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Medicine > Clinical Pharmacology > Flashcards

Clinical Pharmacology Flashcards

1
Q

What 2 areas are drugs distributed?

A

Tissue reservoirs

Protein-bound drug

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2
Q

What is bioavailability?

A

Measure of drug absorption where it can be used (F) as compared to when given IV

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3
Q

What things can affect absorption of drugs?

A

Formulation
Age (luminal changes)
Food (chelation, gastric emptying)
Vomiting/ malabsorption (Crohn’s)

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4
Q

What areas are included in first pass metabolism?

A

Gut lumen, gut wall and liver

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5
Q

What factors affect distribution of medication throughout the body?

A 
Blood flow/ capillary structure
Lipophilicity/ hydrophilicity
Acidic/ Basic drugs
Protein binding - 
 Albumin - acidic drugs
 Globulins - hormones
 Lipoproteins - basic drugs
 Glycoproteins - basic drugs
Volume of distribution
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6
Q

What is the equation for volume of distribution?

A

Vd = Dose/ [Drug]plasma

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7
Q

How would you interpret a volume of distribution?

A

A lower Vd is indicative of more drug in the blood and less in the tissues
A higher Vd is indicative of less drug in the blood and more in the tissues

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8
Q

What is the units for volume of distribution?

A

mg/litre

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9
Q

How can dose be calculated from the volume of distribution and the drug concentration in the plasma?

A

Dose = Vd x [Drug]plasma

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10
Q

How many phases of metabolism are there?

A

2 phases

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11
Q

What happens in the phases of metabolism?

A

Phase 1- oxidation - dealkylation or reduction - hydrolysis

Phase 2- Glucuronidation, sulphation, glutathione added, N-cetyl added

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12
Q

What is another name for phase 1 enzymes?

A

Cytochrome P450 enzymes

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13
Q

What found in grapefruit juice is a cyp inhibitor?

A

Furanocoumarins irreversibly inhibit CYP 3A4 which is responsible for metabolising 50% of drugs.

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14
Q

What is the importance of CYP2D6 in caucasians and east africans?

A

Absent in 7% of caucasians

Hyperactive/ increased induction in ~30% of East Africans

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15
Q

Apart from the kidneys what are the other routes of drug elimination?

A

Sweat, tears, genital secretions, saliva, breast milk, faeces, hair, gases - volatile compounds

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16
Q

How can enterohepatic circulation affect drug elimination?

A

When the drug is absorbed and then metabolised by the liver it can then become conjugated with bilirubin and released into the GI system. This would then cause some of the conjugated drug and bilirubin to be reabsorbed with fats and so the drug would then potentially be reabsorbed distal to the common bile duct.

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17
Q

What is zero order kinetics for drug elimination?

A

The drug is eliminated at a constant rate over time

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18
Q

What is first order kinetics for drug elimination?

A

The drug elimination is exponentially decreasing. As time increases the elimination decreases. Log of the drug concentration produces a straight curve

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19
Q

How is half life related to kinetics?

A

Half life is related to first order kinetics
It is independent of concentration
1/time

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20
Q

Define the clearance of drugs?

A

Constant proportion not amount of drug that is cleared

Volume of blood cleared per unit time (mL/min)

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21
Q

How do you calculate clearance?

A

Rate of elimination from body / drug concentration in plasma

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22
Q

What is the relationship between drug concentration and clearance?

A

The higher the drug concentration the higher the elimination rate and more drug cleared

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23
Q

At therapeutic doses what type of kinetics do most drugs have?

A

First order kinetics therefore half life is constant

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24
Q

What effect does a high dose have on the kinetics?

A

As the enzymes become saturated at high doses the elimination can become zero order and so a set amount of the drug is eliminated at a constant rate

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25
Q

What factors of PK affect elimination of a drug?

A

Vd
Clearance
Half life

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26
Q

How quickly is steady state achieved in most drugs?

A

5.5 half lives

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27
Q

What equation calculates dosing interval?

A

[Dose x Bioavailability correction] /

Dose interval

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28
Q

What calculation gives the loading dose for most drugs?

A

Loading dose = Steady state plasma concentration x Vd

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29
Q

How do clearance and elimination rate differ?

A

Clearance takes into account the rate of elimination from the body/drug concentration in plasma
Clearance is a constant proportion and not an amount but the elimination rate is the volume of blood cleared per unit time so is variable and an amount not a proportiob

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30
Q

To increase or decrease the Css, what dosing parameters could you change?

A

Volume of distribution
Dose of drug
Loading dose

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31
Q

What equation gives the mean arterial pressure?

A

Cardiac output x total peripheral resistance

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32
Q

What equation gives the cardiac output?

A

Stroke volume x heart rate

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33
Q

How is the radius of blood vessels related to the resistance?

A

As the radius increases by a number the resistance to flow increases by a factor of 4 (radius to the power of 4)

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34
Q

What are 3 subcategories of elevated blood pressure?

A

Essential
Primary
Idiopathic

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35
Q

What is NICE’s definition of HTN?

A

Elevated blood pressure that is associated with an increase in risk of some harm
>140/90 mmHg = HTN

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36
Q

When do we treat HTN?

A

140/90 <80yrs old including type 2 diabetics
150/90 >80 years old
135/85 type 1 diabetics

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37
Q

What is stage 1 of HTN?

A

Clinic BP = 140/90 - 159/99mmHg

ABPM average or HBPM average from 135/85 to 149/94mmHg

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38
Q

What is stage 2 HTN?

A

Clinic BP = 160/100 to 180/120

ABPM or HBPM average of >150/95

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39
Q

What is stage 3 HTN?

A

Clinic SBP = >180 or

Clinic DBP = >120

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40
Q

What is prehypertension?

A

> 120/80 <140/90 mmHg

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41
Q

What enzyme does Ramipril inhibit?

A

Angiotensin converting enzyme

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42
Q

What angiotensin receptor do ARB’s block?

A

Angiotensin 1 receptor

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43
Q

What are the 5 effects of Angiotensin 2?

A

1- Increased sympathetic activity
2- Tubular Na Cl reabsorption and K retention. H20 retention
3- Adrenal cortex release of renin - H20 retention
4- Arteriolar vasoconstriction. Increase in blood pressure
5- Posterior Pituitary gland - ADH secretion - H20 absorption in the collecting duct

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44
Q

Where are the ACE found predominantly?

A

Luminal surface of capillary endothelial cells, predominantly in the lungs

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45
Q

How do ACEi cause hyperkalaemia?

A

Lowers aldosterone which causes an increase in K+

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46
Q

How can ACEi cause renal failure?

A

Renal artery stenosis - constriction of efferent arterioles

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47
Q

How do ACEi work in the vasculature?

A

Potentiates bradykin - vasodilation via NOS/NO and PGIs. ACEi causes vasodilation in low-renin hypertensives

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48
Q

How do ARBs work?

A

Block AT1 and AT2 receptors - no effect on bradykinin

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49
Q

In low-renin hypertensives which drug is better ACEi or ARBs?

A

ACEi because it works at the rate limiting step stage from Ang1 to Ang2 conversion. The more renin the more Ang1 there is and so the more ACE converts 1 to 2 but ACEi will stop this. If there is a low renin then the pathway is not upregulated anyway and so won’t have much of an effect by blocking the receptors in ARBs

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50
Q

By targeting AT1 receptors with ARBs what is the result?

A

Inhibiting Ang-2 mediated vasoconstriction - chymase production

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51
Q

What type of CCB is amlodipine?

A

dihydropyridine

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52
Q

What type of CCB is diltiazem?

A

Non-dihydropyridine

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53
Q

What is an uncommon but important side effect of dihydropyridine CCBs?

A

Palpitations (compensatory tachycardia)

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54
Q

Name a phenylalkylamine CCB

A

Verapamil

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55
Q

How does verapamil work?

A

Class IV anti-arrhythmic agent/ prolongs action potentials/ effective refractory period

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56
Q

How does verapamil affect chronotropic and ionotropic results on the heart?

A

Negative chronotropic and ionotropic

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57
Q

Name a benzothiazine CCB

A

Diltiazem

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58
Q

Where in the nephron do thiazide and thiazide-like diuretics work?

A

distal tubule

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59
Q

How do thiazide and thiazide-like diuretics work?

A

Block sodium chloride co-transporter which then reduces sodium resorption and therefore water

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60
Q

What are common side effects of thiazides and thiazide-like diuretics?

A

Hypokalaemia, hyponatraemia, hyperuricaemia, hyperglycaemia, hypercholesterolaemia, hypertriglyceridaemia

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61
Q

What is the difference in the pathway of treating HTN in diabetics and non-diabetics?

A

First line in diabetics is ACEi regardless of age rather than CCB in non-diabetics

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62
Q

How does hydralazine work?

A

Arteriolar vasodilation and reduction in TPR - actual MAO is unknown

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63
Q

How does ivabradine work?

A

Blocks the If current that controls spontaneous depolarisation in SA node

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64
Q

Does furosemide affect preload or afterload?

A

reduces preload

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65
Q

How does spironolactone work?

A

Aldosterone receptor antagonist

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66
Q

How does secubitril work?

A

Inhibits natriuretic inactivating enzymes - potentiates effects of ANP and BNP

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67
Q

Why are beta blockers given in heart failure?

A

Reduce HR and therefore allow blood to enter the ventricles during diastole. They therefore increase diastole and allow enough perfusion of the cardiac myocytes

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68
Q

What is the medical term for water loss without electrolytes?

A

Aquaretic

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69
Q

What is the medical term for increased production of urine?

A

Diuretic

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70
Q

Where do carbonic anhydrase inhibitors work?

A

PCT of the renal tubule

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71
Q

Where do osmotic diuretics work?

A

PCT

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72
Q

Where do SGLT2 inhibitors work?

A

PCT

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73
Q

Where do loop diuretics work?

A

Ascending loop of henle

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74
Q

Where do thiazides work?

A

DCT

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75
Q

Where do potassium sparing diuretics work?

A

CD

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76
Q

What do carbonic anydrase inhibitors do?

A

Block CA which prevents bicarbonate breaking down into water and CO2 and so bicarb is lost

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77
Q

By what mechanism do CA inhibitors cause hypokalaemia?

A

On the basolateral surface Na/K ATPase brings sodium into the cell and potassium out of the blood into the cell. CA reduces the H2CO3 break down intracellularly which therefore means less H+ dissociates in the cell and so less Na enters cell by the Na/H+ exchanger on the luminal surface. More Na delivery to the CD and more Na reabsorbed through the ENaC channels in exchange for K+. Causing Hypokalaemic metabolic acidosis

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78
Q

Give an example of an osmotic diuretic

A

Mannitol

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79
Q

How do SGLT2 inhibitors work?

A

Prevent the glucose entering the cell through the SGLT2 channel in the PCT therefore osmotic effect more water is retained in the lumen and so more water is lost plus glucose.

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80
Q

How do loop diuretics work?

A

Block NKCC2 channel in basolateral side in thick ascending limb. Therefore more Na in the lumen and therefore more water loss.

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81
Q

What is a problem with loop diuretics in relation to K+ and pH?

A

Hypokalaemic metabolic alkalosis. Na/H channel works too effectively as more Na in lumen and therefore more H+ is lost from the cell and so creating alkalosis

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82
Q

How do thiazide diuretics work?

A

Block Na/Cl co-transporter in DCT. Reduced Na entry into cell therefore increased calcium reabsorption through Na/Ca antiporter on basolateral surface

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83
Q

What effect does aldosterone have on ENaC and Na/K ATPase channels?

A

Increases their expression in principal cells of the CD therefore increased reabsorption of Na and therefore H2O

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84
Q

Name an aquaretic and how would it work?

A

Tolvaptan - ADH antagonist

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85
Q

What are aquaretics used for?

A

Treat hyponatreamia (and prevent cyst enlargement in Adult polycystic CDK)

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86
Q

How does alcohol work as a diuretic?

A

Inhibits ADH release and doesnt block the receptor

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87
Q

What is nephrotic syndrome characterised by?

A

Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and hypertension

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88
Q

What are the stages of kidney disease and what are their respective % renal function?

A 
Stage 1 - 90%
Stage 2 - 89-60%
Stage 3 - 59-30%
Stage 4 - 29-15%
Stage 5 - <15%
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89
Q

What is Bartter’s syndrome?

A

NKCC2 channel reduced or no function in the thick ascending loop of henle.

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90
Q

What is Gitelman’s syndrome?

A

Reduced or no functioning NaCl co-transporter in the DCT

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91
Q

How could Bartter’s and Gitelman’s syndrome be treated?

A

Loop diuretics for Bartter’s and thiazide diuretics for Gitelman’s

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92
Q

What are broadly the four mechanisms of an ADR?

A

Exaggerated response
Desired pharmacological effect at an alternative site
Additional/ secondary pharmacological effect (QT prolongation)
Triggering immunological response (anaphylaxis)

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93
Q

What is a split antigen?

A

A subset of the antigen that may cause a reaction

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94
Q

Why are ACEi not first line in African Caribbean populations?

A

They have typically lower renin levels and so they wouldnt be making much of the Ang1 anyway plus angioedema is more prevalent than in young white caucasians

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95
Q

Why are east asians less able to metabolise alcohol?

A

They have a mutated aldehyde dehydrogenase enzyme - single amino acid mutation

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96
Q

Why is CYP2D6 an important enzyme?

A

approx 25% drug are metabolised by it. 6% of caucasians carry two null alleles therefore decreased first pass metabolism for metoprolol for example.

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97
Q

What do oestrogens, progestagens and androgens have in common?

A

They are all sex steroid hormones

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98
Q

What chemical structures make the steroid hormone base?

A

3 benzene rings and 1 pentameric ring

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99
Q

In outline how are steroid hormones made?

A

Cholesterol to pregnenolone to then 2 pathways one leads to androstenedione then to estrone and the second pathway to testosterone then to estradiol. At the level of the androsetenedione and testosterone there can be a conversion

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100
Q

Using what enzyme can androstenedione be made into testosterone?

A

17beta-HSD

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101
Q

Where do steroid hormones mainly act?

A

Intracellularly by causing changes in gene transcription and expression hence the lag in the effects

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102
Q

Why do steroid hormones take long to exert its effects?

A

causing changes in gene transcription and expression hence the lag in the effects

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103
Q

Which steroid hormone also has a membrane bound receptor?

A

Oestrogen

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104
Q

What is the major effect of oestradiol?

A

Growth of endometrium and breast also stimulates production of progesterone receptor

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105
Q

What is the major effect of progesterone?

A

Stimulates growth of endometrium and breast, maintains pregnancy, inhibits production of oestrogen receptor

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106
Q

What is the major effect of testosterone?

A

Stimulates male characteristics, anabolism

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107
Q

How does oestrogen affect HDL and LDL?

A

It lowers LDL and raises HDL

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108
Q

Name a side effect of progesterone on mood?

A

Can get irritability depression and pms, lack of concentration

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109
Q

Name a side effect of testosterone?

A

Male secondary characteristics, anabolic, acne, voice changes, increases aggression, adverse effects on lipid profile particularly HDL-C/LDL-C ratio

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110
Q

Why does carbamazepine interact with COCP?

A

Increase production of CPY enzymes and therefore reduces their efficacy

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111
Q

Name 2 indications for prescribing of HRT?

A

Symptoms of menopause - hot flushes, sweats and dyspareunia

Oesteoporosis

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112
Q

What are the risks of opposed oestrogen?

A

Increases risk of developing breast cancer

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113
Q

What are the risks of unopposed oestrogen?

A

Increases risks of developing endometrial and ovarian cancers

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114
Q

How do oestrogens increase risk of VTE?

A

Increased activated protein C resistance, increased thrombin activation, decreased anti-thrombin 3 activity, decreased protein S levels, decreased factor VII levels and decreased tissue factor pathway inhibitor - only for oral delivery systems. - in essence, it puts the blood into a procoagulative state

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115
Q

What is mifepristone and how does it work?

A

progesterone receptor antagonist, sensitising the myometrium to prostaglandin-induced contractions. Used for termination of pregnancy

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116
Q

What is clomiphene used for?

A

Anovulation - competes with oestrogen for ER binding, leads to ovulation induction through increased production of anterior pituitary hormones

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117
Q

How does ulipristal work?

A

Selective progesterone receptor modulator

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118
Q

What is ulipristal used for?

A

EHC

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119
Q

why do we treat high total cholesterol?

A

It is linked to CHD

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120
Q

For how much LDL cholesterol needs to be reduced for a 20% reduction in CVD risk?

A

1mmol/L

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121
Q

MOA of statins?

A

HMG-CoA reductase inhibitor - upregulation of hepatic LDL receptors therefore increased clearance of LDL

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122
Q

Apart from the common MOA of statins how else to they work?

A

Increased NO release, VEGF release and decreased endothelin production
Stabilization of atherosclerotic plaque - reduced SMC proliferation and increased collagen
Improved hemostasis - decreased fibrinogen, platelet aggregation and increased fibrinolysis

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123
Q

Is Simvastatin a prodrug or active ingredient?

A

Prodrug

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124
Q

Is Atorvastatin a prodrug or active ingredient?

A

Active ingredient

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125
Q

What scoring system is used to determine if someone should be on a statin?

A

QRISK

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126
Q

At what QRISK score to we give someone statins for primary prevention?

A

10 year 10% QRISK and above

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127
Q

What % reduction at we looking for in a patients bloods post statin therapy?

A

> 40% reduction in non-HDL-C after 3 months

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128
Q

Why is simvastatin taken at night?

A

Circadian rhythm of LDL receptor synthesis/ activity is at night and so this is when you want it to take effect

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129
Q

How do fibrates work?

A

Peroxisome proliferation-activation receptor activator - PPARalpha is a nuclear transcription factor that regulates expression of genes that control lipoprotein metabolism - increased production of lipoprotein lipase

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130
Q

Give an example of a cholesterol absorption inhibitor

A

Ezetimibe

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131
Q

MOA of cholesterol absorption inhibitor?

A

Inhibit NPC1L1 transporter which reduces absorption of cholesterol by the gut ~50%, hepatic LDLD receptor expression increased and therefore lowers total cholesterol ~15% and LDL ~20%.

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132
Q

As a guide for those being treated for secondary prevention with statins what is the target LDL-C and total cholesterol?

A

2mmol/L - LDL-C

4mmol/L - Total

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133
Q

How do PCSK9 inhibitors work?

A

Protein that binds internalised LDL-R directing them for degradation

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134
Q

Name a PCSK9 inhibitor?

A

Alirocumab

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135
Q

What are rough NNT for statins?

A

17-20

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136
Q

What is insulin secreted in response to?

A

Increased glucose, Increased incretins (GLP-1 and GIP)

Glucagon, Parasympathetic activity M3

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137
Q

What inhibits the release of insulin?

A

Decreased glucose, cortisol, sympathetic activity (Alpha2)

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138
Q

What 4 categories of insulins are there in relation to their onset of action?

A

Rapid, shore, intermediate and long

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139
Q

How quickly do rapid acting insulins act?

A

within 10-20minutes

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140
Q

How quickly do short acting insulins act?

A

within 30-60mins

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141
Q

How quickly do intermediate acting insulins act?

A

within 60-120mins

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142
Q

How quickly do long acting insulins act?

A

60-90mins

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143
Q

When do short acting insulins peak in their activity?

A

2-5hours

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144
Q

When do rapid acting insulins peak in their activity?

A

40-50mins

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145
Q

When do intermediate acting insulins peak in their activity?

A

4-12hours

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146
Q

When do long acting insulins peak in their activity?

A

plateau between 2-20hours

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147
Q

How long do rapid acting insulins act for?

A

3-5hours

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148
Q

How long do short acting insulins act for?

A

5-8hrs

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149
Q

How long do intermediate acting insulins act for?

A

18-24hrs

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150
Q

How long do long acting insulins act for?

A

20-24hrs

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151
Q

What is the most common insulin dosing regimen?

A

basal bolus regimen

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152
Q

Give a name for a rapid acting insulin

A

Insulin aspart

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153
Q

Give a name for a fast acting insulin

A

Soluble insulin, humulin S, actrapid

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154
Q

Give a name for an intermediate acting insulin

A

Isophane insulin

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155
Q

Give a name for long acting insulin

A

Insulin glargine

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156
Q

What is DKA?

A

Ketonaemia, hyperglycaemia, acidosis. Although DKA can present with low blood ketones and hyperglycemia may not always present

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157
Q

On the NICE T2DM guidelines when do you consider adding medication?

A

If HbA1c is above 48mmol/mol (6.5%)

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158
Q

What is the first line treatment for T2DM?

A

Metformin

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159
Q

After which HbA1c result after starting metformin would you consider adding a second agent?

A

HbA1c level above 58mmol/mol (7.5%)

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160
Q

What drugs can be used second line in T2DM?

A

DDP-4i, pioglitazone, SU, SGLT-2

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161
Q

If HbA1c rises above 58mmol/mol(7.5%) after 2 agents used what else can you use?

A

combination of any of these with a metformin backbone which includes an insulin based treatment, or a GLP-1 analogue

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162
Q

Name a GLP-1 analogue

A

Liraglutide, dulaglutide, semaglutide

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163
Q

MOA of biguanides

A

decrease hepatic glucose output (gluconeogenesis, glycogenolysis) and increase glucose utilisation in skeletal muscles, suppress appetite so limit weight gain

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164
Q

MOA of sulfonylureas

A

stimulate beta-cell pancreatic insulin secretion blocking ATP-dependent potassium channels

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165
Q

What is a problem with sulfonylurea use?

A

Need residual pancreatic function

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166
Q

How is insulin normally released from the pancreatic beta cell?

A

Glucose enters the cell through GLUT-2 transporters on the cell membrane. Glucose is metabolised and causing a rise in ATP. This then causes ATP-dependent potassium channels to start to close which causes cell membrane depolarisation allowing calcium to enter the cell. The calcium entering the cell will cause the vesicles which house the insulin to fuse with the cell membrane then release the insulin

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167
Q

What is a side effect of sulfonylureas that is potentially unpleasant?

A

Weight gain as there is more insulin being released and so you get anabolic effects

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168
Q

MOA of thiozolidinediones?

A

Insulin sensitisation in muscle and adipose tissues. Decreased hepatic glucose output. Activation of PPAR-gamma which cause increased gene transcription to allow glucose to be made into triglycerides in the cells.

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169
Q

Why do thiozolidinediones take so long to work?

A

Affect gene transcription and so this takes 6-8weeks for effect

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170
Q

Why do you get weight gain when using pioglitazone?

A

Fat cell differentiation - increase in the physical number of fat cells

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171
Q

MOA of SGLT-2 inhibitors

A

Block the sodium-glucose 2 transporter in the renal PCT. Causes decreased glucose absorption from tubular filtrate and so increased urinary glucose

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172
Q

What is a risk of SGLT-2 inhibitors?

A

As they physically prevent glucose re-entering the blood they can cause hypoglycaemia but much less compared to the other oral antihyperglycaemic agents

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173
Q

What is a side effect of the SGLT-2 inhibitors that would potentially require treatment with antibiotics?

A

UTI and genital infections as there is more glucose present and so would allow bacteria to grow faster

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174
Q

What are the 5 effects of GLP-1 analogues?

A

Pancreas- increased insulin biosynthesis and secretion, decreased glucagon secretion
Bain - decreased food intake through increased satiety
Liver (indirect) - decreased glucose production
Stomach- delayed gastric emptying
Muscle (indirect) - increased glucose uptake

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175
Q

MOA of DPP4- inhibitors

A

Prevent incretin degradation which are glucose dependent (therefore post-prandial) action. Do not stimulate insulin secretion at normal blood glucose - therefore lower hypoglycemic rik

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176
Q

What is good about DPP4-i for normal weight patients?

A

Weight neutral - suppresses appetite so no changes in weight

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177
Q

MOA of GLP-1 analogues

A

Increase glucose dependent synthesis of insulin secretion from beta-cells activate GLP-1 receptors and therefore are not degraded by DPP-4

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178
Q

What is added to insulin preparations to alter their release from the site of injection?

A

Zinc or protamine or a combination of the two

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179
Q

Looking at a cardiac cause what can cause a blackout?

A

Bradyarrhythmias —> palpitations —> blackout

Tachyarrhythmias can also cause the same

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180
Q

In a fast cardiac action potential what ionic change causes the upstroke of the potential?

A

Sodium influx into the cell

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181
Q

In a fast cardiac action potential what ionic change causes the first (1) downward stroke of the potential?

A

Opening of potassium channels causing potassium to leave the cells

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182
Q

In a fast cardiac action potential what ionic change causes the second (2) downstroke of the potential?

A

Calcium entry into the cell causes the maintenance of AP temporarily

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183
Q

In a fast cardiac action potential what ionic change causes the third (3) downstroke of the potential?

A

The exit of potassium from inside the cell to outside maintains the downward stroke of the AP

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184
Q

In a fast cardiac action potential what ionic change causes the fourth (4) downstroke of the potential?

A

Plateau phase where the sodium/potassium ATPase pump is exchanging sodium to leave the cell and potassium to enter the cell making it even more negative

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185
Q

What is a class 1 anti-arrhythmic?

A

Sodium channel blocker that causes a marked slowing conduction of the tissue (phase 0) - minor effects on AP duration

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186
Q

What is a class 2 anti-arrhythmic?

A

Beta blockers - diminish phase 4 depolarisation and automaticity (focal arrhythmia).
They work on phase 2 of the cardiac AP

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187
Q

What is a class 3 anti-arrhythmic?

A

Potassium channel blocker - block the 3rd phase. This would extend the refractory period.

Increases action potential duration and so would extend the QT - pro-arrhythmic agent.

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188
Q

What is a class 4 anti-arrhythmic?

A

Calcium channel blockers decrease inward calcium currents resulting in a decrease of phase 4 spontaneous depolarisation. Effect is a plateau phase of action potential. This would affect phase 2 of the cardiac AP

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189
Q

There is a slow cardiac action potential which can be found in which part of the heart?

A

SA and AV node

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190
Q

What is stage 4 of the funny current?

A

Sodium and potassium entry into the cell

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191
Q

What is stage 0 of he slow cardiac AP?

A

Upward stroke - calcium entry into the cell

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192
Q

What is stage 2 of the slow cardiac AP?

A

Calcium entry into the cell causes a peak in the current

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193
Q

What is stage 3 of the slow cardiac AP?

A

Potassium leaving the cell causes a downward trend

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194
Q

How would calcium channel blockers affect the funny current?

A

Slope of phase 0 is more flat which is the conduction velocity. Due to slow conduction through the SA and AV node. This would then mean that the refractory period is shifted to later causing a bradycardia

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195
Q

How could drugs affect automaticity of the SA and AV nodes?

A

B agonists would increase the slope at phase 4 of the funny current. This increases the speed of action potential.

Muscarinic agonists or adenosine would cause phase 4 slope of the funny current to become flatter and a longer period of time before AP activation

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196
Q

Name two abnormal impulse generations

A

Automatic rhythms

Triggered rhythms

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197
Q

Name the subsets of the automatic rhythms

A

Enhanced normal automaticity - increase AP from SA node - tachycardia

Ectopic focus - AP arises from sites other than SA node. Abnormal electrical conduction due to ventricular ectopic foci

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198
Q

Name the subtypes of triggered rhythms

A

Delayed afterdepolarisation - arises from the resting potential that doesn’t result in a full AP

Early afterdepolarisation - AP arises from the plateau phase

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199
Q

Name the two subsets of abnormal conduction

A

Conduction blocking

Re-entry

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200
Q

Name the subtypes of conduction blocking during an AP

A

1st, 2nd and 3rd degree heart block.

This is when the impulse is not conducted from the atria to the ventricles

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201
Q

Name the 2 subtypes of re-entry rhythms

A

Circus movement and reflection

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202
Q

What is a bundle of Kent and what is the result?

A

Accessory pathway in the heart that leads to preexcitation and then Wolf-Parkinson-White syndrome (WPW)

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203
Q

What is a re-entry rhythm in cardiology?

A

In a circuit the pathway leaves and comes back around another conduction pathway back around on itself

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204
Q

What is the worst side effect of a re-entrant rhythm?

A

SVT - a constant re-entry of AP through the AV node that has some APs leaving and entering the Bundle of His through the ventricles

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205
Q

What drugs can be used for abnormal AP generation?

A

Beta blockers of CCB - decreases phase 4 slope in the pacemaker cells and rises the threshold

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206
Q

In case of abnormal conduction what drugs can be used to treat it?

A

Decrease in conduction velocity phase 0 is affected which would be a sodium channel blocker.

Effective refractory period would increase (so the cell wont be reexcited again) - class 3

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207
Q

What are the Vaughan-Williams Classification classes and how do they affect action potentials?

A 
Class:
1A - moderate phase 0 effects
1B - no change in phase 0
1C - marked phase 0 effects
2 - beta-blockers
3 - prolonged repolarisation
4 - CCB
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208
Q

What drugs are in the Vaughan-WIlliams Classification classes?

A 
1A - Quinidine and procainamide
1B - Lidocaine
1C - Flecainide and propafenone
2 - Bisoprolol, metoprolol, propranolol
3 - Amiodarone and sotalol
4 - Verapamil and diltiazem
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209
Q

How do class 1A antiarrhythmics work and their effects on ECGs?

A

Decrease conduction in phase 0
Increase refractory period (increase APD and sodium inactivation)
Decrease automaticity (decrease slope of phase 4, fast potentials)
Increase threshold for sodium

Increase QRS and QT

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210
Q

What can class 1A anti-arrhythmics be used for?

A

Quinidine - Maintain sinus rhythm in AF and A flutter and to prevent recurrence

Procainamide - acute IV Tx of supreventricular and ventricular arrhythmias

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211
Q

How do class 1B anti-arrhythmics effect cardiac activity?

A

Fast binding

No change in phase 0 in normal tissue

APD slightly decreased

Increased threshold for sodium channels

Decreased phase 0 conduction in fast beating or ischaemic tissue

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212
Q

How do class 1B anti-arrhythmics affect the ECG?

A

None in normal tissues, in fast beating or ischaemic tissues increases the QRS width

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213
Q

What can class 1B antiarrhythmics be used for?

A

VT especially during ischaemia

Not used in atrial arrhythmias or AV junction arrhythmias

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214
Q

How do class 1C antiarrhythmics effect cardiac activity?

A

Very slow binding

Significantly decrease phase 0 (sodium)

Decrease automaticity (increased threshold)

Increased APD (potassium) and increased refractory period especially in depolarising atrial tissue

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215
Q

How do class 1C antiarrhythmics effect ECGs?

A

Increased PR and QRS and QT

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216
Q

What can class 1C antiarrhythmics be used for?

A

Supraventricular arrhythmias (fibrillation and flutter)

Premature ventricular contractions

WPW syndrome

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217
Q

What are class 2 antiarrhythmics cardiac affects?

A

Increase APD and refractory period in AV node to slow AV conduction velocity

Decreased phase 4 depolarisation (catecholamine dependent)

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218
Q

How do class 2 antiarrhythmics affect ECGs?

A

Increased PR and decreased HR

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219
Q

What can class 2 antiarrhythmics be used to treat?

A

Sinus and catecholamine dependent tachycardia

Converting restraint arrhythmias at AV node

Protecting the ventricles from high atrial rates (slow AV conduction) in atrial flutter/ fibrillation

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220
Q

What are class 3 antiarrhythmics cardiac affects?

A

Increase refractory period and increase APD (potassium channels)

Decreased phase 0 and conduction (sodium)

Increased threshold

Decrease phase 4 (beta blocking and calcium channel block)

Decreased speed of AV conduction

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221
Q

How do class 3 antiarrhythmics affect ECGs?

A

Increase PR, QRS and QT

Decreased HR

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222
Q

What can class 3 antiarrhythmics be used for?

A

Effective for most arrhythmias e.g. VT and SVT

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223
Q

What are the ECG changes seen with class 3 antiarrhythmics?

A

Increased APD and refractory period in atrial and ventricular tissues

Slow phase 4 (beta blocker at lower doses)

Slow AV conduction

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224
Q

What are class 4 antiarrhythmics cardiac effects?

A

Slow conduction through AV (calcium channels)

Increase refractory period in AV node and increase slope of phase 4 in SA node to slow HR

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225
Q

What are class 4 antiarrhythmics effects on the ECG?

A

Increase PR

Increase/decrease HR depending on blood pressure response and baroreflex

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226
Q

What can class 4 antiarrhythmics be used for?

A

Control ventricles during SVT

Convert SVT (re-entry around AV)

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227
Q

How does adenosine work as an antiarrhythmic?

A

Natural nucleoside that binds A1 receptors and activates potassium currents in AV and SA node decreasing APD

Hyperpolarisation causing decreased HR

Decreased calcium currents - increase refractory period in AV node

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228
Q

What can adenosine be used for?

A

Convert re-entrant SVT

Diagnosis of coronary artery disease (scans - give to slow the HR)

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229
Q

How does vernakalant work?

A

Blocks atrial specific potassium channels (outward channel class 3)

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230
Q

How does vernakalant affect the heart?

A

Slows atrial conduction

Increases potency with higher heart rates

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231
Q

What is vernakalant used for?

A

Convert recent onset AF to normal sinus rhythm

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232
Q

How does ivabradine work?

A

Blocks If ion current highly expressed in sinus node

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233
Q

What can ivabradine be used for?

A

Reduce inappropriate sinus tachycardia

Reduce heart rate in HF and angina (avoiding blood pressure drops)

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234
Q

How does digoxin work?

A

Enhances vagal activity (increases potassium currents, decreases calcium currents and increases refractory period)

Slows AV conduction and slows HR

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235
Q

What can digoxin be used for?

A

Reduces ventricular rates in AF and Aflutter

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236
Q

How does atropine work?

A

Selective muscarinic antagonist

Blocks vagal activity to speed AV conduction and increase HR

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237
Q

What is atropine used for?

A

Treat vagal bradycardia

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238
Q

Should flecainide be used alone in atrial flutter and if not with what?

A

No, give AV nodal blocking drugs to reduce ventricular rates in Atrial Flutter

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239
Q

Which drug would you give IV for VT?

A

Metoprolol/ lignocaine or amiodarone

240
Q

Which drugs would you give to treat AF?

A

Rate control - slows conduction through AV node to reduce HR - Bisoprolol, verapamil, diltiazem +/- digoxin

Rhythm control - sotalol, flecainide with bisoprolol, amiodarone

241
Q

Which drug is best used in WPW syndrome?

A

Ablation is best treatment but flecainide is best or amiodarone

242
Q

List drugs that could be used in re-entrant narrow complex tachycardia (SVT)

A

Acutely (IV)
Adenosine, verapamil, flecainide

Chronic (repeated episodes, orally)
Bisoprolol, verapamil, sotalol, flecainide, procainamide, amiodarone

243
Q

Which drugs for ectopic beats?

A

Bisoprolol first line

Flecainide, sotalol or amiodarone

244
Q

Which drugs can be used to treat sinus tachycardia?

A

Ivabradine (no drop in blood pressure)

Bisoprolol, verapamil

245
Q

What substance is released by the healthy endothelium that inhibits platelet aggregation?

A

Prostacyclin

246
Q

What is the cascade of prostacyclin release inhibiting platelet aggregation?

A

PGI2 bings to platelet receptors which increases cAMP in the platelets which decreases calcium release preventing platelet aggregation which results in reduced platelet aggregators agents and stabilises GPIIbIIIa receptors

247
Q

What substances are released from platelets to cause clotting?

A 
ADP
Thromboxane A2
Serotonin
Platelet activation factor
Thrombin
248
Q

What causes the initial activation of platelets in clot formation?

A

The collagen negative charge on the damaged endothelium

249
Q

Why are arterial thrombi “white”?

A

Platelet rich

250
Q

Why are venous thrombi “red”?

A

Lower platelet content and more fibrin formation

251
Q

MOA of aspirin?

A

Irreversible binding and inhibitor of COX enzymes (1 and 2) which reduces production of thromboxane A2 and therefore reduces platelet aggregation

252
Q

Why are higher doses (>75mg) of aspirin used and why?

A

Inhibit endothelial prostacyclin (PGI2) which is pro-inflammatory (anti-inflammatory effects) which is good for pain relief

253
Q

Why is aspirin contraindicated in <16year olds?

A

Theoretically can get Reyes Syndrome which is swelling of the liver and the brain post viral infection commonly flu and chicken pox. Therefore aspirin shouldn’t be used in children recovering from viral infections for pain/pyrexia

254
Q

What is the lifespan of a platelet?

A

7-10days

255
Q

Why does inhibition of the COX enzyme in platelets last their life time?

A

They lack a nucleus and so cant produce more COX enzymes

256
Q

For ACS what is the dosing of aspirin?

A

300mg loading dose then 75mg OD thereafter

257
Q

For acute ischaemic stroke what is the anti platelet treatment?

A

Aspirin - 300mg daily for 2 weeks

258
Q

MOA of clopidogrel, prasugrel, ticagrelor?

A

ADP receptor antagonists

Prevent ADP binding to P2Y12 receptor which then inhibits the activation of GP2b3a receptors

259
Q

What is the target difference between clopidogrel, prasugrel and ticagrelor?

A

Clopidogrel and prasugrel are irreversible inhibitors of P2Y12 - they are pro drugs and therefore slower onset of action

Ticagrelor acts reversible and non-competitively at different site to clopidogrel - has active metabolites

Ticagrelor and prasugrel have a more rapid onset of action

260
Q

How long before surgery would clopidogrel need to be stopped before?

A

7 days due to irreversible binding and hepatic transformation from the prodrug

261
Q

How long before surgery does ticagrelor need to be stopped?

A

5 days as a quicker onset of action

262
Q

If using clopidogrel for NSTEMI how long would you use it for?

A

Up to 12 months

263
Q

If using clopidgrel for STEMI with a stent how long would you use it for?

A

12 months

264
Q

What DAPT have better outcomes for ACS?

A

Ticagrelor and aspirin

265
Q

MOA of abciximab?

A

Glycoprotein 2b3a inhibitor

Blocks binding of fibrinogen and Von Willebrand factor

Target is final common pathway - more complete platelet aggregation

266
Q

What is the specialist use of abciximab?

A

High risk percutaneous trans luminal coronary angioplasty

267
Q

MOA of dipyridamole?

A

Inhibits cellular uptake of adenosine -> increases plasma adenosine -> inhibits platelet aggregation via A2 receptors

Also acts as a phosphodiesterase inhibitor which prevents cAMP degradation -> inhibits expression of GP2b3a receptors

268
Q

What is dipyridamole used for?

A

Secondary prevention of ischaemic stroke and TIAs

Adjunct for prophylaxis of thromboembolism following valve replacement

269
Q

How do fibrinolytic drugs work?

A

Dissolve the fibrin mesh work of thrombus

Streptokinase activates plasminogen which produces more plasmin which then causes fibrinolysis

Plasminogen activators like alteplase attach to fibrin which potentiates plasmin attachment and therefore fibrin clot breakdown

270
Q

Up to how long after an ischaemic stroke can alteplase be used?

A

Up to 4.5hours

271
Q

What is the caveat to the use of streptokinase?

A

Can only be used once as antibodies develop against it and render it useless in the future

272
Q

What is the pathway to production of prostanoids and leukotrienes?

A

Prostanoids: Phospholipids -> Arachidonic acid -> PGG2 -> PGH2 -> Prostanoids
Leukotrienes: Phospholipids -> Arachidonic acid -> Lipoxygenase pathways

273
Q

What pathway point of the production of prostanoids does COX1/2 affect it?

A

PGG2 conversion to PGH2 which are endoperoxidases

274
Q

What prostanoid does Aspirin inhibit?

A

Thromboxane A2 - platelet aggregation, vasoconstriction

275
Q

Name 3 prostanoids we need to know?

A

Prostaglandins, prostacyclin and thromboxanes

276
Q

Why are NSAIDs of benefit in terms of the arachidonic acid pathway?

A

Inhibit down stream products of arachidonic acid.

Many adverse effects stem from the inhibition of this pathway too.

277
Q

Where is the most amount of arachidonic acid found in the body?

A

Muscle, brain, liver

278
Q

What is PGE2 protective of?

A

GI mucosal protection

279
Q

What eicosanoids are implicated for pain, pyrexia, inflammation?

A

PGE2, PGF2alpha, PGD2

280
Q

What is PGI2 (prostacyclin) useful for?

A

Inhibits platelet aggregation, Vasodilation of lots of organs therefore cytoprotective in the CVS

281
Q

What is thromboxane A2 used for?

A

Platelet aggregation, vasoconstriction, therefore generally bad for the CVS

282
Q

Why is COX 2 a target for NSAIDS?

A

Inducible - mostly in chronic inflammation.
Constitutively produced in brain, kidney and bone (plus some other tissues). This then means that it can be targeted in inflammation

283
Q

What pathological functions are targets for COX2?

A

Chronic inflammation, chronic pain, fever, blood vessel permeability, tumour cell growth

284
Q

What homeostatic functions does COX2 have?

A

Renal, tissue repair and healing, uterine contractions, inhibit platelet aggregation

285
Q

What pathological functions are targets for COX1?

A

Chronic inflammation, chronic pain, raised blood pressure

286
Q

What homeostatic functions does COX1 have?

A

GI protection, platelet aggregation, vascular resistance

287
Q

What autocoids enhance the effects of prostanoids?

A

Bradykinin and histamine (small amount of effect from serotonin)

288
Q

An imbalance in which prostanoids is implicated in HTN, MI and strokes?

A

TXA2 and PGI2 (prostacyclin)

289
Q

What is one theory in the benefit of diet rich in fish oils (omega fatty acids)?

A

Conversion to TXA2 and PGI3 which are better prostanoids and result in a lower incidence of CVD

290
Q

MOA of NSAIDS?

A

Inhibition of COX enzymes which reduce the production of prostaglandin, prostacyclin and TXA2.
Compete for active site on COX with arachidonic acid

291
Q

Peripherally how do NSAIDs work?

A

Reduce peripheral pain fibre sensitivity by blocking PGE2

292
Q

Centrally how do NSAIDs work?

A

Decreased PGE2 synthesis in dorsal root ganglion therefore less neurotransmitter release therefore reduced excitability of neurones in pain relay pathway

293
Q

How do NSAIDs affect pyrexia?

A

PGE2 is critical component in preoptic area of the hypothalamus - thermoregulatory centre.
Inhibition of prostaglandins will block the pathway of prostaglandins increase the thermoregulatory centre and increases the set point causing the patient to become febrile

294
Q

NSAID use cautions?

A

Elderly, Glucocorticoid steroids concomitant use, anticoagulants, H. pylori infection (past and present)

295
Q

NSAID contraindications?

A

Exacerbation of IBD.

Local irritation and bleeding from rectal administration

296
Q

What are the renal ADR’s of NSAIDS?

A

reduce GFR in already predisposed patients, those also using nephrotoxic medications, CKD, HF

297
Q

How do NSAIDs affect sodium levels?

A

Prostagladins inhibit sodium absorption in the collecting duct - natriuresis - NSAIDs inhibit this action - which increases serum sodium therefore serum water therefore increase blood pressure.

298
Q

What is the main problem with COX-2 inhibitors?

A

Unopposed TXA2 activity and therefore a slightly increased amount of platelet aggregation, vasoconstriction.
Renal ADRs are similar to non-selective.

299
Q

What 3 drugs need to be monitored in NSAID use?

A

Competitive displacement of these drugs leads to:
Sulfonylureas - hypoglycaemia
MTX - accumulation, hepatotoxicity, leukopenia, RA
Warfarin - increased bleeding risk

300
Q

What is the problem in paracetamol overdose?

A

Paracetamol is broken down in a phase 1 reaction to NAPQI. This is a toxic metabolite which covalently binds to macromolecules in the cell causing cellular necrosis.
Glutathione is then used in the phase 2 reaction to convert NAPQI into a toxic reactive metabolite conjugate that can be further metabolised and cleared safely. This uses up glutathione which cant be replaced as quickly as required and so giving acetylcisteine donates a methionine (sulphur) group which is used to oxidise glutathione.

301
Q

Define nociception

A

Non-conscious neural traffic due to trauma or potential trauma to tissue

302
Q

Define pain?

A

Complex, unpleasant awareness of sensation modified by experience, expectation, immediate context and culture

303
Q

What is the pain pathway?

A

Nociceptors stimulated -> release of substance P and glutamate -> Afferent nerve stimulated -> Fibres decussate -> Action potentials ascend -> Synapse in thalamus -> project to post central gyrus

304
Q

What are the two pain fibres and what is the difference between them?

A

Adelta- myelinated - fast transmission, sharp pain

C - unmyelinated - slow transmssion, dull aches

305
Q

Where are the two methods of intrinsic pain modulation?

A

Peripherally - substantia gelatinosa

Centrall - Per aqueductal grey

306
Q

Where is the substantia gelatinosa found?

A

In the dorsal horn

307
Q

What is the peripheral method of pain modulation?

A

“Rub it better” - activates Abeta fibres which activates the substantia gelatinosa at the lamina which sends inhibitory signals going to the thalamus. This then overrides the signals from the Adelta and C fibres and prevents them signalling up to the thalamus

308
Q

What is the central method of pain modulation?

A

Signals sent from Adelta and C fibres. They travel to the thalamus which then signals to the Cortex and peri aqueductal grey matter. The Cortex then signals stimulatory signals to the PAG. The PAG then sends inhibitory signals to the dorsal root ganglion using neurotransmitters 5-HT and enkaphalins.

309
Q

Name the endogenous opioids?

A

Enkephalins, Dynorphins, B-endorphins

310
Q

Endogenous opioids work on what type of receptor?

A

GPCR therefore affect cAMP levels

311
Q

Where are mu opioid receptors found?

A

Supraspinal/ GI tract

312
Q

Where are delta opioid receptors found?

A

Wide distribution

313
Q

Where are kappa opioid receptors found?

A

Spinal cord/ Brain/ Periphery

314
Q

What does the Mu receptor GPCR cause?

A

Efflux of potassium

315
Q

What does the Delta receptor GPCR cause?

A

Influx of calcium

316
Q

What does the Kappa receptor GPCR cause?

A

Efflux of potassium and influx of calcium

317
Q

What are the effects of the opitate receptors?

A

Hyperpolarisation and decrease substance P release

Increase dopamine release

318
Q

What endogenous opiate acts on Mu receptors?

A

Enkephalins and beta-endorphins

319
Q

What endogenous opiate acts on Delta receptors?

A

Enkephalins

320
Q

What endogenous opiate acts on Kappa receptors?

A

Dynorphins

321
Q

What opiate receptor is responsible for respiratory depression and dependence?

A

Mu opioid receptor

322
Q

Why should morphine be used in caution in asthmatics?

A

Histamine release causes problems in asthmatics

323
Q

Why is fentanyl better than morphine?

A

More potent so less drug required (100x more potent)

Less histamine release, sedation and constipation

324
Q

How is codeine metabolised?

A

Liver CYP2D6 which is also inhibited by fluoxetine

325
Q

MOA of buprenorphine?

A

Partial agonist at mu opioid receptor

326
Q

What is naloxone?

A

Opiate receptor antagonist with affinity to m>d>k receptors

327
Q

What 2 methods are responsible for opioid tolerance?

A

1 - phosphorylation and uncoupling

2 - cAMP production

328
Q

How does phosphorylation and uncoupling lead to opioid tolerance?

A

Arrestin inside the cells attaches to the opioid receptor and uncouples it to the G-protein. This is intracellular phosphorylation related. This then results in more cAMP production and neuronal excitability and then withdrawal symptoms.

329
Q

What are contraindications to opiates?

A

Hepatic failure, acute respiratory distress, comatose, head injuries, raised ICP

330
Q

What are the two subsections of anaesthesia?

A

Local and general

331
Q

What are the methods of delivery of general anaesthesia?

A

Inhalation (volatile)

Intravenous

332
Q

What is a subsection of local anaesthetic?

A

Regional anaesthesia

333
Q

What are the 7 stages of anaesthesia from a practical viewpoint?

A

Premedication (benzodiazepine)
Induction (usually IV)
Intraoperative analgesia (usually an opioid)
Muscle paralysis-facilitate intubation/ ventilation/ stillness
Maintenance (intravenous/ inhalational)
Reversal of muscle paralysis and recovery + post op analgesia
Provision for post op nausea and vomiting (PONV)

334
Q

How are volatile anaesthetics delivered to the patient?

A

Inhalation via lungs

335
Q

Name 2 intravenous anaesthetics

A

Propofol
Barbiturates
Etomidate
Ketamine

336
Q

What are the stages of Guedel’s signs?

A

Stage 1 - analgesia and consciouness
Stage 2 - unconscious, breathing erratic but delirium could occur, leading to an excitement phase
Stage 3 - Surgical anaesthesia, with four levels describing increasing depth until breathing weak
Stage 4 - respiratory paralysis and death

337
Q

In Guedel’s signs describe what happens to the breathing

A

S1 - breathing is normal
S2 - breathing is erratic and different strengths and frequencies
S3a-S3d - Normal regular breathing initially but decreasing power and strength from a-c. S3d breathing is shallow and erratic
S4 - respiratory paralysis and breathing does not occur at any meaningful level

338
Q

At what stage during Guedel’s signs does eye movement stop?

A

Stage 3 b

339
Q

What happens to muscle tone during the advancing Guedel’s signs?

A

S1 - normal
S2 - normal to markedly increasing
S3a - Slightly relaxed S3b - moderately relaxed S3c-d - markedly relaxed
S4 - flaccid

340
Q

During what stages of Guedel’s signs is surgical anaesthesia reached?

A

Stage 3

341
Q

What is anaesthesia a combination of?

A

Analgesia
Hypnosis
Depression of spinal reflexes
Muscle relaxation

342
Q

What measurement is used to describe potency of volatile anaesthetics?

A

Mean alveolar concentration

343
Q

Describe mean alveolar concentration

A

The minimum alveolar concentration (MAC) of volatile agents is a term used to describe the potency of anaesthetic vapours. It is defined as the concentration that prevents movement in response to skin incision in 50% of unpremedicated subjects studied at sea level (1 atmosphere), in 100% oxygen. Hence, it is inversely related to potency and the more potent the agent, the lower the MAC value

344
Q

What is the connection with lipid solubility and anaesthetic potency?

A

The more lipid soluble a chemical the higher the anaesthetic potency

345
Q

What is the connection between lipid solubility and mean alveolar concentration?

A

The more potent the agent, the lower the MAC value. Inversely proportional.

346
Q

At equilibrium how does mean alveolar concentration relate to concentration at the active site?

A

At eqm [alevolar] = [spinal cord]

347
Q

What is MAC-BAR?

A

minimum alveolar concentration to block autonomic reflexes to nociceptive stimuli (1.7-2.0 MAC)

348
Q

What is MACawake?

A

The concentration required to block voluntary reflexes and control perceptive awareness (0.3-0.5 MAC)

349
Q

What factors would affect induction and recovery in anaesthesia?

A

Partition coefficients (solubility)
Blood:Gas partition (in the blood)
Oil:Gas partition (in fat)

350
Q

How would a higher or lower blood:gas partition coefficient affect induction and recovery?

A

A low value would mean fast induction and recovery

A higher value is visa versa

351
Q

How would oil:gas partition coefficient affect potency and accumulation?

A

The oil:gas coefficient is an index of potency and is inversely related to MAC. The higher the coefficient the more potent the drug

352
Q

What affects MAC?

A

Age (high in infants and lower in elderly)
Hyperthermia (increased); hypothermia (decreased) (temp affects gas solubility)
Pregnancy (increased)
Alcoholism (increased)
CNS stimulants (increased)
Other anaesthetics and sedatives (decreased)
Opioids (decreased) (MAC sparring)

353
Q

What drug is often added to other volatile agents to reduce the MAC?

A

N2O nitrous oxide

354
Q

How do GABAa receptors work?

A

They are Cl channels which hyperpolarises neurones and depresses CNS activity

355
Q

What receptor do most anaesthetics work on?

A

GABAa

356
Q

What anaesthetics don’t work on GABAa channels?

A

Xe, N2O and Ketamine

357
Q

What is the major excitatory neurotransmitter?

A

Glutamate

358
Q

What is type of receptor is an NMDA receptor?

A

Calcium channel that leads to excitation

359
Q

What 2 receptors in the brain have fine balance over consciousness?

A

Glutamate receptors and GABAa receptors

360
Q

What part of the brain is the target for anaesthetics?

A

Reticular formation - hindbrain, midbrain and thalamus
Thalamus -transmits and modifies sensory information
Hippocampus depression (memory)
Brainstem depression (respiratory and some CVS)
Spinal cord depression dorsal horn (analgesia) and motor neuronal activity (MAC)

361
Q

Why is the reticular system a target for anaesthetics?

A

It is referred to as the activating system and is involved in arousal. This is then shut off and so the patients falls asleep

362
Q

What receptor does ketamine work on?

A

NMDA receptor which is a Calcium channel

363
Q

Name a few characteristics of local anaesthetics

A

Lipid solubility is high
Dissociation constant - pKa - lower pKa faster onset
Protein binding - higher therefore longer duration of action

364
Q

Why is cocaine used as a local anaesthetic?

A

Competitive inhibitor of the sodium channel
Cocaine is lipophilic and so passes through the lipid bilayer. Once it passes through cocaine becomes positively charged -> enters the sodium channel -> cant leave the active site and so blocks it

365
Q

What is regional anaesthesia?

A

Selectively anaesthetising a part of the body
Block of a nerve and hence patient remains awake
Uses local anaesthetic or an opioid

366
Q

What are the main anaesthetic side effects?

A

GA - post op n&V, CVS - hypotension, post-op cognitive dysfunction, chest infection - poor cough reflex
LA/RA - lidocaine sodium channel blocking - cardiovascaular toxicity

367
Q

Describe asthma in terms of medication?

A

Reversible intermittent airway obstruction and hyper-reactivity to small airways

368
Q

What is defined as uncontrolled asthma?

A

Coughing, wheezing, SOB and chest tightness.
>= 3 days a week with symptoms OR >= 3 days a week with required use of a SABA for symptomatic relief OR >=1 nights a week with awakening due to asthma

369
Q

What is the asthma management pathway?

A 
-SABA as a baseline reliever therapy
S1- low dose ICS
S2 - low dose ICS + LTRA
S3 - low dose ICS + LABA / + LTRA
S4 - medium dose ICS + LABA / + LTRA
S5 - high dose ICS + LABA / + LTRA OR medium dose ICS+LABA/+LTRA + LAMA/Theophylline
370
Q

How do ICS work?

A

Activate cytoplasmic receptors, activated receptor then passes in to nucleus to modify transcription.
ICS’s increase beta receptors on the cell surface
Stop inflammatory mediators, interleukins, chemokins and cytokine production therefore gene repression.

371
Q

What is the function of ICS in asthma?

A

Reduces mucosal inflammation, widens airways and reduces mucus
Reduces symptoms, exacerbations
Pneumonia risk in COPD

372
Q

What are the ADRs of beta agonists?

A

Tachycardia, palpitations, anxiety and tremor
Increase SAN activity, therefore increase HR therefore decrease refractory period at AVN.
Beta blockers interact with beta agonists

373
Q

Which LABA is more potent formoterol or salmeterol?

A

Formoterol > salmeterol

374
Q

How do LTRA work?

A

LTC4 released by mast cells/ eosinophils -> increase bronchonconstriction/ mucus/ oedema through CysLT1 - GPCR

375
Q

How do LAMA work?

A

Relatively selective antagonist activity for M3 receptors

376
Q

How does theophylline work?

A

Adenosine receptor antagonist + phosphodiesterase effects too

377
Q

Define acute severe and life threatening asthma

A
  • unable to complete sentences
  • Peak flow >33-50% best or predicted
  • Resp rate >= 25ml/min
  • HR >=110BPM
    PLUS the following to make life threatening:
  • Peak flow <33% best or predicted
  • arterial SpO2 <92%
  • Normal PaCO2 (4.6-6kPa)
  • Silent chest, cyanosis, poor respiratory effort, arrhythmia, exhaustion, altered conscious level, hypotension
378
Q

How would you treat acute severe and life-threatening asthma?

A

High dose nebulised SABA (salbutamol nebs),
Oral steroids 5-7 days continue alongside ICS
Neb SAMA alongside nebs SABA
Consider IV aminophylline if life threatening

379
Q

What are the 5 tasks of medicines management of stable COPD?

A 
Confirm diagnosis of COPD
Stop smoking
Record MRC dyspnoea score
Flu/ pneumococcal vaccination
Consider medication - drug treatment
380
Q

How is acute COPD managed?

A

Nebs Salbutamol/ Ipratropium if patient hypercapnic or acidotic nebs should be driven by air and not oxygen
Oral steroids is eosinophil count high
Antibiotics

381
Q

What are the 3 inhaler options?

A

MDI, breath-actuated pMDI, DPI

382
Q

Why should a LABA only be prescribed with ICS?

A

LABA alone can mask airway inflammation and near - fatal and fatal attacks. As a result increased risk of death when prescribed alone.

383
Q

What is rheumatoid arthritis?

A

Autoimmune multi-system disease
Initially localised to synovium
Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone

384
Q

Describe the rheumatoid arthritis pathogenesis

A

There are pro-inflammatory mediators and anti-inflammatory mediators. When these are off kilter it produces the disease of rheumatoid.

385
Q

What are the 3 main pro-inflammatory mediators in rheumatoid arthritis?

A

IL-1
IL-6
TNF-alpha

386
Q

What are the 2 main anti-inflammatory mediators in RA that are not produced in as high quantity causing the disease?

A

IL-4

TGF-beta

387
Q

What role do matrix metalloproteinases play in rheumatoid arthritis?

A

They are stimulated by the interleukins which then break down the extracellular matrix and the proteoglycans in them. They also break down collagen which surrounds the connective tissues. Collagen type 1 = bones, collagen type 2 = cartilage

388
Q

How do we diagnose RA?

A

Clinical criteria:

  • Morning stiffness >=1hour
  • Arthritis of >= 3 joints
  • Arthritis of hand joints
  • Symmetrical arthritis
  • Rheumatoid nodules

Non-clinical criteria (prognosis features):

  • Serum rheumatoid factor/ Anti-CCP antibodies
  • X-ray changes
389
Q

What are the RA treatment goal?

A

Symptomatic relief

Prevention of joint destruction

390
Q

What major sign is typical for SLE?

A

Butterfly rash over the cheeks and nose

391
Q

What is SLE?

A

Autoimmune condition with genetic predisposition

Cause is currently unknown but affects all systems of the body

392
Q

What is the most common demographic of being diagnosed with Lupus?

A

90% are women

80% develop lupus between 15-45years old

393
Q

What is vasculitis?

A

Vessel inflammation and technically can affect any organ that is supplied by blood
Can have pulmonary haemorrhage, can affect the kidneys, skin etc.
Tx is with immunosuppression

394
Q

What are the treatment goals in SLE and vasculitis?

A

Symptomatic relief e.g. arthralgia, Raynaud’s phenomenon
Reduction in mortality
Prevention of organ damage
Reduction in long term morbidity caused by disease and by drugs

395
Q

What is a simple way or remembering the sides effects of corticosteroids?

A

All things that happen to anyone aged 70years old and above are potential side effects

396
Q

MOA of corticosteroids?

A

Prevent interleukins (IL1 and IL6) production by macrophages
Inhibit all stages of T-cell activation
Glucocorticoid receptor -> GRalpha -> enters nucleus as a dimer -> affects gene transcription to reduce proinflammatory proteins

397
Q

What indications is azathioprine used for?

A

SLE, vasculitis, RA (v. weak evidence), IBD
Atopic dermatitis, bullous skin disease.
Many other uses as ‘steroid sparing’ drug

398
Q

What is important to test before prescribing azathioprine?

A 
Thiopurine methyltransferase (TPMT) levels. Gene is highly polymorphic
Low/absent TPMT levels = risk of myelosuppression
399
Q

MOA azathioprine?

A

Azathioprine is cleaved to 6-mercaptopurine (6-MP)
Anti-metabolite that decreases DNA and RNA synthesis. Inhibition of de novo purine synthesis and another metabolite is incorporated into DNA

400
Q

What are the side effects of azathioprine?

A

Bone marrow suppression - monitor FBC
Increased risk of malignancy - esp transplanted patients
Increased risk of infection
Hepatitis - monitor LFT’s

401
Q

Name the 2 calcineurin inhibitors used in practice

A

Ciclosporin

Tacrolimus

402
Q

MOA of calcuneurin inhibitors?

A

Activity against help T-cells preventing production of IL-2 via calcineurin inhibition
Ciclosporin binds to cyclophilin protein
Tacrolimus binds to tacrolimus binding protein
Drug/protein complexes bind calcineurin
Calcineurin exerts phosphatase activity of activated T-cells then nuclear factor migration starts IL-2 transcription which modulates leukocyte

403
Q

What can mycophenolate be used for?

A

Lupud nephritis/ vasculitis maintenance, transplants

404
Q

MOA of mycophenolate?

A

Pro-drug derived from fungus Penicillium stoloniferum
Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)
Impairs B and T cell proliferation
Spares other rapidly dividing cells (due to guanosine salvage pathways in other cells)

405
Q

Important ADRs of mycophenolate?

A

Most serious is myelosuppression but less myelosuppression than AZA

406
Q

MOA of cyclophospamide?

A

Alkylating agent - cross links DNA so that it cannot replicate
Pro-drug
Active metabolite is 4-hydroxycyclophosphamide aldophosphamide -> phospharamide mustard (main active metabolite)

407
Q

What are the indications of cyclophosphamide?

A

Lymphoma, leukaemia, solid cancers, lupus nephritis, Wegner’s granulomatosis (ANCA-vasculitis)

408
Q

What is the most important ADR that needs to be controlled in cyclophosphamide use?

A

Cyclophosphamide excretion via the kidneys
Acrolein, metabolite is toxic to the bladder epithelium and can lead to haemorrhagic cystitis
This can be prevented through the use of aggressive hydration and/or mesna

409
Q

What are important considerations when using cyclophosphamide?

A

Increased risk of bladder cancer, lymphoma and leukaemia
Infertility related to cumulative dose and patient age
Monitor FBC and adjust dose in renal impairement

410
Q

What can methotrexate be used for?

A

RA

Malignancy, crohns, psoriasis, inflammatory myopathies, vasculitis, steroid sparing in asthma

411
Q

MOA of methotrexate?

A

Competitively and reversibly inhibits dihydrofolate reductase (DHFR)
MTX 1000x affinity than that of folate
DHFR catalyses the conversion of dihydrofolate to tetrahydrofolate a carbon unit used in purine and thymidine synthesis. Therefore inhibits DNA and RNA and protein synthesis. MTX acts during DNA/RNA synthesis during S-phase therefore greater toxic effect on rapidly dividing cells

412
Q

What part of MTX action are responsible for RA treatment?

A

Anti-folate action is NOT the MOA for RA

  • Inhibition of accumulation of adenosine
  • Inhibition of T-cell activation
  • Suppression of intercellular adhesion molecule expression by T-cells
413
Q

Why are NSAIDs contraindication in use with MTX?

A

NSAIDs displace MTX off proteins and so more available in the circulation
Renal excretion too so reducing GFR means more MTX in circulation

414
Q

What are important S/E of MTX?

A

Mucositis
Marrow suppression
Both respond to folic acid supplementation

Hepatitis and cirrhosis
Pneumonitis
Infection risk
Highly teratogenic and abortifacient - used for ectopic pregnancies

415
Q

Why cant patients allergic to aspirin not be given sulphasalazine?

A

Similar molecular shape to aspirin

5aminosalicylic acid

416
Q

What are the immunological effects of sulphasalazine?

A 
T-cell:
-inhibition of proliferation
-possible T-cell apoptosis
-inhibition of IL-2 production
Neutrophil
- reduced chemotaxis
- reduced degranulation
417
Q

Why is sulphasalazine so good in IBD?

A

Sulphasalazine is broken down in the proximal colon, where it makes the 5-aminosalicylic acid which is largely unabsorbed or enter enterohepatic circulation. This then has local effects for IBD

418
Q

What are the s/e of sulfasalazine?

A

Myelosuppression
Hepatitis - drug related not viral
Rash

419
Q

What are the good points of use of sulfasalazine?

A

Favourable toxicity
Long term blood monitoring not always needed
Very few drug interactions
Non-carcinogenic and therefore safe in pregnancy

420
Q

What are the effects of blocking TNF-alpha?

A
  • Decreased inflammation due to reduced cytokine cascade and therefore reduced leukocyte recruitment to the joint.
  • Decreased angiogenesis and therefore VEGF levels
  • Decreased joint destruction MMPs and other destructive enzymes, reduced bone resorption and erosion and therfore cartilage too
421
Q

What is a big risk of anti-TNF therapy?

A

TB reactivation
TNFalpha is released by macrophages in response to Mycobacterium tuberculosis infection
TNFa is essential for development and maintenance of granulomata which encapsulates the TB
Screening for TB is essential prior to treatment

422
Q

How does Rituximab work?

A

Binds specifically to CD20 found on a subset of Bcells but not on stem cells, pro-B cells, plasma cells or any other type of cell.
B cell function: antigen presentation, produce cytokines and antibodies. Rituximab causes B-cell apoptosis therefore very good in RA

423
Q

What is are the lower and upper limits of a detectable cancer called and what is the number of cells correlating to each?

A

Lower: Limit of clinical detection - 10^9 cells
Upper: Host death - 10^12 cells

424
Q

What is the range in time of cell proliferation?

A

9-43hours

425
Q

During which stages are cells targets for cancer therapies?

A

Growth phase 1, Synthesis phase (DNA), Growth phase 2 and then mitosis.

426
Q

Roughly how long does each cell last in each stage of growth?

A

Mitosis - 1 hour
S - 6-8 hours
G1 - 0-30hours
G2 - 2-4hours

427
Q

What is the fractional cell kill hypothesis?

A

At each drug administration cancer cells are killed off and their numbers drop. By default bone marrow cells also will get killed off quicker and by more. However, the bone marrow cell numbers will bounce back quicker than the cancer cells. So, with each round of chemotherapy the number of cancer cells decreases more rapidly compared to the bone marrow cells to a point where there are no more cancer cells but the bone marrow can still produce the bodies own cells.

428
Q

What are the sites of action of cytotoxic agents on a cellular level?

A

Anti-metabolites
Alkylating agents - affecting DNA
Intercalating agents - affect DNA transcription and translation
Spindle poisons - affect Mitosis

429
Q

How do alkylating agents work?

A

They link the two strands of DNA together and prevent replication from occurring. Formation of platinated inter- and intra-strand adducts.
G-G adducts: 55%
G-A adducts: 31%

430
Q

Name an alkylating agent?

A

Cisplatin, oxaliplatin. Platinum based drug

431
Q

MOA of antimetabolites?

A

5-FU inhibits thymidylate synthase which is used to produce DNA . It also works by inhibiting the folate cycle which produces dihydrofolate, which then makes -> tetrahydrofolate, which uses DHFR which is also a target for MTX.

432
Q

Name 2 antimetabolites drugs used?

A

5-FU and methotrexate

433
Q

How do spindle poisons work?

A

Once chromosomes are aligned in metaphase plate, spindle microtubules depolymerise, moving sister chromatids toward opposite poles.
Microtubule-binding agents inhibit polymerisation or stimulate polymerisation and prevent depolymerisation. microtubule.

434
Q

How do cells gain resistance against alkylating agents?

A

1- decreased entry or increased exit of agent
2 - inactivation of agent in cell
3 - enhanced repair of DNA lesions produced by alkylation

435
Q

What are the side effects of chemotherapy?

A

Mucositis, Alopecia, Pulmonary fibrosis, N&V, Diarrhoea, Cardiotoxicity, Cystitis, Local reaction, Sterility, Renal failure, Myalgia, Myelosuppression, Neuropathy, Phlebitis

436
Q

Why can patients get acute renal failure with chemotherapy?

A

Often multifactorial

Hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules

437
Q

Why can patients get GI perforation at site of tumour?

A

It is reported more commonly in lymphoma
Lymphoma’s cover one patch of GI and when they peel away you get a hole in the GI tract. Perforation is treated with TPN and supportive therapy.

438
Q

Why can patients get DIC during chemotherapy?

A

Onset within a few hours of starting treatment for Acute myeloid leukaemia

439
Q

Why do patients get vomiting during chemotherapy?

A

Multifactoral but includes direct action of chemotherapy drugs in the central chemoreceptor trigger zone

440
Q

What are the patterns of emesis post chemotherapy?

A

Acute phase 4-12 hours
Delayed onset 2-5 days later
Chronic phase may persist up to 14 days

441
Q

What drugs most commonly cause hair loss in relation to chemotherapy?

A

Doxorubicin, vinca alkaloids, cyclophosphamide

442
Q

What skin toxicities occur with chemotherapy?

A

Local: irritation, thrombophlebitis of veins, extravasation
General: Bleomycin- hyperkeratosis, hyperpigmentation, ulcerated pressure sores
Busulphan, doxorubicin, cyclophosphamide, actinomycin D - hyperpigmentation

443
Q

What is mucositis and why does it occur in chemotherapy?

A

GI epithelial damage. Can be whole GI tract but most commonly worst in oropharynx. Secondary infection like thrush is common

444
Q

What cardio-toxic effects can be seen in chemotherapy?

A

Cardio-myopathy in doxorubicin or high dose cyclophosphamide

Arrhythmias - cyclophosphamide or etoposide

445
Q

Why can patients get lung toxicity in chemotherapy?

A

Bleomycin used for testicular tumours can get pulmonary fibrosis which is worse with high flow oxygen. Concurrent radiotherapy can make the side effects worse. It is thought to do with TNF-alpha upregulation in the lungs as a sign of inflammation

446
Q

What are some haematological toxic s/e of chemotherapy?

A

Neutropenia
Lymphopenia
Thrombocytopenia

447
Q

Why can having more free drug present due to hypoalbuminaemia be a problem?

A

Having more free drug in the blood does mean more drug is available to be used in its action but also it means that there is more drug to be metabolised/ eliminated and so would need higher doses of drugs or more frequent administration

448
Q

Name the 4 most important drug-drug interactions for chemotherapy

A

Vincristine and itraconazole - more neuropathy
Capecitabine (oral 5FU) and warfarin - increased risk of bleeding (inc effects of warfarin)
MTX caution with penicillin and NSAID’s - increased toxicity/ bleeding
Capecitabine and St Johns Wort, grapefruit juice - nothing listed in BNF

449
Q

How can response to chemotherapy drug be checked?

A

Radiological imaging
Tumour marker blood tests
Bone marrow/ cytogenetics

450
Q

How can we check for signs of cardio and reno toxicity in chemotherapy?

A

Creatinine clearance

Echocardiogram/ ECG

451
Q

What are the stages of drug development in simple terms?

A 
1 - Chemical engineering/ serendipity
2 - Pre-clinical studies, animal and human modelling
3 - 3 phases of clinical trials
4 - Licence for FDA, MHRA, EMEA
5 - NICE guidance
6 - Clinical use
452
Q

What are the 7 steps of vomiting?

A

1- Vomiting centra in medulla signals to vomit
2- Nausea, salivation, sweating
3- Retrograde peristalsis (Duodenum and stomach)
4 - Deep inspiration
5 - Closure of glottis (prevent aspiration)
6 - Abdominal muscles contract
7 - LOS relaxes

453
Q

What makes the vomiting centre go?

A
  • Direct triggers - Drugs/ Hormones
  • Visceral afferents from gut - from vagus nerve
  • Vestibular nuclei - motion sickness, middle ear infections
  • Sensory afferents via midbrain - vomiting on sight/ smell/ sound etc.
    ALL feed into the chemoreceptor trigger zone - vomiting centre
454
Q

What drugs act on the vestibular nuclei to treat N&V?

A

Muscarinic receptor antagonists

H1 receptor antagonists

455
Q

How do muscarinic receptor antagonists treat N&V?

A

Competitive blocking of mAChR in vestibular nuclei and CTZ - these receptors are all over the body in the parasympathetic NS.

456
Q

What are s/e of muscarinic receptor antagonists?

A

Drug mouth, drug eyes, sedation, glaucoma, memory problems, constipation

457
Q

How do H1 receptor antagonists treat N&V?

A

Acts on vestibular nuclei

For motion sickness and morning sickness in pregnancy

458
Q

Where is the Chemoreceptor Trigger Zone found?

A

Medulla

459
Q

Why are H1 antagonists used in treating N&V bad in elderly and children?

A

Sedation and excitation - but don’t know their own limits and cause problems.
Elderly - QT prolongation
Constipation, urinary retention, dry mouth

460
Q

What drug classes are used on visceral afferents in the GIT to treat N&V?

A

5-HT3 receptors antagonists

D2 receptor antagonists

461
Q

What is the effect of serotonin on the GIT?

A

Smooth muscle contraction increases motility
Increases gut secretions
Regulates appetite

462
Q

How do 5HT3 antagonists work in treating N&V?

A

Peripherally - Reduces GI motility and secretions

Centrally - inhibition of CTZ

463
Q

Side effects of 5HT3 antagonists?

A

Constipation, headache, elevated liver enzymes, prolonged QT, extra-pyrimidal effects - dystonia, parkinsonism

464
Q

How do dopamine antagonists (non-antipsychotics) work in treating N&V?

A
  • Increases ACh at muscarinic receptors in GIT
  • Promotes gastric emptying - increased tone at LOS, increased tone and amplitude of gastric contractions, decreased tone of pylorus
  • Increases peristalsis
465
Q

What are common s/e of D2 receptor antagonists in treating N&V?

A 
Galactorrhoea via prolactin release
Extra-pyrimadal effects - dystonia and parkinsonism
Sudden cardiac death - prolonged QT
Sedation
Hypotension
466
Q

How do antipsychotic dopamine antagonists work in treating N&V?

A

Act on CTZ directly

May also block H1 and antimuscarinic receptors

467
Q

How do corticosteroids act in treating N&V?

A

CTZ

D2 antagonistic activity

468
Q

What are side effects of corticosteroids in the context of treating N&V?

A

Insomnia
Increased appetite
Hyperglycaemia

469
Q

How do cannbinoids act in treating N&V?

A

CTZ - Nabilone

470
Q

How do neurokinin 1 receptor antagonists act in treating N&V?

A

Antagonists against substance P and act at CTZ and in peripheral nerves

471
Q

How does midazolam work in treating N&V?

A

CTZ
Binding GABA
Decreased 5HT secretion

472
Q

How does gabapentin work in treating N&V?

A

Mitigation of effects of neurokinins and tachykinins

473
Q

How does mirtazapine work in treating N&V?

A

Effects on 5HT

474
Q

What is first line in motion sickness treatment?

A 
Hyoscine hydrobromide (KWELLS)
Cinnarizine has fewer s/e though - without sedation
475
Q

When can prokinetics be used and not used?

A

Used: GORD, ileus

Not used: Obstruction or risk of perforation e.g. ischaemic GIT

476
Q

What are the first 3 treatments of N&V?

A

Ondansetron
Cyclizine
Dexamethasone

477
Q

What are the treatments for hyperemesis gravidarum in terms of antiemetics?

A

Promethazine/ prochlorperazine
Metoclopramide
Ondansetron
RCOG guidelines say ondansetron increased risk of cleft palate in first trimester

478
Q

What drugs would be used in patients at high risk of emesis in chemotherapy?

A

Dexamethasone first
Ondansetron
Aprepitant
Metoclopramide

479
Q

How many drugs should be used in patients at high risk of post op N&V?

A

2 antiemetics of different classes

480
Q

How is infective gastroenteritis treated?

A

fluids

antibiotics if toxin mediated

481
Q

MOA of loperamide?

A

Specific to mu opioid receptors in myenteric plexus

482
Q

Effects of loperamide on GIT?

A

Decreases tone of longitudinal and circular smooth muscle
Reduces peristalsis but increases segmental contractions
Decreases colonic mass movement by suppressing gastrocolic reflex

483
Q

What are the s/e of using opioid receptor antagonists in N&V?

A

Paralytic ileus
N&V
Sedation and addiction if using codeine/ morphine

484
Q

What is the difference between lactulose and macrogols in constipation in terms of fluid?

A

Lactulose draws fluid in whereas macrogols retain the fluid they came with

485
Q

What is good about docusate sodium?

A

Stimulant and stool softener together

486
Q

What is the main treatment of GORD?

A

-PPI - provides rapid relief and healing in >80%
8 weeks initial trial
-H2 antagonists
-Fundoplication

487
Q

What is the most common combination of treatments for H. pylori eradication?

A

PPI + Amoxicillin + Clarithromycin

488
Q

What are the drugs in quadruple therapy for H. pylori eradication?

A

PPI + Amoxicillin + Clarithromycin + Bismuth subsalicylate

489
Q

What is the treatment for autoimmune gastritis?

A

Cyanocobalamin

490
Q

If we need to treat elderly patients with an NSAID and they have peptic ulcer disease then what drug can we use?

A

Misoprostol

491
Q

What is the H. pylori test?

A

Urea breath test or stool antigen test or lab-based serology

492
Q

What are the effects of PGE2 and PGI2 on the GIT?

A
  • Potent vasodilators
  • Decrease acid secretion (at relatively high levels)
  • Stimulate mucus and bicarbonate secretion in stomach (and elsewhere in GIT)
  • Reduce permeability of epithelium to back flow of acid
  • Reduce the release of inflammatory mediators (histamine, certain interleukins) that may contribute to mucosal injury
  • Promote ulcer healing (potentially by increasing blood flow to ulcer margin)
493
Q

MOA of PPIs?

A

Pro-drugs
PPIs are weak bases and accumulate in acidic space of the secretory canaliculus giving PPIs a high concentration in the luminal surface of he parietal cell
PPIs need enteric coating to prevent premature activation in stomach
Bind covalently to gastric H+, K+ - ATPase irreversibly and block function. Hence prolonged and nearly complete suppression of acid secretion

494
Q

What is one interaction to note of PPIs?

A

Clopidogrel and omeprazole therefore need to change omeprazole to lansoprazole. Clopidogrel uses CYP2C19 to be activated and so does omeprazole therefore potentially reduced amount of clopidogrel available.

495
Q

What are the cautions with PPI use?

A
  • Increased levels of gastrin -> parietal cell and ECL hyperplasia -> ?gastric carcinoid tumours
  • Inc Hip fractures due to reduced gastric absorption of soluble calcium
  • Inc risk of infections due to reduced innate barrier properties e.g. c.diff
496
Q

MOA of H2 antagonists in relation to the GIT?

A

Competitively and reversibly inhibits binding of histamine to H2 receptors. Indirectly block effects of gastrin and ACh on the parietal cell. Activation of PKA helps change shape of the parietal cell.

497
Q

How does misoprostol treat NSAID induced ulcers?

A

Prostaglandin analogue

Acts on PGE2, affects a similar pathway to H2RAs.

498
Q

Name the 4 antacid products used

A

Aluminium hydroxide
Magnesium hydroxide
Sodum bicarbonate
Calcium carbonate

499
Q

What are the problems with aluminium hydroxide when used in antacids?

A

Constipation as a side effect
Can bind phosphate resulting in low phosphate levels
In presence of renal failure can cause neurotoxicity

500
Q

What are the problems with magnesium hydroxide when used in antacids?

A

Diarrhoea

Avoid in renal failure (leads to increased magnesium levels

501
Q

What are the problems with sodium bicarbonate when used in antacids?

A

Reacts with HCL to form water CO2 and salt

Avoid in hypertension and fluid overload

502
Q

How long is the course of H pylori treatment?

A

10-14 days

503
Q

What are the targets for antibiotics?

A 
Inhibition of cell wall synthesis
Inhibiting nucleic acid synthesis
Stopping metabolite production
Inhibiting cell membrane synthesis
Inhibiting protein synthesis
504
Q

What classes of antibiotics inhibit cell wall synthesis?

A

Beta lactams and vancomycin

505
Q

What classes of antibiotics inhibit nucleic acid synthesis?

A

Fluoroquinolones

Rifamycins

506
Q

What clases of antibiotics inhibits metabolite production?

A

Trimethoprim

Sulfonamides

507
Q

What class of antibiotics inhibits cell membrane synthesis?

A

Daptomycin

508
Q

What classes of antibiotics inhibits protein synthesis?

A

Linezolid
Tetracyclines
Macrolides
Aminoglycosides

509
Q

What is the difference between bactericidal and bacteriostatic?

A

Bactericidal is killing bacteria

Bacteriostatic is stopping divisions and replications to allow the body to kill the bacteria

510
Q

Are penicillins bactericidal or bacteriostatic or both?

A

Bactericidal

511
Q

Are cefalosporins bactericidal or bacteriostatic or both?

A

Bactericidal

512
Q

Are Quinolones bactericidal or bacteriostatic or both?

A

BOTH

513
Q

Are macrolides bactericidal or bacteriostatic or both?

A

Bacteriostatic

514
Q

Are tetracyclines bactericidal or bacteriostatic or both?

A

Bacteriostatic

515
Q

Are aminoglycosides bactericidal or bacteriostatic or both?

A

BOTH

516
Q

Are glycopeptides bactericidal or bacteriostatic or both?

A

Bactericidal

517
Q

Are carbopenams bactericidal or bacteriostatic or both?

A

Bactericidal

518
Q

What are ways that bacteria can gain resistance to antibiotics?

A
  • Efflux
  • Immunity and bypass
  • Target modification
  • Inactivating enzymes
519
Q

Why do we do TDM?

A

Narrow therapeutic window
Maximum effect of antibiotic
Risk of toxicity

520
Q

What is MIC?

A

Minimum inhibitory concentration the minimum amount of drug required to kill the bacteria at the active sites. Longer half lives mean more drug available at the active site

521
Q

What is the difference between concentration dependent and time dependent antibiotics?

A 
Concentration= Cmax is reached and that is what is required to kill the bacteria.
Time= the maximum amount of time above the MIC is what is required to kill the bacteria
522
Q

Why do we give co-amoxiclav together?

A

Clavulanic acid to block the beta-lactamase enzyme

Amoxicillin to cause bactericidal effects

523
Q

How do we know which antibiotic to use?

A 
Source of infection
Source = common groups of bacteria
Patient high risk group
Trends - previous susceptibilities to antibiotics
Hepatic/ renal impairment/ pregnancy
Allergies and previous reactions
524
Q

What is antimicrobial stewardship?

A

Questioning if the patient even needs antibiotics

IF they do starting broad (empirical) and then narrowing to more appropriate

525
Q

When can aciclovir be used in the treatment of herpes simplex virus?

A 
Simple treatment (non-genital) - 200mg 5 times a day
Treatment (non-genital) in immunocompromised of if absorptions impaired - 400mg 5times a day
526
Q

What clotting factors does warfarin work on?

A

Factor 7a, 9a, 10a and 2a (prothrombin)

527
Q

What clotting factors does unfractionated heparin-AT (anti-thrombin) work on?

A

Factor 2a, 10a, 12a, 11a, 9a

528
Q

What clotting factors do LMWH, rivaroxaban, fondaparinux, apixaban and edoxaban work?

A

Factor 10a

529
Q

What clotting factor does dabigatran work on?

A

thrombin- factor 2a

530
Q

Where is heparin naturally produced?

A

Mast cells and vascular endothelium

531
Q

MOA of heparin?

A

Heparin attaches to antithrombin.
It accelerates activity of antithrombin against both thrombin and factor Xa.
To catalyse the inhibition of thrombin (F2a) heparin needs to simultaneously bind antithrombin and thrombin.
To catalyse the inhibition of FXa it only needs antithrombin binding to it

532
Q

Why does fractionated heparin have a longer half life?

A

Does not bind to epithelial cells, plasma proteins and macrophages

533
Q

What is the activity of fractionated heparin against clotting factors?

A

Not long enough to cause an effect against F2a

Enhances activity like unfractionated heparin of antithrombin

534
Q

Why and how do we monitor unfractionated heparin?

A

aPTT used to monitor the effects due to unpredictable pharmacokinetics - mixed elimination of the drug that is unpredictable at times

535
Q

What can heparins be used for?

A

DVT/PE - treatment and prevention including oncology patients and pregnancy as does not cross the placenta - monitored with caution
ACS - short term reducing extension/ recurrence of coronary artery thrombosis post STEMI

536
Q

What are the ADR’s of heparins?

A

Bruising and bleeding at any site of the body incl intracranial, GI tract, lungs, nose
HIT - autoimmune response 2-14 days after initiation of heparin. autoantibodies to heparin platelet factor 4 complex causing depletion of platelets.
Hyperkalaemia due to inhibition of aldosterone secretion

537
Q

How do we reverse the effects of heparin and LMWH?

A

Protamine sulphate
Forms inactive complexes with heparin, dissociates heparin from antithrombin irreversibly.
No effect on fondaparinux

538
Q

How do vitamin k antagonists work?

A

Inhibit Vit K dependent clotting factors
Inhibits VKOR which is used to reduce Vit K epoxide to Vit K which then activates clotting factors by itself becoming oxidised to Vit K epoxide

539
Q

Which clotting factors require Vit K as a co-factor to be activated?

A

Factors II, VII, IX and X

540
Q

Why is the delayed onset of action with Vit K?

A

Circulating active clotting factors are present for days and need to be removed from the blood before the effects of the newly produced clotting factors (non-carboxylated forms - inactive forms) can replace those.

541
Q

What can warfarin be used for?

A

VTE - DVT/PE treatment and prevention
AF
Heart valve replacement - bio-prosthetic and some mechanical

542
Q

Why are there significant inter-patient variability in the drug dosing?

A

CYP2C9 polymorphisms

Vitamin K intake in different forms

543
Q

Significant ADR’s to warfarin?

A

Epistaxis

Spontaneous retroperitoneal bleeding

544
Q

Can warfarin be used in pregnancy?

A

No
tetratogenic in 1st trimester
haemorrhagic in 3rd trimester

545
Q

How do we reverse warfarin?

A

Vitamin K1
Prothrombin complex concentrate
Stop warfarin

546
Q

What are important drug-drug interactions of warfarin?

A

Inhibition of hepatic CYP2C9 - amiodarone, clopidogrel, intoxicating dose of alcohol
Reduces vitamin K by eliminating gut bacteria that produce it - cephalosporins
Displacement of warfarin from plasma proteins - NSAID’s
Acceleration of metabolism - barbiturates, phenytoin, rifampicin

547
Q

What indications have a target INR of 2.5?

A

DVT
PE
AF

548
Q

What indications have a target INR of 3- 3.5?

A

Recurrent DVT/ PE in patients already on warfarin/ anticoagulants

549
Q

MOA of apixaban/ rivaroxaban/ edoxaban?

A

Factor Xa inhibitors of free FXa and ones bound with antithrombin

550
Q

MOA of dabigatran?

A

Direct thrombin inhibitor - selective competitive thrombin inhibitor both circulating and thrombus bound FIIa

551
Q

ADR’s of DOACs?

A

Bleeding - caution and dose adjustment in GI bleeding risk groups

552
Q

What drugs can be used in idiopathic parkinsons disease?

A 
Levodopa
Dopamine receptor agonists
MAOI type B inhibitors
COMT inhibitors
Anticholinergics
Amantadine
553
Q

Why do we use levodopa rather than dopamine?

A

L-Dopa crosses the BBB whereas dopamine does not

554
Q

Why in advanced stages of idiopathic parkinsons disease does L-dopa treatment not work as effectively?

A

L-dopa must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine. Fewer remaining cells in later disease therefore less reliable effect of L-dopa therefore motor fluctuations are more common

555
Q

How much of the administered dose of L-dopa enters the CNS and why?

A

<1% enter CNS
90% of ingested dose is inactivated by monoamine oxidase and dopa decarboxylase by the GIT
9% converted to dopamine in peripheral tissues by dopa decarboxylase

556
Q

What antiemetic should be avoided in N&V in parkinsons?

A

Domperidone which is a dopamine antagonist

557
Q

6 main side effects of L-dopa treatment?

A

Nausea and anorexia
Hypotension - central and peripheral
Psychosis - schizophrenia like effects, hallucinations/ delusions/ paranoia
Tachycardia
Involuntary movements
Motor complications - on/off, wearing off, dyskinesia, dystonia, freezing

558
Q

What are the main interactions of L-dopa treatment?

A

Pyridoxine (Vit B6) increases peripheral breakdown of L-dopa
MAOIs risk hypertensive crisis
Many antipsychotic drugs block dopamine receptors and Parkinsonism is a side effect (newer atypical have less effects)

559
Q

What are 4 classes of dopamine receptor agonists?

A

Ergot derived - bromocryptine, pergolide, cabergoline
Non-ergot derived - ropinorole, pramipexole
Patch - rotigotine
Subcutaneous - apomorphine

560
Q

What are the benefits of dopamine receptor agonists?

A

Direct acting
Less dyskinesias/ motor complications
Possible neuroprotection

561
Q

What are the disadvantages of dopamine receptor agonists?

A

Less efficacy than L-dopa
Impulse control disorders
More psychiatric s/e - dose limiting OCD and paranoia
Expensive

562
Q

What are the symptoms of impulse control disorders/ dopamine dysregulation syndrome in dopamine agonist treatment?

A 
Pathological gambling
Hyper-sexuality
Compulsive shopping
Desire to increase dose
Punding - collecting and rearranging pointless things
563
Q

5 s/e of Dopamine receptor agonists?

A 
Sedation
Hallucinations
Confusion
Nausea
Hypotension
564
Q

MOA of MAOBI?

A

MAOB metabolises dopamine and predominates in dopamine containing regions in brain therefore they enhance dopamine levels in the brain

565
Q

Benefits of MAOBIs in parkinsons disease?

A

Can be used alone in PD
Prolong action of L-dopa
Smooths out motor response
May be neuroprotective

566
Q

What are COMT inhibitors used for?

A

Preventing peripheral breakdown of L-dopa to 3-O-methyldopa which competes with L-dopa across CNS therefore more L-dopa reaches the brain
Has a L-dopa sparing effect
Prolongs motor response to L-dopa
Entacapone doesnt cross BBB but Tolcapone does

567
Q

What is the use of anticholinergics in PD?

A

Antagonistic effects to dopamine therefore minor role in treatment of PD. Help balance the effects of decreased dopamine by reducing neuronal ACh activation and therefore improving the neurochemical balance in the brain. Ok for tremors; not great for bradykinesia

568
Q

MOA of amantadine in PD?

A

Enhanced dopamine release OR

Anticholinergic NMDA inhibition

569
Q

What is the role of surgery in parkinsons diease?

A

Good for patients who are dopamine responsive but are having significant s/e with L-dopa but NO psychiatric illness
Target each s/e’s related lesion e.g. thalamus for tremor or globus pallidus interna for dyskinesias
Deep brain stimulation of the subthalamic nucleus

570
Q

What drugs are contra-indicated in myasthenia gravis and why?

A

Affect the NMJ

Aminoglycosides, Beta-blockers, CCBs, quinidine, chloroquine, magnesiu, ACEi

571
Q

What are complications of myasthenia gravis?

A

Acute exacerbation - myasthenic crisis

Overtreatment - cholinergic crisis

572
Q

MOA AChE inhibitors?

A

Block the breakdown of acetylcholine in the synaptic cleft
Enhance neuromuscular transmission
Excess dose can cause depolarising block - cholinergic crisis

573
Q

What are the symptoms of excess anticholinergic activity?

A 
Miosis and SSLUDGE syndrome
Salivation
Sweating
Lacrimation
Urinary incontinence
Diarrhoea
GI upset and hypermobility
Emesis
574
Q

What scan can be done to help see abnormal brains in parkinsons disease?

A

DAT scan
radiolabelled tracer
NOT diagnostic
Helpful for causes of PD and side effects: Tremor, Neuroleptic or Vascular causes

575
Q

Why are some patients referred to as seropositive rheumatoid arthritis?

A

Test positive for anti-CCP an autoantibody against cyclic citrullinated proteins.
Citrullination is a normal physiological process occuring in dying cells and dying cells will release the enzymes causing arginine containing proteins elsewhere to become modified. RA patients most commonly will have a raised anti-CCP antibody

576
Q

What does giving allopurinol and azathioprine concurrently benefit?

A

Increased amounts of 6MP (one step active metabolite of AZA) available as allopurinol block xanthine oxidase which breaks down 6MP. Therefore need to give a lower dose of AZA which overall means less side effects

577
Q

What are the important ADRs of ciclosporin use?

A

Eye discomfort
Nephotoxicity
Hepatitis
Gingival hyperplasia

578
Q

What are the 3 steps of treatment of non-renal SLE?

A

1st Hydroxychloroquine
2nd Glucocortioids - prednisolone
3rd Calcineurin inhibitors - Ciclosporin/ tacrolimus

579
Q

MOA of hydroxychloroquine

A

Enters organelles and raises the pH in them. This then prevents dimerisation of the MHC molecules. Inhibits antigen presentation and then reduces inflammatory response. Also reduces release of inflammatory cytokines via toll-like receptors.

580
Q

What are the 5 management principles in overdosing?

A

1 - Prevent absorption - gastric lavage, activated charcoal
2 - Immediate actions - remove the person physically away, vita signs and obvious injury
3 - Supportive measures - HR, O2 sats, electrolyte imbalances, cardiac toxicity, BP, neurotoxicity, rhabdomyolysis
4 - Enhance elimination - continued activated charcoal, sodium bicarbonate - increased alkaline diuresis, forced diuresis, haemodialysis - small volume of distribution.
5 - Antidotes - chelating agents, competitive antagonists, manipulating drug metabolism (fomepizole, NAC), antibodies - antivenom/ DigiFab.

581
Q

After which period of time should treatment for a seizure start?

A

5 minutes after if no signs of self termination

582
Q

What are the 5 steps of treatment for status epilepticus?

A 
1 - wait 5 mins
2 - Benzodiazepine
3 - Benzo
4 - Phenytoin/ Levetiracetam
5 - Thiopentone/anaesthetics - ITU
583
Q

What are the 3 benzo treatment options for status epilepticus?

A

Lorazepam IV
Diazepam PR
Midazolam buccal/ intranasal

584
Q

MOA of phenytoin?

A

Sodium channel blocker (fast inactivation)

585
Q

MOA of Carbamazepine?

A

Sodium channel blocker (fast inactivation)

586
Q

MOA of Valproate?

A

Sodium channel blocker (fast inactivation)
Calcium channel blocker (post synaptic inhibition)
GABA agonist permitting hyperpolarisation

587
Q

MOA Lamotrigine?

A

Sodium channel blocker (fast inactivation)

Calcium channel blocker (post synaptic inhibition)

588
Q

MOA of Barbiturates?

A

GABA agonist permitting hyperpolarisation

589
Q

MOA of Levetiracetam?

A

SV2a vesicle inhibition - decreased excitatory synaptic activity.
Synaptic vesicle glycoprotein binder. Stops release of neurotransmitters into synapse and reduces neuronal activity

590
Q

Why is sodium channel blockade good for treatment of epilepsy?

A

Blocking Na slows recovery of neurones from inactive to closed state thereby reducing neuronal transmission

591
Q

As per the leicester guidelines which is the first two treatments of generalised epilepsy?

A

Sodium valproate

Lamotrigine

592
Q

What are some side effects we need to be weary of with sodium valproate?

A

Liver failure
Pancreatitis
Lethargy

593
Q

What are significant side effects of AEDs?

A 
Tiredness/ drowsiness
N&amp;V
Mood changes and suicidal ideation
Osteoporosis
Rashes including Steven Johnson Syndrome - most likely in carbamazepine or phenytoin
Anaemia
Thrombocytopenia
Bone marrow failure
594
Q

What are important drug drug interactions?

A 
Inducers= Phenytoin, Carbamazepine, Barbiturates
Inhibitors= Valproate
595
Q

What are the family planning concerns with anti-epileptic drugs?

A

Risk of congenital malformations with all AEDs
Risk is greatest with Valproate 10% risk
Lamotrigine and particularly levetiracetam are the safest

596
Q

How does epilepsy impact driving?

A

Seizure - temporary loss of license and need to be seizure free for 1 year before reapplying
For bus/ lorry/ coach drivers need to be seizure free for 5 years off medication for a single seizure or 10 years if had multiple
Patients responsibility to inform DVLA

Medicine (15 decks)

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