Clinical Pharmacology Flashcards
What 2 areas are drugs distributed?
Tissue reservoirs
Protein-bound drug
What is bioavailability?
Measure of drug absorption where it can be used (F) as compared to when given IV
What things can affect absorption of drugs?
Formulation
Age (luminal changes)
Food (chelation, gastric emptying)
Vomiting/ malabsorption (Crohn’s)
What areas are included in first pass metabolism?
Gut lumen, gut wall and liver
What factors affect distribution of medication throughout the body?
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
What is the equation for volume of distribution?
Vd = Dose/ [Drug]plasma
How would you interpret a volume of distribution?
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
What is the units for volume of distribution?
mg/litre
How can dose be calculated from the volume of distribution and the drug concentration in the plasma?
Dose = Vd x [Drug]plasma
How many phases of metabolism are there?
2 phases
What happens in the phases of metabolism?
Phase 1- oxidation - dealkylation or reduction - hydrolysis
Phase 2- Glucuronidation, sulphation, glutathione added, N-cetyl added
What is another name for phase 1 enzymes?
Cytochrome P450 enzymes
What found in grapefruit juice is a cyp inhibitor?
Furanocoumarins irreversibly inhibit CYP 3A4 which is responsible for metabolising 50% of drugs.
What is the importance of CYP2D6 in caucasians and east africans?
Absent in 7% of caucasians
Hyperactive/ increased induction in ~30% of East Africans
Apart from the kidneys what are the other routes of drug elimination?
Sweat, tears, genital secretions, saliva, breast milk, faeces, hair, gases - volatile compounds
How can enterohepatic circulation affect drug elimination?
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.
What is zero order kinetics for drug elimination?
The drug is eliminated at a constant rate over time
What is first order kinetics for drug elimination?
The drug elimination is exponentially decreasing. As time increases the elimination decreases. Log of the drug concentration produces a straight curve
How is half life related to kinetics?
Half life is related to first order kinetics
It is independent of concentration
1/time
Define the clearance of drugs?
Constant proportion not amount of drug that is cleared
Volume of blood cleared per unit time (mL/min)
How do you calculate clearance?
Rate of elimination from body / drug concentration in plasma
What is the relationship between drug concentration and clearance?
The higher the drug concentration the higher the elimination rate and more drug cleared
At therapeutic doses what type of kinetics do most drugs have?
First order kinetics therefore half life is constant
What effect does a high dose have on the kinetics?
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
What factors of PK affect elimination of a drug?
Vd
Clearance
Half life
How quickly is steady state achieved in most drugs?
5.5 half lives
What equation calculates dosing interval?
[Dose x Bioavailability correction] /
Dose interval
What calculation gives the loading dose for most drugs?
Loading dose = Steady state plasma concentration x Vd
How do clearance and elimination rate differ?
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
To increase or decrease the Css, what dosing parameters could you change?
Volume of distribution
Dose of drug
Loading dose
What equation gives the mean arterial pressure?
Cardiac output x total peripheral resistance
What equation gives the cardiac output?
Stroke volume x heart rate
How is the radius of blood vessels related to the resistance?
As the radius increases by a number the resistance to flow increases by a factor of 4 (radius to the power of 4)
What are 3 subcategories of elevated blood pressure?
Essential
Primary
Idiopathic
What is NICE’s definition of HTN?
Elevated blood pressure that is associated with an increase in risk of some harm
>140/90 mmHg = HTN
When do we treat HTN?
140/90 <80yrs old including type 2 diabetics
150/90 >80 years old
135/85 type 1 diabetics
What is stage 1 of HTN?
Clinic BP = 140/90 - 159/99mmHg
ABPM average or HBPM average from 135/85 to 149/94mmHg
What is stage 2 HTN?
Clinic BP = 160/100 to 180/120
ABPM or HBPM average of >150/95
What is stage 3 HTN?
Clinic SBP = >180 or
Clinic DBP = >120
What is prehypertension?
> 120/80 <140/90 mmHg
What enzyme does Ramipril inhibit?
Angiotensin converting enzyme
What angiotensin receptor do ARB’s block?
Angiotensin 1 receptor
What are the 5 effects of Angiotensin 2?
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
Where are the ACE found predominantly?
Luminal surface of capillary endothelial cells, predominantly in the lungs
How do ACEi cause hyperkalaemia?
Lowers aldosterone which causes an increase in K+
How can ACEi cause renal failure?
Renal artery stenosis - constriction of efferent arterioles
How do ACEi work in the vasculature?
Potentiates bradykin - vasodilation via NOS/NO and PGIs. ACEi causes vasodilation in low-renin hypertensives
How do ARBs work?
Block AT1 and AT2 receptors - no effect on bradykinin
In low-renin hypertensives which drug is better ACEi or ARBs?
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
By targeting AT1 receptors with ARBs what is the result?
Inhibiting Ang-2 mediated vasoconstriction - chymase production
What type of CCB is amlodipine?
dihydropyridine
What type of CCB is diltiazem?
Non-dihydropyridine
What is an uncommon but important side effect of dihydropyridine CCBs?
Palpitations (compensatory tachycardia)
Name a phenylalkylamine CCB
Verapamil
How does verapamil work?
Class IV anti-arrhythmic agent/ prolongs action potentials/ effective refractory period
How does verapamil affect chronotropic and ionotropic results on the heart?
Negative chronotropic and ionotropic
Name a benzothiazine CCB
Diltiazem
Where in the nephron do thiazide and thiazide-like diuretics work?
distal tubule
How do thiazide and thiazide-like diuretics work?
Block sodium chloride co-transporter which then reduces sodium resorption and therefore water
What are common side effects of thiazides and thiazide-like diuretics?
Hypokalaemia, hyponatraemia, hyperuricaemia, hyperglycaemia, hypercholesterolaemia, hypertriglyceridaemia
What is the difference in the pathway of treating HTN in diabetics and non-diabetics?
First line in diabetics is ACEi regardless of age rather than CCB in non-diabetics
How does hydralazine work?
Arteriolar vasodilation and reduction in TPR - actual MAO is unknown
How does ivabradine work?
Blocks the If current that controls spontaneous depolarisation in SA node
Does furosemide affect preload or afterload?
reduces preload
How does spironolactone work?
Aldosterone receptor antagonist
How does secubitril work?
Inhibits natriuretic inactivating enzymes - potentiates effects of ANP and BNP
Why are beta blockers given in heart failure?
Reduce HR and therefore allow blood to enter the ventricles during diastole. They therefore increase diastole and allow enough perfusion of the cardiac myocytes
What is the medical term for water loss without electrolytes?
Aquaretic
What is the medical term for increased production of urine?
Diuretic
Where do carbonic anhydrase inhibitors work?
PCT of the renal tubule
Where do osmotic diuretics work?
PCT
Where do SGLT2 inhibitors work?
PCT
Where do loop diuretics work?
Ascending loop of henle
Where do thiazides work?
DCT
Where do potassium sparing diuretics work?
CD
What do carbonic anydrase inhibitors do?
Block CA which prevents bicarbonate breaking down into water and CO2 and so bicarb is lost
By what mechanism do CA inhibitors cause hypokalaemia?
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
Give an example of an osmotic diuretic
Mannitol
How do SGLT2 inhibitors work?
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.
How do loop diuretics work?
Block NKCC2 channel in basolateral side in thick ascending limb. Therefore more Na in the lumen and therefore more water loss.
What is a problem with loop diuretics in relation to K+ and pH?
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
How do thiazide diuretics work?
Block Na/Cl co-transporter in DCT. Reduced Na entry into cell therefore increased calcium reabsorption through Na/Ca antiporter on basolateral surface
What effect does aldosterone have on ENaC and Na/K ATPase channels?
Increases their expression in principal cells of the CD therefore increased reabsorption of Na and therefore H2O
Name an aquaretic and how would it work?
Tolvaptan - ADH antagonist
What are aquaretics used for?
Treat hyponatreamia (and prevent cyst enlargement in Adult polycystic CDK)
How does alcohol work as a diuretic?
Inhibits ADH release and doesnt block the receptor
What is nephrotic syndrome characterised by?
Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and hypertension
What are the stages of kidney disease and what are their respective % renal function?
Stage 1 - 90% Stage 2 - 89-60% Stage 3 - 59-30% Stage 4 - 29-15% Stage 5 - <15%
What is Bartter’s syndrome?
NKCC2 channel reduced or no function in the thick ascending loop of henle.
What is Gitelman’s syndrome?
Reduced or no functioning NaCl co-transporter in the DCT
How could Bartter’s and Gitelman’s syndrome be treated?
Loop diuretics for Bartter’s and thiazide diuretics for Gitelman’s
What are broadly the four mechanisms of an ADR?
Exaggerated response
Desired pharmacological effect at an alternative site
Additional/ secondary pharmacological effect (QT prolongation)
Triggering immunological response (anaphylaxis)
What is a split antigen?
A subset of the antigen that may cause a reaction
Why are ACEi not first line in African Caribbean populations?
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
Why are east asians less able to metabolise alcohol?
They have a mutated aldehyde dehydrogenase enzyme - single amino acid mutation
Why is CYP2D6 an important enzyme?
approx 25% drug are metabolised by it. 6% of caucasians carry two null alleles therefore decreased first pass metabolism for metoprolol for example.
What do oestrogens, progestagens and androgens have in common?
They are all sex steroid hormones
What chemical structures make the steroid hormone base?
3 benzene rings and 1 pentameric ring
In outline how are steroid hormones made?
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
Using what enzyme can androstenedione be made into testosterone?
17beta-HSD
Where do steroid hormones mainly act?
Intracellularly by causing changes in gene transcription and expression hence the lag in the effects
Why do steroid hormones take long to exert its effects?
causing changes in gene transcription and expression hence the lag in the effects
Which steroid hormone also has a membrane bound receptor?
Oestrogen
What is the major effect of oestradiol?
Growth of endometrium and breast also stimulates production of progesterone receptor
What is the major effect of progesterone?
Stimulates growth of endometrium and breast, maintains pregnancy, inhibits production of oestrogen receptor
What is the major effect of testosterone?
Stimulates male characteristics, anabolism
How does oestrogen affect HDL and LDL?
It lowers LDL and raises HDL
Name a side effect of progesterone on mood?
Can get irritability depression and pms, lack of concentration
Name a side effect of testosterone?
Male secondary characteristics, anabolic, acne, voice changes, increases aggression, adverse effects on lipid profile particularly HDL-C/LDL-C ratio
Why does carbamazepine interact with COCP?
Increase production of CPY enzymes and therefore reduces their efficacy
Name 2 indications for prescribing of HRT?
Symptoms of menopause - hot flushes, sweats and dyspareunia
Oesteoporosis
What are the risks of opposed oestrogen?
Increases risk of developing breast cancer
What are the risks of unopposed oestrogen?
Increases risks of developing endometrial and ovarian cancers
How do oestrogens increase risk of VTE?
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
What is mifepristone and how does it work?
progesterone receptor antagonist, sensitising the myometrium to prostaglandin-induced contractions. Used for termination of pregnancy
What is clomiphene used for?
Anovulation - competes with oestrogen for ER binding, leads to ovulation induction through increased production of anterior pituitary hormones
How does ulipristal work?
Selective progesterone receptor modulator
What is ulipristal used for?
EHC
why do we treat high total cholesterol?
It is linked to CHD
For how much LDL cholesterol needs to be reduced for a 20% reduction in CVD risk?
1mmol/L
MOA of statins?
HMG-CoA reductase inhibitor - upregulation of hepatic LDL receptors therefore increased clearance of LDL
Apart from the common MOA of statins how else to they work?
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
Is Simvastatin a prodrug or active ingredient?
Prodrug
Is Atorvastatin a prodrug or active ingredient?
Active ingredient
What scoring system is used to determine if someone should be on a statin?
QRISK
At what QRISK score to we give someone statins for primary prevention?
10 year 10% QRISK and above
What % reduction at we looking for in a patients bloods post statin therapy?
> 40% reduction in non-HDL-C after 3 months
Why is simvastatin taken at night?
Circadian rhythm of LDL receptor synthesis/ activity is at night and so this is when you want it to take effect
How do fibrates work?
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
Give an example of a cholesterol absorption inhibitor
Ezetimibe
MOA of cholesterol absorption inhibitor?
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%.
As a guide for those being treated for secondary prevention with statins what is the target LDL-C and total cholesterol?
2mmol/L - LDL-C
4mmol/L - Total
How do PCSK9 inhibitors work?
Protein that binds internalised LDL-R directing them for degradation
Name a PCSK9 inhibitor?
Alirocumab
What are rough NNT for statins?
17-20
What is insulin secreted in response to?
Increased glucose, Increased incretins (GLP-1 and GIP)
Glucagon, Parasympathetic activity M3
What inhibits the release of insulin?
Decreased glucose, cortisol, sympathetic activity (Alpha2)
What 4 categories of insulins are there in relation to their onset of action?
Rapid, shore, intermediate and long
How quickly do rapid acting insulins act?
within 10-20minutes
How quickly do short acting insulins act?
within 30-60mins
How quickly do intermediate acting insulins act?
within 60-120mins
How quickly do long acting insulins act?
60-90mins
When do short acting insulins peak in their activity?
2-5hours
When do rapid acting insulins peak in their activity?
40-50mins
When do intermediate acting insulins peak in their activity?
4-12hours
When do long acting insulins peak in their activity?
plateau between 2-20hours
How long do rapid acting insulins act for?
3-5hours
How long do short acting insulins act for?
5-8hrs
How long do intermediate acting insulins act for?
18-24hrs
How long do long acting insulins act for?
20-24hrs
What is the most common insulin dosing regimen?
basal bolus regimen
Give a name for a rapid acting insulin
Insulin aspart
Give a name for a fast acting insulin
Soluble insulin, humulin S, actrapid
Give a name for an intermediate acting insulin
Isophane insulin
Give a name for long acting insulin
Insulin glargine
What is DKA?
Ketonaemia, hyperglycaemia, acidosis. Although DKA can present with low blood ketones and hyperglycemia may not always present
On the NICE T2DM guidelines when do you consider adding medication?
If HbA1c is above 48mmol/mol (6.5%)
What is the first line treatment for T2DM?
Metformin
After which HbA1c result after starting metformin would you consider adding a second agent?
HbA1c level above 58mmol/mol (7.5%)
What drugs can be used second line in T2DM?
DDP-4i, pioglitazone, SU, SGLT-2
If HbA1c rises above 58mmol/mol(7.5%) after 2 agents used what else can you use?
combination of any of these with a metformin backbone which includes an insulin based treatment, or a GLP-1 analogue
Name a GLP-1 analogue
Liraglutide, dulaglutide, semaglutide
MOA of biguanides
decrease hepatic glucose output (gluconeogenesis, glycogenolysis) and increase glucose utilisation in skeletal muscles, suppress appetite so limit weight gain
MOA of sulfonylureas
stimulate beta-cell pancreatic insulin secretion blocking ATP-dependent potassium channels
What is a problem with sulfonylurea use?
Need residual pancreatic function
How is insulin normally released from the pancreatic beta cell?
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
What is a side effect of sulfonylureas that is potentially unpleasant?
Weight gain as there is more insulin being released and so you get anabolic effects
MOA of thiozolidinediones?
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.
Why do thiozolidinediones take so long to work?
Affect gene transcription and so this takes 6-8weeks for effect
Why do you get weight gain when using pioglitazone?
Fat cell differentiation - increase in the physical number of fat cells
MOA of SGLT-2 inhibitors
Block the sodium-glucose 2 transporter in the renal PCT. Causes decreased glucose absorption from tubular filtrate and so increased urinary glucose
What is a risk of SGLT-2 inhibitors?
As they physically prevent glucose re-entering the blood they can cause hypoglycaemia but much less compared to the other oral antihyperglycaemic agents
What is a side effect of the SGLT-2 inhibitors that would potentially require treatment with antibiotics?
UTI and genital infections as there is more glucose present and so would allow bacteria to grow faster
What are the 5 effects of GLP-1 analogues?
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
MOA of DPP4- inhibitors
Prevent incretin degradation which are glucose dependent (therefore post-prandial) action. Do not stimulate insulin secretion at normal blood glucose - therefore lower hypoglycemic rik
What is good about DPP4-i for normal weight patients?
Weight neutral - suppresses appetite so no changes in weight
MOA of GLP-1 analogues
Increase glucose dependent synthesis of insulin secretion from beta-cells activate GLP-1 receptors and therefore are not degraded by DPP-4
What is added to insulin preparations to alter their release from the site of injection?
Zinc or protamine or a combination of the two
Looking at a cardiac cause what can cause a blackout?
Bradyarrhythmias —> palpitations —> blackout
Tachyarrhythmias can also cause the same
In a fast cardiac action potential what ionic change causes the upstroke of the potential?
Sodium influx into the cell
In a fast cardiac action potential what ionic change causes the first (1) downward stroke of the potential?
Opening of potassium channels causing potassium to leave the cells
In a fast cardiac action potential what ionic change causes the second (2) downstroke of the potential?
Calcium entry into the cell causes the maintenance of AP temporarily
In a fast cardiac action potential what ionic change causes the third (3) downstroke of the potential?
The exit of potassium from inside the cell to outside maintains the downward stroke of the AP
In a fast cardiac action potential what ionic change causes the fourth (4) downstroke of the potential?
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
What is a class 1 anti-arrhythmic?
Sodium channel blocker that causes a marked slowing conduction of the tissue (phase 0) - minor effects on AP duration
What is a class 2 anti-arrhythmic?
Beta blockers - diminish phase 4 depolarisation and automaticity (focal arrhythmia).
They work on phase 2 of the cardiac AP
What is a class 3 anti-arrhythmic?
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.
What is a class 4 anti-arrhythmic?
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
There is a slow cardiac action potential which can be found in which part of the heart?
SA and AV node
What is stage 4 of the funny current?
Sodium and potassium entry into the cell
What is stage 0 of he slow cardiac AP?
Upward stroke - calcium entry into the cell
What is stage 2 of the slow cardiac AP?
Calcium entry into the cell causes a peak in the current
What is stage 3 of the slow cardiac AP?
Potassium leaving the cell causes a downward trend
How would calcium channel blockers affect the funny current?
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
How could drugs affect automaticity of the SA and AV nodes?
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
Name two abnormal impulse generations
Automatic rhythms
Triggered rhythms
Name the subsets of the automatic rhythms
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
Name the subtypes of triggered rhythms
Delayed afterdepolarisation - arises from the resting potential that doesn’t result in a full AP
Early afterdepolarisation - AP arises from the plateau phase
Name the two subsets of abnormal conduction
Conduction blocking
Re-entry
Name the subtypes of conduction blocking during an AP
1st, 2nd and 3rd degree heart block.
This is when the impulse is not conducted from the atria to the ventricles
Name the 2 subtypes of re-entry rhythms
Circus movement and reflection
What is a bundle of Kent and what is the result?
Accessory pathway in the heart that leads to preexcitation and then Wolf-Parkinson-White syndrome (WPW)
What is a re-entry rhythm in cardiology?
In a circuit the pathway leaves and comes back around another conduction pathway back around on itself
What is the worst side effect of a re-entrant rhythm?
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
What drugs can be used for abnormal AP generation?
Beta blockers of CCB - decreases phase 4 slope in the pacemaker cells and rises the threshold
In case of abnormal conduction what drugs can be used to treat it?
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
What are the Vaughan-Williams Classification classes and how do they affect action potentials?
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
What drugs are in the Vaughan-WIlliams Classification classes?
1A - Quinidine and procainamide 1B - Lidocaine 1C - Flecainide and propafenone 2 - Bisoprolol, metoprolol, propranolol 3 - Amiodarone and sotalol 4 - Verapamil and diltiazem
How do class 1A antiarrhythmics work and their effects on ECGs?
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
What can class 1A anti-arrhythmics be used for?
Quinidine - Maintain sinus rhythm in AF and A flutter and to prevent recurrence
Procainamide - acute IV Tx of supreventricular and ventricular arrhythmias
How do class 1B anti-arrhythmics effect cardiac activity?
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
How do class 1B anti-arrhythmics affect the ECG?
None in normal tissues, in fast beating or ischaemic tissues increases the QRS width
What can class 1B antiarrhythmics be used for?
VT especially during ischaemia
Not used in atrial arrhythmias or AV junction arrhythmias
How do class 1C antiarrhythmics effect cardiac activity?
Very slow binding
Significantly decrease phase 0 (sodium)
Decrease automaticity (increased threshold)
Increased APD (potassium) and increased refractory period especially in depolarising atrial tissue
How do class 1C antiarrhythmics effect ECGs?
Increased PR and QRS and QT
What can class 1C antiarrhythmics be used for?
Supraventricular arrhythmias (fibrillation and flutter)
Premature ventricular contractions
WPW syndrome
What are class 2 antiarrhythmics cardiac affects?
Increase APD and refractory period in AV node to slow AV conduction velocity
Decreased phase 4 depolarisation (catecholamine dependent)
How do class 2 antiarrhythmics affect ECGs?
Increased PR and decreased HR
What can class 2 antiarrhythmics be used to treat?
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
What are class 3 antiarrhythmics cardiac affects?
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
How do class 3 antiarrhythmics affect ECGs?
Increase PR, QRS and QT
Decreased HR
What can class 3 antiarrhythmics be used for?
Effective for most arrhythmias e.g. VT and SVT
What are the ECG changes seen with class 3 antiarrhythmics?
Increased APD and refractory period in atrial and ventricular tissues
Slow phase 4 (beta blocker at lower doses)
Slow AV conduction
What are class 4 antiarrhythmics cardiac effects?
Slow conduction through AV (calcium channels)
Increase refractory period in AV node and increase slope of phase 4 in SA node to slow HR
What are class 4 antiarrhythmics effects on the ECG?
Increase PR
Increase/decrease HR depending on blood pressure response and baroreflex
What can class 4 antiarrhythmics be used for?
Control ventricles during SVT
Convert SVT (re-entry around AV)
How does adenosine work as an antiarrhythmic?
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
What can adenosine be used for?
Convert re-entrant SVT
Diagnosis of coronary artery disease (scans - give to slow the HR)
How does vernakalant work?
Blocks atrial specific potassium channels (outward channel class 3)
How does vernakalant affect the heart?
Slows atrial conduction
Increases potency with higher heart rates
What is vernakalant used for?
Convert recent onset AF to normal sinus rhythm
How does ivabradine work?
Blocks If ion current highly expressed in sinus node
What can ivabradine be used for?
Reduce inappropriate sinus tachycardia
Reduce heart rate in HF and angina (avoiding blood pressure drops)
How does digoxin work?
Enhances vagal activity (increases potassium currents, decreases calcium currents and increases refractory period)
Slows AV conduction and slows HR
What can digoxin be used for?
Reduces ventricular rates in AF and Aflutter
How does atropine work?
Selective muscarinic antagonist
Blocks vagal activity to speed AV conduction and increase HR
What is atropine used for?
Treat vagal bradycardia
Should flecainide be used alone in atrial flutter and if not with what?
No, give AV nodal blocking drugs to reduce ventricular rates in Atrial Flutter
Which drug would you give IV for VT?
Metoprolol/ lignocaine or amiodarone
Which drugs would you give to treat AF?
Rate control - slows conduction through AV node to reduce HR - Bisoprolol, verapamil, diltiazem +/- digoxin
Rhythm control - sotalol, flecainide with bisoprolol, amiodarone
Which drug is best used in WPW syndrome?
Ablation is best treatment but flecainide is best or amiodarone
List drugs that could be used in re-entrant narrow complex tachycardia (SVT)
Acutely (IV)
Adenosine, verapamil, flecainide
Chronic (repeated episodes, orally)
Bisoprolol, verapamil, sotalol, flecainide, procainamide, amiodarone
Which drugs for ectopic beats?
Bisoprolol first line
Flecainide, sotalol or amiodarone
Which drugs can be used to treat sinus tachycardia?
Ivabradine (no drop in blood pressure)
Bisoprolol, verapamil
What substance is released by the healthy endothelium that inhibits platelet aggregation?
Prostacyclin
What is the cascade of prostacyclin release inhibiting platelet aggregation?
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
What substances are released from platelets to cause clotting?
ADP Thromboxane A2 Serotonin Platelet activation factor Thrombin
What causes the initial activation of platelets in clot formation?
The collagen negative charge on the damaged endothelium
Why are arterial thrombi “white”?
Platelet rich
Why are venous thrombi “red”?
Lower platelet content and more fibrin formation
MOA of aspirin?
Irreversible binding and inhibitor of COX enzymes (1 and 2) which reduces production of thromboxane A2 and therefore reduces platelet aggregation
Why are higher doses (>75mg) of aspirin used and why?
Inhibit endothelial prostacyclin (PGI2) which is pro-inflammatory (anti-inflammatory effects) which is good for pain relief
Why is aspirin contraindicated in <16year olds?
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
What is the lifespan of a platelet?
7-10days
Why does inhibition of the COX enzyme in platelets last their life time?
They lack a nucleus and so cant produce more COX enzymes
For ACS what is the dosing of aspirin?
300mg loading dose then 75mg OD thereafter
For acute ischaemic stroke what is the anti platelet treatment?
Aspirin - 300mg daily for 2 weeks
MOA of clopidogrel, prasugrel, ticagrelor?
ADP receptor antagonists
Prevent ADP binding to P2Y12 receptor which then inhibits the activation of GP2b3a receptors
What is the target difference between clopidogrel, prasugrel and ticagrelor?
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
How long before surgery would clopidogrel need to be stopped before?
7 days due to irreversible binding and hepatic transformation from the prodrug
How long before surgery does ticagrelor need to be stopped?
5 days as a quicker onset of action
If using clopidogrel for NSTEMI how long would you use it for?
Up to 12 months
If using clopidgrel for STEMI with a stent how long would you use it for?
12 months
What DAPT have better outcomes for ACS?
Ticagrelor and aspirin
MOA of abciximab?
Glycoprotein 2b3a inhibitor
Blocks binding of fibrinogen and Von Willebrand factor
Target is final common pathway - more complete platelet aggregation
What is the specialist use of abciximab?
High risk percutaneous trans luminal coronary angioplasty
MOA of dipyridamole?
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
What is dipyridamole used for?
Secondary prevention of ischaemic stroke and TIAs
Adjunct for prophylaxis of thromboembolism following valve replacement
How do fibrinolytic drugs work?
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
Up to how long after an ischaemic stroke can alteplase be used?
Up to 4.5hours
What is the caveat to the use of streptokinase?
Can only be used once as antibodies develop against it and render it useless in the future
What is the pathway to production of prostanoids and leukotrienes?
Prostanoids: Phospholipids -> Arachidonic acid -> PGG2 -> PGH2 -> Prostanoids
Leukotrienes: Phospholipids -> Arachidonic acid -> Lipoxygenase pathways
What pathway point of the production of prostanoids does COX1/2 affect it?
PGG2 conversion to PGH2 which are endoperoxidases
What prostanoid does Aspirin inhibit?
Thromboxane A2 - platelet aggregation, vasoconstriction
Name 3 prostanoids we need to know?
Prostaglandins, prostacyclin and thromboxanes
Why are NSAIDs of benefit in terms of the arachidonic acid pathway?
Inhibit down stream products of arachidonic acid.
Many adverse effects stem from the inhibition of this pathway too.
Where is the most amount of arachidonic acid found in the body?
Muscle, brain, liver
What is PGE2 protective of?
GI mucosal protection
What eicosanoids are implicated for pain, pyrexia, inflammation?
PGE2, PGF2alpha, PGD2
What is PGI2 (prostacyclin) useful for?
Inhibits platelet aggregation, Vasodilation of lots of organs therefore cytoprotective in the CVS
What is thromboxane A2 used for?
Platelet aggregation, vasoconstriction, therefore generally bad for the CVS
Why is COX 2 a target for NSAIDS?
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
What pathological functions are targets for COX2?
Chronic inflammation, chronic pain, fever, blood vessel permeability, tumour cell growth
What homeostatic functions does COX2 have?
Renal, tissue repair and healing, uterine contractions, inhibit platelet aggregation
What pathological functions are targets for COX1?
Chronic inflammation, chronic pain, raised blood pressure
What homeostatic functions does COX1 have?
GI protection, platelet aggregation, vascular resistance
What autocoids enhance the effects of prostanoids?
Bradykinin and histamine (small amount of effect from serotonin)
An imbalance in which prostanoids is implicated in HTN, MI and strokes?
TXA2 and PGI2 (prostacyclin)
What is one theory in the benefit of diet rich in fish oils (omega fatty acids)?
Conversion to TXA2 and PGI3 which are better prostanoids and result in a lower incidence of CVD
MOA of NSAIDS?
Inhibition of COX enzymes which reduce the production of prostaglandin, prostacyclin and TXA2.
Compete for active site on COX with arachidonic acid
Peripherally how do NSAIDs work?
Reduce peripheral pain fibre sensitivity by blocking PGE2
Centrally how do NSAIDs work?
Decreased PGE2 synthesis in dorsal root ganglion therefore less neurotransmitter release therefore reduced excitability of neurones in pain relay pathway
How do NSAIDs affect pyrexia?
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
NSAID use cautions?
Elderly, Glucocorticoid steroids concomitant use, anticoagulants, H. pylori infection (past and present)
NSAID contraindications?
Exacerbation of IBD.
Local irritation and bleeding from rectal administration
What are the renal ADR’s of NSAIDS?
reduce GFR in already predisposed patients, those also using nephrotoxic medications, CKD, HF
How do NSAIDs affect sodium levels?
Prostagladins inhibit sodium absorption in the collecting duct - natriuresis - NSAIDs inhibit this action - which increases serum sodium therefore serum water therefore increase blood pressure.
What is the main problem with COX-2 inhibitors?
Unopposed TXA2 activity and therefore a slightly increased amount of platelet aggregation, vasoconstriction.
Renal ADRs are similar to non-selective.
What 3 drugs need to be monitored in NSAID use?
Competitive displacement of these drugs leads to:
Sulfonylureas - hypoglycaemia
MTX - accumulation, hepatotoxicity, leukopenia, RA
Warfarin - increased bleeding risk
What is the problem in paracetamol overdose?
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.
Define nociception
Non-conscious neural traffic due to trauma or potential trauma to tissue
Define pain?
Complex, unpleasant awareness of sensation modified by experience, expectation, immediate context and culture
What is the pain pathway?
Nociceptors stimulated -> release of substance P and glutamate -> Afferent nerve stimulated -> Fibres decussate -> Action potentials ascend -> Synapse in thalamus -> project to post central gyrus
What are the two pain fibres and what is the difference between them?
Adelta- myelinated - fast transmission, sharp pain
C - unmyelinated - slow transmssion, dull aches
Where are the two methods of intrinsic pain modulation?
Peripherally - substantia gelatinosa
Centrall - Per aqueductal grey
Where is the substantia gelatinosa found?
In the dorsal horn
What is the peripheral method of pain modulation?
“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
What is the central method of pain modulation?
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.
Name the endogenous opioids?
Enkephalins, Dynorphins, B-endorphins
Endogenous opioids work on what type of receptor?
GPCR therefore affect cAMP levels
Where are mu opioid receptors found?
Supraspinal/ GI tract
Where are delta opioid receptors found?
Wide distribution
Where are kappa opioid receptors found?
Spinal cord/ Brain/ Periphery
What does the Mu receptor GPCR cause?
Efflux of potassium
What does the Delta receptor GPCR cause?
Influx of calcium
What does the Kappa receptor GPCR cause?
Efflux of potassium and influx of calcium
What are the effects of the opitate receptors?
Hyperpolarisation and decrease substance P release
Increase dopamine release
What endogenous opiate acts on Mu receptors?
Enkephalins and beta-endorphins
What endogenous opiate acts on Delta receptors?
Enkephalins
What endogenous opiate acts on Kappa receptors?
Dynorphins
What opiate receptor is responsible for respiratory depression and dependence?
Mu opioid receptor
Why should morphine be used in caution in asthmatics?
Histamine release causes problems in asthmatics
Why is fentanyl better than morphine?
More potent so less drug required (100x more potent)
Less histamine release, sedation and constipation
How is codeine metabolised?
Liver CYP2D6 which is also inhibited by fluoxetine
MOA of buprenorphine?
Partial agonist at mu opioid receptor
What is naloxone?
Opiate receptor antagonist with affinity to m>d>k receptors
What 2 methods are responsible for opioid tolerance?
1 - phosphorylation and uncoupling
2 - cAMP production
How does phosphorylation and uncoupling lead to opioid tolerance?
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.
What are contraindications to opiates?
Hepatic failure, acute respiratory distress, comatose, head injuries, raised ICP
What are the two subsections of anaesthesia?
Local and general
What are the methods of delivery of general anaesthesia?
Inhalation (volatile)
Intravenous
What is a subsection of local anaesthetic?
Regional anaesthesia
What are the 7 stages of anaesthesia from a practical viewpoint?
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)
How are volatile anaesthetics delivered to the patient?
Inhalation via lungs
Name 2 intravenous anaesthetics
Propofol
Barbiturates
Etomidate
Ketamine
What are the stages of Guedel’s signs?
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
In Guedel’s signs describe what happens to the breathing
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
At what stage during Guedel’s signs does eye movement stop?
Stage 3 b
What happens to muscle tone during the advancing Guedel’s signs?
S1 - normal
S2 - normal to markedly increasing
S3a - Slightly relaxed S3b - moderately relaxed S3c-d - markedly relaxed
S4 - flaccid
During what stages of Guedel’s signs is surgical anaesthesia reached?
Stage 3
What is anaesthesia a combination of?
Analgesia
Hypnosis
Depression of spinal reflexes
Muscle relaxation
What measurement is used to describe potency of volatile anaesthetics?
Mean alveolar concentration
Describe mean alveolar concentration
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
What is the connection with lipid solubility and anaesthetic potency?
The more lipid soluble a chemical the higher the anaesthetic potency
What is the connection between lipid solubility and mean alveolar concentration?
The more potent the agent, the lower the MAC value. Inversely proportional.
At equilibrium how does mean alveolar concentration relate to concentration at the active site?
At eqm [alevolar] = [spinal cord]
What is MAC-BAR?
minimum alveolar concentration to block autonomic reflexes to nociceptive stimuli (1.7-2.0 MAC)
What is MACawake?
The concentration required to block voluntary reflexes and control perceptive awareness (0.3-0.5 MAC)
What factors would affect induction and recovery in anaesthesia?
Partition coefficients (solubility)
Blood:Gas partition (in the blood)
Oil:Gas partition (in fat)
How would a higher or lower blood:gas partition coefficient affect induction and recovery?
A low value would mean fast induction and recovery
A higher value is visa versa
How would oil:gas partition coefficient affect potency and accumulation?
The oil:gas coefficient is an index of potency and is inversely related to MAC. The higher the coefficient the more potent the drug
What affects MAC?
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)
What drug is often added to other volatile agents to reduce the MAC?
N2O nitrous oxide
How do GABAa receptors work?
They are Cl channels which hyperpolarises neurones and depresses CNS activity
What receptor do most anaesthetics work on?
GABAa
What anaesthetics don’t work on GABAa channels?
Xe, N2O and Ketamine
What is the major excitatory neurotransmitter?
Glutamate
What is type of receptor is an NMDA receptor?
Calcium channel that leads to excitation
What 2 receptors in the brain have fine balance over consciousness?
Glutamate receptors and GABAa receptors
What part of the brain is the target for anaesthetics?
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)
Why is the reticular system a target for anaesthetics?
It is referred to as the activating system and is involved in arousal. This is then shut off and so the patients falls asleep
What receptor does ketamine work on?
NMDA receptor which is a Calcium channel
Name a few characteristics of local anaesthetics
Lipid solubility is high
Dissociation constant - pKa - lower pKa faster onset
Protein binding - higher therefore longer duration of action
Why is cocaine used as a local anaesthetic?
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
What is regional anaesthesia?
Selectively anaesthetising a part of the body
Block of a nerve and hence patient remains awake
Uses local anaesthetic or an opioid
What are the main anaesthetic side effects?
GA - post op n&V, CVS - hypotension, post-op cognitive dysfunction, chest infection - poor cough reflex
LA/RA - lidocaine sodium channel blocking - cardiovascaular toxicity
Describe asthma in terms of medication?
Reversible intermittent airway obstruction and hyper-reactivity to small airways
What is defined as uncontrolled asthma?
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
What is the asthma management pathway?
-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
How do ICS work?
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.
What is the function of ICS in asthma?
Reduces mucosal inflammation, widens airways and reduces mucus
Reduces symptoms, exacerbations
Pneumonia risk in COPD
What are the ADRs of beta agonists?
Tachycardia, palpitations, anxiety and tremor
Increase SAN activity, therefore increase HR therefore decrease refractory period at AVN.
Beta blockers interact with beta agonists
Which LABA is more potent formoterol or salmeterol?
Formoterol > salmeterol
How do LTRA work?
LTC4 released by mast cells/ eosinophils -> increase bronchonconstriction/ mucus/ oedema through CysLT1 - GPCR
How do LAMA work?
Relatively selective antagonist activity for M3 receptors
How does theophylline work?
Adenosine receptor antagonist + phosphodiesterase effects too
Define acute severe and life threatening asthma
- 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
How would you treat acute severe and life-threatening asthma?
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
What are the 5 tasks of medicines management of stable COPD?
Confirm diagnosis of COPD Stop smoking Record MRC dyspnoea score Flu/ pneumococcal vaccination Consider medication - drug treatment
How is acute COPD managed?
Nebs Salbutamol/ Ipratropium if patient hypercapnic or acidotic nebs should be driven by air and not oxygen
Oral steroids is eosinophil count high
Antibiotics
What are the 3 inhaler options?
MDI, breath-actuated pMDI, DPI
Why should a LABA only be prescribed with ICS?
LABA alone can mask airway inflammation and near - fatal and fatal attacks. As a result increased risk of death when prescribed alone.
What is rheumatoid arthritis?
Autoimmune multi-system disease
Initially localised to synovium
Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone
Describe the rheumatoid arthritis pathogenesis
There are pro-inflammatory mediators and anti-inflammatory mediators. When these are off kilter it produces the disease of rheumatoid.
What are the 3 main pro-inflammatory mediators in rheumatoid arthritis?
IL-1
IL-6
TNF-alpha
What are the 2 main anti-inflammatory mediators in RA that are not produced in as high quantity causing the disease?
IL-4
TGF-beta
What role do matrix metalloproteinases play in rheumatoid arthritis?
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
How do we diagnose RA?
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
What are the RA treatment goal?
Symptomatic relief
Prevention of joint destruction
What major sign is typical for SLE?
Butterfly rash over the cheeks and nose
What is SLE?
Autoimmune condition with genetic predisposition
Cause is currently unknown but affects all systems of the body
What is the most common demographic of being diagnosed with Lupus?
90% are women
80% develop lupus between 15-45years old
What is vasculitis?
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
What are the treatment goals in SLE and vasculitis?
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
What is a simple way or remembering the sides effects of corticosteroids?
All things that happen to anyone aged 70years old and above are potential side effects
MOA of corticosteroids?
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
What indications is azathioprine used for?
SLE, vasculitis, RA (v. weak evidence), IBD
Atopic dermatitis, bullous skin disease.
Many other uses as ‘steroid sparing’ drug
What is important to test before prescribing azathioprine?
Thiopurine methyltransferase (TPMT) levels. Gene is highly polymorphic Low/absent TPMT levels = risk of myelosuppression
MOA azathioprine?
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
What are the side effects of azathioprine?
Bone marrow suppression - monitor FBC
Increased risk of malignancy - esp transplanted patients
Increased risk of infection
Hepatitis - monitor LFT’s
Name the 2 calcineurin inhibitors used in practice
Ciclosporin
Tacrolimus
MOA of calcuneurin inhibitors?
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
What can mycophenolate be used for?
Lupud nephritis/ vasculitis maintenance, transplants
MOA of mycophenolate?
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)
Important ADRs of mycophenolate?
Most serious is myelosuppression but less myelosuppression than AZA
MOA of cyclophospamide?
Alkylating agent - cross links DNA so that it cannot replicate
Pro-drug
Active metabolite is 4-hydroxycyclophosphamide aldophosphamide -> phospharamide mustard (main active metabolite)
What are the indications of cyclophosphamide?
Lymphoma, leukaemia, solid cancers, lupus nephritis, Wegner’s granulomatosis (ANCA-vasculitis)
What is the most important ADR that needs to be controlled in cyclophosphamide use?
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
What are important considerations when using cyclophosphamide?
Increased risk of bladder cancer, lymphoma and leukaemia
Infertility related to cumulative dose and patient age
Monitor FBC and adjust dose in renal impairement
What can methotrexate be used for?
RA
Malignancy, crohns, psoriasis, inflammatory myopathies, vasculitis, steroid sparing in asthma
MOA of methotrexate?
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
What part of MTX action are responsible for RA treatment?
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
Why are NSAIDs contraindication in use with MTX?
NSAIDs displace MTX off proteins and so more available in the circulation
Renal excretion too so reducing GFR means more MTX in circulation
What are important S/E of MTX?
Mucositis
Marrow suppression
Both respond to folic acid supplementation
Hepatitis and cirrhosis
Pneumonitis
Infection risk
Highly teratogenic and abortifacient - used for ectopic pregnancies
Why cant patients allergic to aspirin not be given sulphasalazine?
Similar molecular shape to aspirin
5aminosalicylic acid
What are the immunological effects of sulphasalazine?
T-cell: -inhibition of proliferation -possible T-cell apoptosis -inhibition of IL-2 production Neutrophil - reduced chemotaxis - reduced degranulation
Why is sulphasalazine so good in IBD?
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
What are the s/e of sulfasalazine?
Myelosuppression
Hepatitis - drug related not viral
Rash
What are the good points of use of sulfasalazine?
Favourable toxicity
Long term blood monitoring not always needed
Very few drug interactions
Non-carcinogenic and therefore safe in pregnancy
What are the effects of blocking TNF-alpha?
- 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
What is a big risk of anti-TNF therapy?
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
How does Rituximab work?
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
What is are the lower and upper limits of a detectable cancer called and what is the number of cells correlating to each?
Lower: Limit of clinical detection - 10^9 cells
Upper: Host death - 10^12 cells
What is the range in time of cell proliferation?
9-43hours
During which stages are cells targets for cancer therapies?
Growth phase 1, Synthesis phase (DNA), Growth phase 2 and then mitosis.
Roughly how long does each cell last in each stage of growth?
Mitosis - 1 hour
S - 6-8 hours
G1 - 0-30hours
G2 - 2-4hours
What is the fractional cell kill hypothesis?
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.
What are the sites of action of cytotoxic agents on a cellular level?
Anti-metabolites
Alkylating agents - affecting DNA
Intercalating agents - affect DNA transcription and translation
Spindle poisons - affect Mitosis
How do alkylating agents work?
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%
Name an alkylating agent?
Cisplatin, oxaliplatin. Platinum based drug
MOA of antimetabolites?
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.
Name 2 antimetabolites drugs used?
5-FU and methotrexate
How do spindle poisons work?
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.
How do cells gain resistance against alkylating agents?
1- decreased entry or increased exit of agent
2 - inactivation of agent in cell
3 - enhanced repair of DNA lesions produced by alkylation
What are the side effects of chemotherapy?
Mucositis, Alopecia, Pulmonary fibrosis, N&V, Diarrhoea, Cardiotoxicity, Cystitis, Local reaction, Sterility, Renal failure, Myalgia, Myelosuppression, Neuropathy, Phlebitis
Why can patients get acute renal failure with chemotherapy?
Often multifactorial
Hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules
Why can patients get GI perforation at site of tumour?
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.
Why can patients get DIC during chemotherapy?
Onset within a few hours of starting treatment for Acute myeloid leukaemia
Why do patients get vomiting during chemotherapy?
Multifactoral but includes direct action of chemotherapy drugs in the central chemoreceptor trigger zone
What are the patterns of emesis post chemotherapy?
Acute phase 4-12 hours
Delayed onset 2-5 days later
Chronic phase may persist up to 14 days
What drugs most commonly cause hair loss in relation to chemotherapy?
Doxorubicin, vinca alkaloids, cyclophosphamide
What skin toxicities occur with chemotherapy?
Local: irritation, thrombophlebitis of veins, extravasation
General: Bleomycin- hyperkeratosis, hyperpigmentation, ulcerated pressure sores
Busulphan, doxorubicin, cyclophosphamide, actinomycin D - hyperpigmentation
What is mucositis and why does it occur in chemotherapy?
GI epithelial damage. Can be whole GI tract but most commonly worst in oropharynx. Secondary infection like thrush is common
What cardio-toxic effects can be seen in chemotherapy?
Cardio-myopathy in doxorubicin or high dose cyclophosphamide
Arrhythmias - cyclophosphamide or etoposide
Why can patients get lung toxicity in chemotherapy?
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
What are some haematological toxic s/e of chemotherapy?
Neutropenia
Lymphopenia
Thrombocytopenia
Why can having more free drug present due to hypoalbuminaemia be a problem?
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
Name the 4 most important drug-drug interactions for chemotherapy
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
How can response to chemotherapy drug be checked?
Radiological imaging
Tumour marker blood tests
Bone marrow/ cytogenetics
How can we check for signs of cardio and reno toxicity in chemotherapy?
Creatinine clearance
Echocardiogram/ ECG
What are the stages of drug development in simple terms?
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
What are the 7 steps of vomiting?
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
What makes the vomiting centre go?
- 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
What drugs act on the vestibular nuclei to treat N&V?
Muscarinic receptor antagonists
H1 receptor antagonists
How do muscarinic receptor antagonists treat N&V?
Competitive blocking of mAChR in vestibular nuclei and CTZ - these receptors are all over the body in the parasympathetic NS.
What are s/e of muscarinic receptor antagonists?
Drug mouth, drug eyes, sedation, glaucoma, memory problems, constipation
How do H1 receptor antagonists treat N&V?
Acts on vestibular nuclei
For motion sickness and morning sickness in pregnancy
Where is the Chemoreceptor Trigger Zone found?
Medulla
Why are H1 antagonists used in treating N&V bad in elderly and children?
Sedation and excitation - but don’t know their own limits and cause problems.
Elderly - QT prolongation
Constipation, urinary retention, dry mouth
What drug classes are used on visceral afferents in the GIT to treat N&V?
5-HT3 receptors antagonists
D2 receptor antagonists
What is the effect of serotonin on the GIT?
Smooth muscle contraction increases motility
Increases gut secretions
Regulates appetite
How do 5HT3 antagonists work in treating N&V?
Peripherally - Reduces GI motility and secretions
Centrally - inhibition of CTZ
Side effects of 5HT3 antagonists?
Constipation, headache, elevated liver enzymes, prolonged QT, extra-pyrimidal effects - dystonia, parkinsonism
How do dopamine antagonists (non-antipsychotics) work in treating N&V?
- 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
What are common s/e of D2 receptor antagonists in treating N&V?
Galactorrhoea via prolactin release Extra-pyrimadal effects - dystonia and parkinsonism Sudden cardiac death - prolonged QT Sedation Hypotension
How do antipsychotic dopamine antagonists work in treating N&V?
Act on CTZ directly
May also block H1 and antimuscarinic receptors
How do corticosteroids act in treating N&V?
CTZ
D2 antagonistic activity
What are side effects of corticosteroids in the context of treating N&V?
Insomnia
Increased appetite
Hyperglycaemia
How do cannbinoids act in treating N&V?
CTZ - Nabilone
How do neurokinin 1 receptor antagonists act in treating N&V?
Antagonists against substance P and act at CTZ and in peripheral nerves
How does midazolam work in treating N&V?
CTZ
Binding GABA
Decreased 5HT secretion
How does gabapentin work in treating N&V?
Mitigation of effects of neurokinins and tachykinins
How does mirtazapine work in treating N&V?
Effects on 5HT
What is first line in motion sickness treatment?
Hyoscine hydrobromide (KWELLS) Cinnarizine has fewer s/e though - without sedation
When can prokinetics be used and not used?
Used: GORD, ileus
Not used: Obstruction or risk of perforation e.g. ischaemic GIT
What are the first 3 treatments of N&V?
Ondansetron
Cyclizine
Dexamethasone
What are the treatments for hyperemesis gravidarum in terms of antiemetics?
Promethazine/ prochlorperazine
Metoclopramide
Ondansetron
RCOG guidelines say ondansetron increased risk of cleft palate in first trimester
What drugs would be used in patients at high risk of emesis in chemotherapy?
Dexamethasone first
Ondansetron
Aprepitant
Metoclopramide
How many drugs should be used in patients at high risk of post op N&V?
2 antiemetics of different classes
How is infective gastroenteritis treated?
fluids
antibiotics if toxin mediated
MOA of loperamide?
Specific to mu opioid receptors in myenteric plexus
Effects of loperamide on GIT?
Decreases tone of longitudinal and circular smooth muscle
Reduces peristalsis but increases segmental contractions
Decreases colonic mass movement by suppressing gastrocolic reflex
What are the s/e of using opioid receptor antagonists in N&V?
Paralytic ileus
N&V
Sedation and addiction if using codeine/ morphine
What is the difference between lactulose and macrogols in constipation in terms of fluid?
Lactulose draws fluid in whereas macrogols retain the fluid they came with
What is good about docusate sodium?
Stimulant and stool softener together
What is the main treatment of GORD?
-PPI - provides rapid relief and healing in >80%
8 weeks initial trial
-H2 antagonists
-Fundoplication
What is the most common combination of treatments for H. pylori eradication?
PPI + Amoxicillin + Clarithromycin
What are the drugs in quadruple therapy for H. pylori eradication?
PPI + Amoxicillin + Clarithromycin + Bismuth subsalicylate
What is the treatment for autoimmune gastritis?
Cyanocobalamin
If we need to treat elderly patients with an NSAID and they have peptic ulcer disease then what drug can we use?
Misoprostol
What is the H. pylori test?
Urea breath test or stool antigen test or lab-based serology
What are the effects of PGE2 and PGI2 on the GIT?
- 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)
MOA of PPIs?
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
What is one interaction to note of PPIs?
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.
What are the cautions with PPI use?
- 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
MOA of H2 antagonists in relation to the GIT?
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.
How does misoprostol treat NSAID induced ulcers?
Prostaglandin analogue
Acts on PGE2, affects a similar pathway to H2RAs.
Name the 4 antacid products used
Aluminium hydroxide
Magnesium hydroxide
Sodum bicarbonate
Calcium carbonate
What are the problems with aluminium hydroxide when used in antacids?
Constipation as a side effect
Can bind phosphate resulting in low phosphate levels
In presence of renal failure can cause neurotoxicity
What are the problems with magnesium hydroxide when used in antacids?
Diarrhoea
Avoid in renal failure (leads to increased magnesium levels
What are the problems with sodium bicarbonate when used in antacids?
Reacts with HCL to form water CO2 and salt
Avoid in hypertension and fluid overload
How long is the course of H pylori treatment?
10-14 days
What are the targets for antibiotics?
Inhibition of cell wall synthesis Inhibiting nucleic acid synthesis Stopping metabolite production Inhibiting cell membrane synthesis Inhibiting protein synthesis
What classes of antibiotics inhibit cell wall synthesis?
Beta lactams and vancomycin
What classes of antibiotics inhibit nucleic acid synthesis?
Fluoroquinolones
Rifamycins
What clases of antibiotics inhibits metabolite production?
Trimethoprim
Sulfonamides
What class of antibiotics inhibits cell membrane synthesis?
Daptomycin
What classes of antibiotics inhibits protein synthesis?
Linezolid
Tetracyclines
Macrolides
Aminoglycosides
What is the difference between bactericidal and bacteriostatic?
Bactericidal is killing bacteria
Bacteriostatic is stopping divisions and replications to allow the body to kill the bacteria
Are penicillins bactericidal or bacteriostatic or both?
Bactericidal
Are cefalosporins bactericidal or bacteriostatic or both?
Bactericidal
Are Quinolones bactericidal or bacteriostatic or both?
BOTH
Are macrolides bactericidal or bacteriostatic or both?
Bacteriostatic
Are tetracyclines bactericidal or bacteriostatic or both?
Bacteriostatic
Are aminoglycosides bactericidal or bacteriostatic or both?
BOTH
Are glycopeptides bactericidal or bacteriostatic or both?
Bactericidal
Are carbopenams bactericidal or bacteriostatic or both?
Bactericidal
What are ways that bacteria can gain resistance to antibiotics?
- Efflux
- Immunity and bypass
- Target modification
- Inactivating enzymes
Why do we do TDM?
Narrow therapeutic window
Maximum effect of antibiotic
Risk of toxicity
What is MIC?
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
What is the difference between concentration dependent and time dependent antibiotics?
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
Why do we give co-amoxiclav together?
Clavulanic acid to block the beta-lactamase enzyme
Amoxicillin to cause bactericidal effects
How do we know which antibiotic to use?
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
What is antimicrobial stewardship?
Questioning if the patient even needs antibiotics
IF they do starting broad (empirical) and then narrowing to more appropriate
When can aciclovir be used in the treatment of herpes simplex virus?
Simple treatment (non-genital) - 200mg 5 times a day Treatment (non-genital) in immunocompromised of if absorptions impaired - 400mg 5times a day
What clotting factors does warfarin work on?
Factor 7a, 9a, 10a and 2a (prothrombin)
What clotting factors does unfractionated heparin-AT (anti-thrombin) work on?
Factor 2a, 10a, 12a, 11a, 9a
What clotting factors do LMWH, rivaroxaban, fondaparinux, apixaban and edoxaban work?
Factor 10a
What clotting factor does dabigatran work on?
thrombin- factor 2a
Where is heparin naturally produced?
Mast cells and vascular endothelium
MOA of heparin?
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
Why does fractionated heparin have a longer half life?
Does not bind to epithelial cells, plasma proteins and macrophages
What is the activity of fractionated heparin against clotting factors?
Not long enough to cause an effect against F2a
Enhances activity like unfractionated heparin of antithrombin
Why and how do we monitor unfractionated heparin?
aPTT used to monitor the effects due to unpredictable pharmacokinetics - mixed elimination of the drug that is unpredictable at times
What can heparins be used for?
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
What are the ADR’s of heparins?
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
How do we reverse the effects of heparin and LMWH?
Protamine sulphate
Forms inactive complexes with heparin, dissociates heparin from antithrombin irreversibly.
No effect on fondaparinux
How do vitamin k antagonists work?
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
Which clotting factors require Vit K as a co-factor to be activated?
Factors II, VII, IX and X
Why is the delayed onset of action with Vit K?
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.
What can warfarin be used for?
VTE - DVT/PE treatment and prevention
AF
Heart valve replacement - bio-prosthetic and some mechanical
Why are there significant inter-patient variability in the drug dosing?
CYP2C9 polymorphisms
Vitamin K intake in different forms
Significant ADR’s to warfarin?
Epistaxis
Spontaneous retroperitoneal bleeding
Can warfarin be used in pregnancy?
No
tetratogenic in 1st trimester
haemorrhagic in 3rd trimester
How do we reverse warfarin?
Vitamin K1
Prothrombin complex concentrate
Stop warfarin
What are important drug-drug interactions of warfarin?
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
What indications have a target INR of 2.5?
DVT
PE
AF
What indications have a target INR of 3- 3.5?
Recurrent DVT/ PE in patients already on warfarin/ anticoagulants
MOA of apixaban/ rivaroxaban/ edoxaban?
Factor Xa inhibitors of free FXa and ones bound with antithrombin
MOA of dabigatran?
Direct thrombin inhibitor - selective competitive thrombin inhibitor both circulating and thrombus bound FIIa
ADR’s of DOACs?
Bleeding - caution and dose adjustment in GI bleeding risk groups
What drugs can be used in idiopathic parkinsons disease?
Levodopa Dopamine receptor agonists MAOI type B inhibitors COMT inhibitors Anticholinergics Amantadine
Why do we use levodopa rather than dopamine?
L-Dopa crosses the BBB whereas dopamine does not
Why in advanced stages of idiopathic parkinsons disease does L-dopa treatment not work as effectively?
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
How much of the administered dose of L-dopa enters the CNS and why?
<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
What antiemetic should be avoided in N&V in parkinsons?
Domperidone which is a dopamine antagonist
6 main side effects of L-dopa treatment?
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
What are the main interactions of L-dopa treatment?
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)
What are 4 classes of dopamine receptor agonists?
Ergot derived - bromocryptine, pergolide, cabergoline
Non-ergot derived - ropinorole, pramipexole
Patch - rotigotine
Subcutaneous - apomorphine
What are the benefits of dopamine receptor agonists?
Direct acting
Less dyskinesias/ motor complications
Possible neuroprotection
What are the disadvantages of dopamine receptor agonists?
Less efficacy than L-dopa
Impulse control disorders
More psychiatric s/e - dose limiting OCD and paranoia
Expensive
What are the symptoms of impulse control disorders/ dopamine dysregulation syndrome in dopamine agonist treatment?
Pathological gambling Hyper-sexuality Compulsive shopping Desire to increase dose Punding - collecting and rearranging pointless things
5 s/e of Dopamine receptor agonists?
Sedation Hallucinations Confusion Nausea Hypotension
MOA of MAOBI?
MAOB metabolises dopamine and predominates in dopamine containing regions in brain therefore they enhance dopamine levels in the brain
Benefits of MAOBIs in parkinsons disease?
Can be used alone in PD
Prolong action of L-dopa
Smooths out motor response
May be neuroprotective
What are COMT inhibitors used for?
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
What is the use of anticholinergics in PD?
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
MOA of amantadine in PD?
Enhanced dopamine release OR
Anticholinergic NMDA inhibition
What is the role of surgery in parkinsons diease?
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
What drugs are contra-indicated in myasthenia gravis and why?
Affect the NMJ
Aminoglycosides, Beta-blockers, CCBs, quinidine, chloroquine, magnesiu, ACEi
What are complications of myasthenia gravis?
Acute exacerbation - myasthenic crisis
Overtreatment - cholinergic crisis
MOA AChE inhibitors?
Block the breakdown of acetylcholine in the synaptic cleft
Enhance neuromuscular transmission
Excess dose can cause depolarising block - cholinergic crisis
What are the symptoms of excess anticholinergic activity?
Miosis and SSLUDGE syndrome Salivation Sweating Lacrimation Urinary incontinence Diarrhoea GI upset and hypermobility Emesis
What scan can be done to help see abnormal brains in parkinsons disease?
DAT scan
radiolabelled tracer
NOT diagnostic
Helpful for causes of PD and side effects: Tremor, Neuroleptic or Vascular causes
Why are some patients referred to as seropositive rheumatoid arthritis?
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
What does giving allopurinol and azathioprine concurrently benefit?
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
What are the important ADRs of ciclosporin use?
Eye discomfort
Nephotoxicity
Hepatitis
Gingival hyperplasia
What are the 3 steps of treatment of non-renal SLE?
1st Hydroxychloroquine
2nd Glucocortioids - prednisolone
3rd Calcineurin inhibitors - Ciclosporin/ tacrolimus
MOA of hydroxychloroquine
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.
What are the 5 management principles in overdosing?
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.
After which period of time should treatment for a seizure start?
5 minutes after if no signs of self termination
What are the 5 steps of treatment for status epilepticus?
1 - wait 5 mins 2 - Benzodiazepine 3 - Benzo 4 - Phenytoin/ Levetiracetam 5 - Thiopentone/anaesthetics - ITU
What are the 3 benzo treatment options for status epilepticus?
Lorazepam IV
Diazepam PR
Midazolam buccal/ intranasal
MOA of phenytoin?
Sodium channel blocker (fast inactivation)
MOA of Carbamazepine?
Sodium channel blocker (fast inactivation)
MOA of Valproate?
Sodium channel blocker (fast inactivation)
Calcium channel blocker (post synaptic inhibition)
GABA agonist permitting hyperpolarisation
MOA Lamotrigine?
Sodium channel blocker (fast inactivation)
Calcium channel blocker (post synaptic inhibition)
MOA of Barbiturates?
GABA agonist permitting hyperpolarisation
MOA of Levetiracetam?
SV2a vesicle inhibition - decreased excitatory synaptic activity.
Synaptic vesicle glycoprotein binder. Stops release of neurotransmitters into synapse and reduces neuronal activity
Why is sodium channel blockade good for treatment of epilepsy?
Blocking Na slows recovery of neurones from inactive to closed state thereby reducing neuronal transmission
As per the leicester guidelines which is the first two treatments of generalised epilepsy?
Sodium valproate
Lamotrigine
What are some side effects we need to be weary of with sodium valproate?
Liver failure
Pancreatitis
Lethargy
What are significant side effects of AEDs?
Tiredness/ drowsiness N&V Mood changes and suicidal ideation Osteoporosis Rashes including Steven Johnson Syndrome - most likely in carbamazepine or phenytoin Anaemia Thrombocytopenia Bone marrow failure
What are important drug drug interactions?
Inducers= Phenytoin, Carbamazepine, Barbiturates Inhibitors= Valproate
What are the family planning concerns with anti-epileptic drugs?
Risk of congenital malformations with all AEDs
Risk is greatest with Valproate 10% risk
Lamotrigine and particularly levetiracetam are the safest
How does epilepsy impact driving?
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
