
  • Increased muscle fat (intracellular lipid)- Increased epicardial fat- Increased liver fat and altered function
101
Q

How is Metabolic syndrome diagnosed?

A

3 or more of- Waist >94cm men, >80cm women (or BMI >30)- Elevated serum triglyceride ( >1.7mM)- Reduced HDL ( <1mM men, <1.3mM women)- Hypertension ( >140/90mmHg)- Elevated fasting blood glucose ( >5.6mM)- Thrombosis- Inflammation

102
Q

What are the sources & utilisation of glucose?

A

Sources- Dietary intake of carbohydrate- Gluconeogenesis- Glycogenolysis- Fatty acid catabolismUtilisation- Glycogenesis- Glycolysis- Fatty acid synthesis

103
Q

How are LDL taken up by cells.

A

They bind to the LDL receptor, and are both taken up by endocytosis.This produces an endosome.The cholesterol is released into the cell.The LDL receptor is then recycled back into the membrane

104
Q

How are LDL receptors controlled.

A

Expression of LDL receptors is controlled by the protein PCSK9.When the levels increase sufficiently, it will interact with the LDL receptor.The LDL receptor is then taken up via endocytosis to produce an endosome.The endosome is converted into a lyzosome to degrade the receptor.–> reduces the number of LDL receptors

105
Q

Describe how an atheromatous plaque forms.

A

1.) Endothelial cell dysfunction (initiaton):-Weakened endothelium due to risk factors–>Hypertension and uncontrolled diabetes in particular-The bioavailability of nitrous oxide is reduced, this leads to an upregulation of endothelial adhesion receptors.-The endothelial permeability to LDL increases-Chemokines and cytokines are released.2.) Lipid accumulation and oxidation:-LDL accumulates in the sub-endothelial space.-Increase of adhesion receptors promote binding of LDL particles to the surface -> results in further penetration of the LDL into the cell-LDL is oxidised by ROS or enzymes (that were released by macrophages/other inflammatory cells).into oxy-LDL particles.–> FORMATION OF OXIDISED LDL PARTICLES & NON-ESTERIFIED CHOLESTEROL CRYSTALS3.) Immune cell accumulation (occurs at the same time as lipid accumulation):-Adhesion and infiltration of monocytes into arterial wall-Monocyte –> macrophage via M-CSF (macrophage colony stimulating factor)-Macrophages then engulf the oxidised LDL–>FORMATION OF FOAM CELLS AND FATTY STREAKS–>INCREASES THE PROINFLAMMATORY CYTOKINE IL-BETA 14.) SM cell recruitment:-Proliferation and migration of smooth muscle cells into the sub endothelial space-There is increased matrix protein synthesis and deposition–>FORMATION OF A STABLE FIBROUS CAP5.) Unstable atheromatous plaque-Increased cell apoptosis and formation of a plaque-Calcification–> RUPTURE OF FIBROUS CAP –> THROMBUS FORMATION AND COAGULATION CASCADE ACTIVATEDACS symptoms?

106
Q

What is lipoprotein(a)

A

Similar to LDL, but has apolipoprotein(a)Competes with plasminogen, but does not elicit fibrinolytic effects.This leads to prothrombotic and profibrotic effects.Contributes to foam cell formation when oxidisedCV risk factor and proatherogenic marker

107
Q

Name some symptoms of familial hypercholesterolaemia

A

Cornal ArcusTendons XanthomataXanthomaSkin Xanthomata

108
Q

Regarding Adipocytes,what are white, brown and brite fats?

A

White fat- major function is to store energy in the form of triglycerideBrown fat- High levels in neonates- Key role in thermogenesis- Level falls with ageBrite fat- potentially important in balancing storage and expenditure

109
Q

What do adipocytes secret?

A

Adipokines- Leptin- Adiponectin- TNF- IL-6- Resistin

110
Q

what is Leptin (adipokines)?

A

Hormones secreted by adipose tissue- produced by adipose tissue- primary action: hypothalamus (stimulates satiety - suppress hunger)Increased in obesity- but resistance to its action occurs- decreased ratio of CSF to serum leptin in obesityMetraleptin- synthetic analogue

111
Q

what is Adiponectin (adipokines)?

A
  • Secreted by adipose tissue: but decreased in obesity- Low plasma adiponectin is risk factor for metabolic syndrome- Stimulates fatty acid catabolism- Decreases hepatic glucose production- Increase insulin sensitivity- Increased by thiazolidinediones
112
Q

What are the mechanisms of vascular dysfunction in metabolic syndrome?

A
  • Decreased nitric oxide signalling- Increased oxidant stress- Triglyceridaemia
113
Q

What does Nitric Oxide do in terms of blood vessel?

A
  • NO is a vasodilator produced by endothelium and some nerves by nitric oxide synthase (NOS)- Produced from L-Arginine
114
Q

What is Advanced Glycation end product (AGEs)?

A
  • Glycation is covalent binding of sugar to protein or lipids- Dietary source from browning meat or fats- Main source if formation in body (blood)- Increased by hyperglycaemia/hyperlipidemia- Fructose much higher glycation capacity than glucose- Increased AGEs associated with cardiovascular disease- Oxidise LDL
115
Q

What is irisin and what is its role?

A
  • Irisin made by skeletal muscle in response to exercise- Activates adipose tissue: Conversion of White fat to Brown fat(Brite): Increased mitochondrial UCP expression: Thermogenesis- Benefits of exercise more tha njust immediate wor kdone
116
Q

Describe role of blood vessels in control of BP

A

BP = CO x TPR (total peripheral resistance)CO = HR x SV- Vasocontriction & Vasodilation occurs on TPR and SV

117
Q

How does blood vessel act as a functional syncyitum?

A
  • Cells are coupled within each layer via intercellular gap junctions- Cells are coupled between layers (smooth muscle and endothelial cells via myoendothelial gap junctions)- Chemical coupling by release of neuromediators and local mediators: from sympathetic nerves: from endothelial cells
118
Q

Give 3 main mechanisms leading to contraction of vascular smooth muscle

A
  1. Initiated by intracellular Ca2+ increase via two parallel pathways (additive)a) Agonist-induced (Gq), IP3-mediated Ca2+ release from SR (sarcoplasmic reticulum)b) Depolarisation-activated Ca2+ influx via voltage-activated calcium channel of L-type (L-VACCs) 2. Determined by phosphorylated state of Myosin Light Chain (MLC)a) Phosphorylation of MLC by MLC Kindase (activated by Ca2+-CaM) causes contractionb) De-phosphrylation of MLC by MLC phosphatase (MLCP) causes relaxation3. Enhance contraction at a constant level of calcium by inhibiting activity of MLCP (calcium sensitisation)a) Agonists via DAG/PKC and phosphorylation of CPI-17 phosphorylationb) Agonists via RhoA & activation of the Rho-associated kinase 2 (ROCK2)
119
Q

How do statins work

A

Reversible competitive inhibition of HMG-CoA ReductaseThis reduces the conversion of HMG-CoA to mevalonateHence, reduction in the formation of cholesterol It also decreases the amount of LDL circulating in the body by increasing the number of LDL-receptors, and increasing its clearance from the body

120
Q

Name 2 statins produced via fungi

A

SimvastatinPravastatin

121
Q

Which drugs should simvastatin/atorvastatin and lovastatin not be prescribed with?

A

Antibiotics – erythromycin, clarithromycinAntifungals – itraconazoleCCB - VerapamilImmunosuppressants – cyclosporin–> These drugs inhibit CYP3A4, which metabolise the listed drugs. –> Potential for toxicity at therapeutic doses of the statins (muscle aches)

122
Q

Name some of the clinical uses for statins. What are the cautions and contraindications of statins?

A

Primary prevention of CHD in patients with other risk factors (kidney disease/diabetes)Secondary prevention of CHDFamiliar hypercholesterolaemiaCautioned in those with liver disease and can cause hypothyroidismCONTRAINDICATED IN PREGNANT WOMEN

123
Q

What are the CV benefits of using statins?

A

Improved endothelial functionAnti-inflammatory effectsAnti-thrombotic/anti-platelets effectsIncrease in vasodilating effectsIncrease in neovascularisation of ischaemic tissue - improved blood supply

124
Q

What are the side effects of statins.

A

Myalgia – muscle painMyopathies (rare):–Myositis -> muscles inflamed–Rhabdomyolysis -> muscle breakdownVery rare:-Hepatitis-Interstitial lung disease

125
Q

How does ezetimibe work

A

Inhibits NPC1L1 transport protein in enterocytes.This reduces the amount of cholesterol absorption in the gut and reduces LDL

126
Q

What are the clinical uses of ezetimibe? What are the side effects?

A

Hypercholesterolaemia-Along side with statins-By itself (when patients are contraindicated against statins)DiarrhoeaAbdominal painHeadachesMyalgia

127
Q

How do fibrates work

A

They bind to and activate the transcription factor PPAR-alphaThis activation results in dimerisation with RXR to produce the heterodimer PPAR-Alpha/RXR.The heterodimer produced activates transcription of lipoprotein lipase (LPL).LPL strips the triglycerides from lipoproteins –> results in less circulating cholesterol in the blood.It also increases expression of Apo-A1 and Apo-A2 (constituents of HDL) causing a greater expression of HDL-lipoproteins

128
Q

What is the effect of using fibrates?

A

Increased LPL activityReduction in circulating VLDL and triglyceridesIncreased plasma levels of HDLIncreased LDL uptake into cells

129
Q

What are the indications of fibrates?

A

-Mixed dyslipidaemia – cholesterol and triglycerides!!!!-Patients that have a high risk of atherosclerosis and low HDL (increases HDL)-Severe treatment-resistant dyslipidaemia with statins

130
Q

Give an example of a fibrate

A

FenofibrateGemfibrozil–> -fibrate drugs

131
Q

When are fibrates contraindicated and what are the side effects.

A

PREGNANCYAbdominal distensionAnorexiaDiarrhoeaNauseaRARE:MyositisRhabdomyolysisMyotoxicity can be increased in patients with:Renal impairmentHypertriglyceridaemia (alcoholics)

132
Q

Give some examples of lipid lowering drugs, and how do they work.

A

ColestyramineColestipolColesevelamBind to bile acids in the gut and reduce cholesterol reabsorption via enterohepatic circulationDecreases LDL, BUT, increases triglycerides.

133
Q

When are lipid lowering drugs used clinically.

A

Hepatic impairment where statins are not recommendedDylipidaemia unresponsive to dietIn pregnant women (cautioned)

134
Q

What are the side effects of lipid lowering drugs.

A

GI disturbanceConstipationBleeding (Vit K deficiency)

135
Q

What is the lipid lowering mechanism of nicotinic acid?

A

Activates Gi/o coupled HCA2 receptors in adipocytes.Inhibits lipolysis, so there is a reduction in triglycerides causing less VLDL and hence LDL.There is also an increase in expression of Apo-A1, causing an increase in HDL

136
Q

Give an example of a nicotinic acid.

A

Niacin/Vitamin B3

137
Q

What is the indication of Niacin? What are some side effects?

A

Hypercholesterolaemia with statinsDyslipoproteinaemia with statinsFacial flushes due to PGD2Other effects are:N&VAllergyLightheadedness and syncopeTachycardia and palpitationsSkin itching/rashes

138
Q

How do fish oil derivatives reduce lipids?

A

Non understood well.Precursors for:Prostaglandin 3Thromboxane 3Leukotriene 5Results in lower triglycerides and LDL

139
Q

What are some recent developments in lowering LDL.

A

Anti-PCSK9 monoclonal antibodies–Evolocumab–AlirocumabPrevents PCSK9 levels from reaching high enough to bind to LDL receptors and causing their breakdownIndicated for hypercholesterolaemia and mixed dyslipidaemia

140
Q

Describe the metabolic autoregulation of CBF in the normal heart

A

Catecholamine binds to the beta 1 receptors in the heart, stimulating a higher heart rate.Due to the heart beating faster, the diastolic time is reduced. This reduces therefore reduces the coronary blood flow.The increase in heart rate also increases the cardiac workload and hence cardiac metabolism. Local metabolites (Adenosine and potassium) are released and hypoxia can occur due to increased oxygen usage. To balance this effect, vasodilation of the coronary arteries occur.

141
Q

How does adenosine cause an increase in coronary blood flow?

A

Increased heart rate results in an increase of the cardiac workload –> ATP breakdown increased.In cardiac myocytes, ATP->ADP->AMP->AdenosineAMP-> Adenosine is facilitated by 5’-nucleotidaseAdenosine binds to Adenosine-A2 receptors on the smooth muscle cells (G⍺s).Adenylyl cyclase stimulates cAMP releasecAMP levels increase and causes vasodilation.Thus, coronary blood flow increases.Adenosine will also bind to Adenosine-A1 receptors which are G⍺i linked. This reduces the heart rate, and reduces the cardiac workload.

142
Q

How does hypoxia and potassium cause an increase in coronary blood flow?

A

An increased workload results in oxygen to be used up at a quicker rate, and hence is less available. This also results in less ATP in the coronary smooth muscle.ATP-sensitive K+ channels are opened, causing hyperpolarisation in the smooth muscles. –> vasodilation increases causing an increase in CBFThe increase in workload will also increase the number of action potentials, resulting in a higher extracellular [K+].Na/K+-ATPase in the coronary SM is activated resulting in a greater electronegativity, and hence hyperpolarisation.–> Greater vasodilation and CBF

143
Q

What is the issue with atheromatous disease regarding the regulation of coronary blood flow.

A

The increased workload causes a decrease in coronary blood flow.The vasodilation is stimulated.However, due to partial or full occlusion of the blood vessels, this does not properly reduce cardiac workload.Adenosine here reduces the heart rate via adenosine A1 receptor binding, and prevents the necessary compensatory increase in the heart rate.–> This results in the characteristic cardiac pain

144
Q

What are the types of angina, and what are the causes as well as when it occurs

A

Myocardial infarction-Coronary thrombosis-Occurs at restUnstable angina-Atheromatous plaque rupture and platelet aggregation-Occurs at restStable angina-Partial coronary artery occlusion-Occurs on exertion or stressVariant angina-Coronary vasospasm-At rest

145
Q

What are the symptoms of stable angina?

A

Tight/dull/heavy pain – some can get sharp stabbing painSpread to left arm, neck, jaw or backTriggered by physical exertion or stressStops within a few minutes of rest–Angina can also cause:-Breathlessness-Nausea-Pain in lower chest or abdomen (Similar to indigestion)-Fatigue

146
Q

How can stable angina be treated

A

Reduce oxygen demandIncrease oxygen supplyUse lipid lowering drugs to prevent the progression of the atheromatous diseaseFirst Line = BB (B1 selective) / CCB (dihydropyridines) Second line = Organic nitrates/Ivabradine/Nicorandil/Ranolazine

147
Q

How do Organic Nitrates work?

A

They are metabolised to release NO –> increasing levels of cGMP…which causes relaxation Causes the systemic vasodilation of veins (decreases preload) and arteries (decrease afterload), which causes a decrease in cardiac oxygen demandAlso causes an increase in the dilation of collateral vessels, which increase oxygen supply

148
Q

How do Nicorandil, Ivabradine and Ranolazine work?

A

Nicorandil –> Activates vascular ATP-sensitive K+ channels, and is also an NO donor – arteriodilation Ivabradine –> Inhibits the pacemaker IF current in the SAN, which decreases HR Ranolazine –> Inhibits late Na+ channels that are activated by ischaemia in cardiac myocytes

149
Q

How do you treat Variant Stable?

A

Nitrate vasodilator and CCBBeta blockers are not effective – only spasms present, heart is not affectedAim to dilate coronary arteries

150
Q

Give the 2 types of unstable angina

A

NSTEMI – Partial artery occlusionSTEMI – Complete artery occlusion

151
Q

Compare pulmonary and periphery oedema

A

Pulmonary = left ventricular hypertrophyPeripheral = CHF

152
Q

Give some common adverse effects in organic nitrates

A

DizzinessPostural hypotensionReflex tachycardiaHeadaches

153
Q

What is Endothelin-1 and where/how does it act?

A
  • Endothelin-1 is a vasoactive and mitogenic polypeptide synthesised and secreted by endothelial cells- It acts on specific receptor ET.A on vascular smooth muscle, causing sustained powerful vasoconstriction, where as binding to ET.B receptor on endothelial cells cause the release of nitric oxide that lead to vascular relaxation
154
Q

Compare T1DM and T2DM.

A

Type 1 = autoimmune disease–Destruction of Beta-islet cells in the pancreas via immune system–Require insulin injections (None is produced)Type 2 –Lack of insulin produced, or lack of a response to insulin–Insulin is typically only used when other method have not worked wellTypically diagnosed in patients about 40yrs +

155
Q

Type of ET receptors on endothelial cells and their role

A
  • Stimulates production of vasodilators (NO, PGI2)- ET-1 clearance
156
Q

Examples of endothelin receptor antagonist drugs?

A

Ends in ‘-entan’1. Bosentan (2001)- first oral dual ET.A/B antagonist2. Macientan (2013)- dual ET.A/B antagonists (50 folds more ET.A selective)3. Ambrisentan (2007)- selective ET.A antagonists

157
Q

Compare insulin and glucagon.

A

Insulin:AnabolicReduces glucose/FFA/AA in the plasmaStimulates glucose utilisation via glycolysis and glycogenesisInhibits gluconeogenesis and glycogenolysisGlucagon:CatabolicIncreases plasma glucose/ketones

158
Q

Compare T1DM and T2DM.

A

Type 1 = autoimmune disease–Destruction of Beta-islet cells in the pancreas via immune system–Require insulin injections (None is produced)Type 2 –

159
Q

What are meglitinides?

A

Non-sulfonylureas – same MoAGreater rapidity in action due to increased rate of absorptionHypoglycaemic effects are elicited via insulin – ineffective drug in T1DMCan be used with metformin

160
Q

What are some of the effects of insulin resistance?

A

Increased thirst/urinationFatigueHypertensionLow HDLIncreased fat storesHyperglycemia

161
Q

Describe how sulfonylureas work. What are the differences between first generation and second generation sulfonylureas?

A

Stimulate insulin secretion They inhibit the ATP-sensitive K+ channel, causing more depolarization…..causing Ca2+ release…..which stimulates insulin secretion___e.g Tolbutamide vs gliclazide-Gliclazide has a greater potency with the same MoA-Second generation drugs have altered onset and duration

162
Q

What are some side effects associated with sulfonylureas.What are some contraindications

A

HypoglycaemiaCan stimulate weight gain due to the promotion of fat storage (esp the potent sulfonyureas)Secondary pancreatic Beta cell failure?Caution when used in patients with renal or hepatic impairmentContraindicated in pregnancy (crosses placenta)

163
Q

What are meglitanides?

A

Non-sulfonylureas – same MoAGreater rapidity in action and duration

164
Q

What are biguanides?

A

Metformin is the only drug licensed in this groupActs only in the presence of endogenous insulin – ineffective in T1DMDecreases hepatic glucose production (by inhibiting gluconeogenesis)Inhibits the mitochondrial respiratory complex 1 (decreased synthesis from ADP –> ATP) – less gluconeogenesisStimulates insulin receptor expression and tyrosine kinase activity (Insulin sensitising) Drug of choice in overweight patients as it does not stimulate weight gain

165
Q

What are thiazolidinediones?

A

Insulin sensitising/anti-hyperglycaemic drugsAgonists at Peroxisome Proliferator-Activated Receptors (PPARs), and so decrease Beta-oxidation of fatty acids and cholesterol synthesisDue to the mechanism, it may take several weeks before effects are fully observedWeight gain is a major side effect (H/e, it is only subcut fat)Regulate complex dyslipidaemia in T2DMMetabolised by CYP450s-glitazone drugs

166
Q

What are some side effects of Metformin?

A

Acute, transient GI fx – metallic taste, diarrhoea, N&VLactic acidosis in contraindicated patients–history of alcoholism–Renal disease–Liver disease–PregnancyPotential interaction if taken with other drugs that are eliminated renally.

167
Q

What are incretins

A

GLP- Glucagon-like peptideGIP- Gastric inhibitory polypeptideThey are hormones released in the GI in response to increased post prandial glucose levels.–> stimulates insulin release from pancreasGLP-1 affects insulin biosynthesis and secretion, but only under hyperglycaemic conditionsGLP-1 inhibits glucagon release, and is a satiety signal leading to a reduction in food intake –> So aimed at overweight patients

168
Q

What are alpha-glucosidase inhibitors

A

They reduce the digestion of complex carbohydrates, and so slows their absorption from the gut.– Reduces postprandial hyperglycaemiaAdverse effects are common (flatulence/diarrhoea), –High discontinuation rateUsed when other drugs are not tolerated Don’t cause hypoglycaemia or weight gain

169
Q

What are thiazolidinediones?

A

Insulin sensitising/anti-hyperglycaemic drugsAgonists at Peroxisome Proliferator-Activated Receptors (PPARs), and so decrease Beta-oxidation of fatty acids and cholesterol synthesisDue to the mechanism, it may take several weeks before effects are fully observedWeight gain is a major side effect (H/e, it is only subcut fat)Regulate complex dyslipidaemia in T2DMMetabolised by CYP450s

170
Q

What are SGLT2 inhibitors and how do they work.

A

Reversibly inhibit the sodium glucose co-transporter 2 (SGLT2) in the renal proximal convulated tubuleThis reduces glucose reabsorption and increases secretionn.b. glucose in the urine of patients is indicative of diabetese.g. canagliflozin-flozin drugs

171
Q

What are incretins

A

GLP- Glucagon-like peptideGIP- Gastric inhibitory peptide

172
Q

Describe how a clot forms

A

Vascular endothelium is damaged, exposing collagen, and stimulating the release of Von Willebrand Factor (VWF) Platelets adhere via VWF bridging between subendothelial macromolecules and platelet glycoprotein Ib (GPIb) receptors Platelet shape changes from disks to spiny spheres –> driven by ADP binding to P2Y1 receptors on platelets–> ADP also bind to P2Y12 stimulating platelet action Secretion of granule contents (2 types)–Dense–Alpha Synthesis of release of Platelet-Activating Factor (PAF) and Thromboxane A2 (TXA2) Aggregation –> caused by expression of GPIIb/IIIa receptors that bind fibrinogen….which links adjacent platelets Exposure of acidic phospholipids on the platelet surface, promoting thrombin activation via thrombin receptors and fibrin formation from fibrinogen caused by the thrombin–>Further platelet activation

173
Q

What a DPP-4 inhibitors. How do they work?

A

Dipeptidyl peptidase.These facilitate the breakdown of incretins.DPP-4 inhibitors prevent this from occurring..So, incretin effects are potentiated.(Glucagon release inhibited, and insulin release increased)Also reduces gastric emptying, so feel satiated for longer. (Less consumption of food – good for overweight patients.E.g. sitagliptin–gliptin drugs

174
Q

Give an example of an adenosine P2Y12 receptor antagonist. How do they work.

A

Inhibits the P2Y12 (Gi) receptors on platelets, causing an increase in Adenylyl Cyclase (AC) –> cAMP –> deactivate platelet aggregation due to prostaglandin I2 production.Destabilises: PARs (Thrombin –> fibrinogen to fibrin)P2Y1 (platelet conformational change)TP (Thromboxane A2) Does this by having its thiol group form a disulphide bond with the cysteine on the receptor (irreversible)-grel drugs ClopidogrelPrasugrelReversible antagonists =Ticagrelor

175
Q

Compare prasugrel and clopidogrel.

A

Clopidogrel is a prodrug – requires CYP450 metabolism in the liver before it elicits its effects.Prasugrel is less dependent on this to be activated.

176
Q

How does aspirin elicit its effects?

A

Irreversible COX inhibitionPrevents platelet aggregation and activation –platelets do not have a nucleus, so COX-1 cannot be resynthesised Takes a moderate amount of time for platelets to be resynthesised

177
Q

Give an example of an adenosine P2Y12 receptor antagonist. How do they work.

A

Inhibits the P2Y12 (Gi) receptors on platelets, causing an increase in Adenylyl Cyclase (AC) –> cAMP –> deactivate platelet aggregation due to prostaglandin I2 production.The inhibition also destabilises P2Y1 receptors that are responsible for the conformational change on platelets to allow aggregation Does this by having its thiol group form a disulphide bond with the cysteine on the receptor (irreversible)

178
Q

Compare prasugrel and clopidogrel.

A

Clopidogrel is a prodrug – requires CYP450 metabolism in the liver before it elicits its effects.Prasugrel is less dependent on this to be activated.

179
Q

What is a common side effect of antiplatelets?

A

Haemorrhages..Though not in dipyridamole

180
Q

What is an example of glycoprotein IIb/IIIa receptor inhibitor

A

Abciximab –> Chimeric monoclonal antibody that is long acting Eptifibatide –> Synthetic cyclic heptapeptide that is reversible Tirofiban –> Synthetic non-peptide agent that is a competitive reversible inhibitor

181
Q

How do phosphodiesterase inhibitors work

A

Increase cAMP and cGMP levels by blocking PDEsThis inhibits platelet aggregation and causes vasodilation Stimulates prostaglandin I2Inhibits Thromboxane A2Also blocks adenosine uptake by platelets/endothelial cells/blood cellsE.g. dipyridamole

182
Q

What is a common side effect of antiplatelets?

A

Haemorrhages..Though not in dipyridamole

183
Q

What’s the difference between an Absolute and an Relative refractory period?

A

Absolute/Effective –> When a second AP isn’t possible regardless of the strength of the stimuli (as phase 0 can’t be reached) Relative –> If a very strong stimulus is created, then a second AP can be caused

184
Q

What do each parts of an ecg mean.

A

P Wave –> Depolarisation of the atria QRS Complex –> Depolarisation of the ventricles T Wave –> Repolarisation of the ventricles

185
Q

What are the different classes of anti-arrhythmia drugs.Vaughan Williams classification

A

Class 1 = Sodium channel blockers-Blocks fast voltage activated sodium channels (Rapid depolarisation stage at phase 0)-Slows down the rate of AP conduction-The ability to block increases as the HR increases (good) 3 types-Ia (Intermediate dissociation from sodium channel) -Disopyramide->Atropine-like fx?-Ib (Quick dissociation from sodium channel)-Lidocaine->CNS fx-Ic (Slow dissociation from sodium channel)->Flecainide->Sudden cardiac death in patients with MIClass 2 = Beta blockers-Block Beta 1 adrenoceptors-Slows down the rate of AVN conduction-Propanolol-Bradycardia/bronchoconstriction..Class 3 = AP duration prolongers-Block voltage activated potassium channels in repolarisation of phase 3 in AP -Amiodarone (reduces expression of Beta 1 adrenoreceptors)-Sotalol (non specific beta blocker)Class 4 = CCB-L-type voltage gated calcium channel blockers-Slows down AV node conduction-Verapamil

186
Q

What’s the difference between an Absolute and an Relative refractory period?

A

Absolute/Effective –> When a second AP isn’t possible regardless of the strength of the stimuli (as phase 0 can’t be reached) Relative –> If a very strong stimulus is created, then a second AP can be caused

187
Q

How are arrhythmias classified

A

Effect on heartEffect on the rhythmSite of originType of QRS complex

188
Q

What are the causes of bradycardia – physiological and pathological

A

Trained athletes.Increased vagal toneHypothermiaEndocrine issuesElectrolyte imbalanceDrugs (rate affecting drugs – verapamil)Sick sinus syndromeAV blockade/heart block

189
Q

What are other anti-arrhythmic drugs available

A

AtropineIsoprenalineAdrenalineAdenosineAtropineDigoxin

190
Q

How are arrhythmias classified

A

Effect on heartEffect on the rhythmSite of originType of QRS complex

191
Q

What are the causes of bradycardia – physiological and pathological

A

Trained athletes.Increased vagal toneHypothermiaEndocrine issuesElectrolyte imbalanceDrugs (rate affecting drugs – verapamil)Sick sinus syndromeAV blockade/heart block

192
Q

What are the types of tachyarrhythmias?

A

SVT – supraventricular tachycardia-Paroxysmal SVT (abrupt start and finish)-AFib-Atrial flutter (AVNRT early after polarisation, AVRT late after polarisation)V. dangerous when these occur (blood supply is altered)VFibVT (ventricular tachycardia)

193
Q

What are the types of AV blocks

A

First degree - PR interval increased (higher than 0.2s)Second degree - missed beats to the ventricle.->Mobitz I = Increasingly greater PR intervals->Mobitz II = no patternThird degree - complete block->No ventricle conduction-> Random P waves-> Random QRS complexes

194
Q

How can pathological bradycardia be treated? (AV block)

A

Atropine or isoprenaline in emergenciesLong term solution to 2nd and 3rd degree blocks–>Implantable transcutaneous pacemaker (Controls the heart rate)

195
Q

What are the 2 mechanisms for tachyarrhythmia?

A

AutomaticityTriggered

196
Q

Describe 2 main mechanisms leading to relaxation of vascular smooth muscle

A
  1. Agonist-mediated and hyperpolarisation dependent relaxation- agonists stimulate endothelial G-protein-coupled receptors , provoking an increase in endothelial cellular calcium, causing opening of endothelial K.ca channel and triggering processes of hyperpolarisation.2. Mechanisms which reduce intracellular calcium levels- Reduced calcium iflux via L-type VACCs: Hyperpolarisation-mediated (opening of K+ channel, increased activity of NA+-K+-ATPase): Phosphorylation dependent inhibition (via PKA & PKG pathways)- Re-uptake by SERCA2 into the smooth muscle (main)- Up-take by mitochondria (minor role in healthy vessels)- Extrusion via: Plasmalemmal Ca2+ -ATPase (Ca-pump): NA+-Ca2+ exchanger (NCX) (minor role in healthy vessel):
197
Q

What is blood vessel relaxation faciliated by?

A
  1. Decrease of phosphorylated state of MLC via two major mechanisms: phosphorylation-dependent inhibition of MLCK by PKA:activation of MLCP via cGMP-PKG mediated pathway2. Decrease in intracellular Ca2+ concentration mainly via: Hyperpolarisation-mediated decrease in L-VACC activity: SERCA-mediated reuptake into the SR(sacroplasmic reticulum) : Extrusion by Ca-ATPase
198
Q

What are the 3 main vasodilator derived from vascular endothelial cells?

A
  • Nitric oxide (EDRF)- Prostaglandin I2 (Prostacyclin)- Endothelium-derived hyperpolarising factors (EDHFs)
199
Q

What is Nitric Oxide Synthase (NOS) and its 3 isoforms?

A

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine1. Endothelial NOS (eNOS)- Consitutively expressed, calcium-dependent- Effect on Blood vessels (via NO): Vasodilation- Effect on platelets (via NO): Reduced platelet adhesion/aggregation2. Neuronal NOS (nNOS)- CNS: Neurotransmission, LTP, plasticity- Peripheral NS: Gastric emptying, penile erection3. Inducible NOS (iNOS) (calcium independent)- Macrophages, neutrophils, leukocytes: host defence

200
Q

What is ADMA (Asymmetric dimethylarginine) ?

A
  • Competitive NOS inhibitor: endogenous- Increased in blood plasma of humans with: Hypertension: Atherosclerosis: Kidney/heart failure- Marker of endothelial dysfunction & risk factor of CVD
201
Q

Name 2 Nitro Oxide (NO) donor drugs

A
  • Glyceryl trinitrate( GTN, Nitroglycerin)- Sodium nitroprusside (SNP)
202
Q

What is Slidenafil and its action?

A
  • Selective PDE5 inhibitor: prevents cGMP breakdownTherapeutic use:- Erectile dysfunction- Pulmonary Arterial hypertension
203
Q

What is prostacyclin?

A
  • is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator
204
Q

Name 3 prostacyclin analogues therapeutically used for pulmonary arterial hypertension

A
  1. Prostacyclin (Epoprostenol)2. iloprost (IV, inhaled)3. Selexipag (oral)- Selective IP receptor agonist
205
Q

What are the potential candidates for an EDH(endothelial-derived hyperpolarisation) factor?

A
  • Ca2+ activated K+ channels in ECs- Ca2+ activated K+ channels in SMs- Electrogenic NA+- K+-ATPase in SMs- Myoendothelial gap junctions- Metabolites of arachidonic acid
206
Q

What is aldosterone?

A
  • Body’s main mineralcorticoid: promotes reuptake of sodium, hence water, by the kidney- Produced exclusively in zona glomerulosa (ZG)- Functions in regulation of ECFV and BP: in circulation, 60% of aldosterone is protein bound (low affinity)- Receptor(MCR) is a member of nuclear receptor superfamily- Synthesis and secretion increased by elevations in blood angiotensin II
207
Q

How is aldosterone secretion regulated?

A
  • Renin-angiotensin systemTriggers for renin release: ↓ BP in afferent arteriole: ↑ Sympathetic nervous activity:↓ [NaCl] in DCT
208
Q

Describe Primary hyperaldosteronism

A
  • Accounts for 5-10% of cases of hypertension: ↑plasma aldosterone:renin ratio (ARR): ↑ plasma aldosterone levels: ↓ serum and increased urinary K+of which, 66% is bilateral adrenal hyperpalsia: treat with aldosterone antagonists33% is unilateral, aldosterone-secreting adenoma: surgical removal
209
Q

What is Cortisol?

A
  • Body’s main glucocorticoid- produced in zonas fasciculate (ZF) and reticularis (ZR)- Infleunces many cardiovascular, metabolic, immunologic and homeostatic functions- Synthesis and secretion is stimulated by ACTH from the pituitary
210
Q

What is Addison’s disease?

A
  • Primary adrenal insufficiency- rare, life-threatening condition- most often caused by autoimmune disease- Characterised by increased production of CRH/ACTH
211
Q

What are the clinical features of primary hypoadrenalism?

A
  • Weight loss- Weakness- Depression- Pigmentation- Postural hypotension
212
Q

What is secondary adrenal insufficiency?

A
  • Adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH). Symptoms are the same as for Addison disease- Most common cause is long-term corticosteroid medication for non-endocrine disease
213
Q

Describe Adrenal insufficiency in childhood

A
  • Most commonly congenital- 90-95% cases due to deficiency in the CP21A2 steroid hydroxylase
214
Q

What is Cushing’s syndrome?

A
  • Hypercortisolism- Metabolic disorder caused by overproduction of corticosteroid hormones by the adrenal cortex and often involving obesity and high blood pressure- Primary or non-ACTH-dependent: 25% of all cases- Secondary or ACTH-dependent: 65% of all cases
215
Q

What are clinical features of Cushing’s syndrome (hypercortisolism)?

A
  • Weight gain- Depression- Insomnia- Plethora- Thin skin- Bruising- Hypertension
216
Q

How is Cushing’s syndrome managed?

A
  • Pharmacological inhibition of cortisol synthesis with Metyrapone- Ketoconazole: synergistic with metyrapone
217
Q

Describe the functions of kiney

A
  • Regulation of extracellular (body) fluid volume- Maintenance of ion balance and pH - Excretion of foregin substances- Renin secretion
218
Q

What is the basic functional unit of the kidney?

A
  • Nephron
219
Q

What is ultrafiltration?

A
  • Blood filtered from Glomerular capillaries into Bowman’s capsule- driving force: Glomerular capillary hydrostatic pressure: oncotic pressure in Bowman’s space- opposing force: oncotic pressure of blood pressure: pressure in Bowman’s space
220
Q

Describe routes of tubular reabsorption and secretion

A

Reabsroption- Tubular lumen -> Tubular enpithelial cell -> Interstitial fluidSecretion- Interstitial fluid -> tight junction -> Tubular lumen

221
Q

Rank main sites for tubular sodium reabsorption by ability to reabsorb salt (NA+ and Cl-)

A
  1. Proximal Convoluted Tubule (PCT)- 60-70%2. Thick Ascending Limb (TAL)- 20-30%3. Disatal Tubule (DT)- 5-10%4. Collecting Tubule & Duct - 1-3%
222
Q

What is Diuresis?

A

Increased excretion of urine

223
Q

What is Natriuresis?

A

Increased excretion of sodium in urine

224
Q

What are the 5 groups of diuretics? Rank by ability to produce diuresis and natriuresis

A
  1. Loop Diuretics- Act on Thick Ascending Limb (TAL) of Loop of Henle2. Thiazides and Thiazide-like- Act on Distal Tubule (DT)3. Potassium Sparing Diuretics- Act on Collecting Tubule & Collecting Duct4. Osmotic Diuretics- Act on Proximal convoluted tubule & Thin Descending Limb of loop of henle5. Carbonic Anhydrase inhibitors- Act on Proximal COnvoluted dtubule
225
Q

In the Proximal Convoluted Tubule (PCT), which structures facilitate tubular reabsorption?a) on the luminal membraneb) on the basolateral membrane

A

a) On luminal membrane- Na+/H+ exchanger (H+ secretion)- Na+ coupled co-transportersb) on basolateral membrane- NA+ - K+ - ATPase (active Na+ reabsorption)- Renal K+ channels

226
Q

What is the driving force of tubular sodium reabsorption in PCT?

A
  • Activity of the basolateral NA+-K+-ATPase: creates Na+ concentration gradient between the tubular lumen and interstitial space
227
Q

Give an example of Carbonic Anhydrase inhibitor drug and explain what it does

A
  • Acetalzolamide- Inhibition of carbonic anhydrase in the PCT- Little use as diuretic agent due to: weak diuretic: self-terminating action- Renal effects of acetazolamide: Moderate decrease in Na+ reabsorption: Mild plasma acidosis: Urine alkalosis
228
Q

Give an example of Osmotic Diuretics and explain what it does

A
  • Mannitol- freely filtered in glomerulus- increases osmolarity of : tubular filtrate (decrease water absroption): blood plasma (increase fluid retention)Acts on parts of nephron freely permeable to water: PCT: Descending limb of loop of henle: CT and CDRenal Primary effect: decrease water absroptionRenal secondary effect: Reduces Na+ reabsorption
229
Q

In the Thick Ascending Limb (TAL), which structures facilitate tubular reabsorption?a) on the luminal membraneb) on the basolateral membrane

A

a) Luminal membrane- Na+/K+/2Cl- co-transporter (NKCC2)- Renal K+ channels (ROMK - Renal Outer medullary Potassium channel)b) Basolateral membrane- Na+-K+-ATPase- K+/Cl- co-transporter- Cl- channels

230
Q

What does Loop diuretic do?

A
  • Inhibition of the luminal Na+/K+/2Cl- co-transporter (NKCC2)Renfal effets: decrease Na+ reabsorption: decrease Cl- reabsorption: increase K+ excretion: increase Ca2+ & Mg2+ secretion
231
Q

Give 2 examples of Loop diuretic drugs and their therapeutic uses

A
  • Furosemide & Bumetanide- Acute pulmonary oedema- Chronic heart failure- Renal failure- Hypertension with complicated renal impairment
232
Q

In the Distal tubule (DT), which structures facilitate tubular reabsorption?a) on the luminal membraneb) on the basolateral membrane

A

a) Luminal membrane: Na+/Cl- co-transporter (NCC): Renal K+ channelsb) Basolateral membrane: Na+-K+-ATPase: K+/Cl- co-transporter

233
Q

What do Thiazide & Thiazide-related diuretics do?

A
  • Inhibition of lunimal Na+/Cl- co-transporter (NCC)- Renal effects: decrease Na+ reabsorption- decrease Cl- reabsorption- increase K+ excretion- increase Ca2+ reabsorption
234
Q

Give examples of Thiazide and Thiazide-related diuretics

A

Thiazides- Hydrochlorothiazide- BendroflumethiazideThiazide-related - Chrlotalidone- Indapramide- Metolazone

235
Q

Compare Thiazide vs Loop Diuretics

A

Thiazide&Thiazide-related diuretics are - less powerful- have more prolonged action- better tolerated than loop diuretics- ave vasodilating properties after prolonged use

236
Q

Whata re the effects of aldosterone in the kidney?

A
  • Regulation of potassium secretionAldosteron- activates renal Na+ channels- increase synthesis of Na+-K+-ATPase
237
Q

What are the 2 groups of Potassium-sparing diuretics and drug in each group

A
  1. Aldosterone antagonists- Spironolactone (pro-drug)- Eplerenone2. Na+ channel blockers- Amiloride- Triamterene
238
Q

What are the therapeutic uses of potassium-sparing diuretics?

A

Weak diuretics- treat hypokalaemia ( due to thiazide or loop diuretics)- Heart failure- Aldosteronisms

239
Q

What is Antidiuretic Hormone (ADH)?

A
  • ADH is also called arginine vasopressin. - It’s a hormone made by the hypothalamus in the brain and stored in the posterior pituitary gland. - It tells your kidneys how much water to conserve
240
Q

Describe mechanism of ADH action

A
  • Acts in the collecting tubule & collecting duct- Increases the expression of Aquaporin-2 on the luminal membraneRenal effects of ADH- Increases water absorption- Controls the rate of urine formation
241
Q

What is Diabetes Insipidu (DI)?

A
  • ADH related disorder- excessive urination (polyuria) and complications thereof, caused by an antidiuretice hormone called a vasopressin
242
Q

What are the 2 types of DI, their causes & therapies?

A
  1. Neurohypophyseal (central) DI- Reduced ADH secretion, normal kidney response- Caused by : Brain trauma: Surgery: Genetics- Treated by: Desmopressin (synthetic ADH)2. Nephrogenic DI- Normal ADH levels, impaired kidney response- Caused by: Lithium poisoning: kidney disease: genetics- Treated by: Thiazides
243
Q

How does Atrial Natriuretic Peptide (ANP) ave diuretic action?

A

In order of1. increased in cardiac preload2. Increased release of Pre-proANP3. Increased ANP4. Activation of NPR-1 & NPR-2 (Guanylyl Clycase coupled)5. Kidney:decrease Na reabsorption: decrease renin release

PA20321 Retake (5 decks)

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