Last min pharm i dont know fuck fuck fuck :P Flashcards by Joe Dalloz

Q

What is the target HbA1c in diabetes?

A

HbA1C = 6.5 – 7.5%

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Q

Outline the side effects of Metformin

A

Limited weight gain and ↓ CVS events
Side effects include GI symptoms
Lactic acidosis rare
Vitamin B12 deficiency uncommon

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Q

Outline the mechanism of action of Acrbose. Outline the adverse side effects of it.

A

Acarbose inhibits enzymes (glycoside hydrolases) needed to digest carbohydrates, specifically, alpha-glucosidase enzymes in the brush border of the small intestines and pancreatic alpha-amylase
Inhibition of these enzyme systems reduces the rate of digestion of complex carbohydrates

Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules (x1)
Flatulence (x½) loose stools/diarhhoea (x½)

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Q

Glitazones. Why are they rarely used nowadays?

A

Concerns regarding weight gain, fluid retention, heart failure, effects on bone metabolism and bladder cancer

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Q

Describe the adverse side effects of GLP-1 agonists

A

Nausea, loose stools, diarrhoea

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Q

Describe the mechanism of action of Gliflozin

A

SGLTs are responsible for mediating glucose reabsorption in the kidneys, as well as in the gut and the heart. SGLT-2 is primarily expressed in the kidney on the epithelial cells lining the S1 segment of the proximal convoluted tubule. (x1)
It is the major transport protein that promotes reabsorption from the glomerular filtration glucose back into circulation and is responsible for approximately 90% of renal glucose reabsorption. (x1)
By inhibiting SGLT-2 it prevents renal reuptake from the glomerular filtrate and subsequently lowers the glucose level in the blood and promotes glucosuria (x1)

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Q

Describe the adverse side effects of Gliflozin

A

Polyuria

UTI’s

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Q

Describe some of the secondary benefits of statin treatment

A

Anti-inflammatory
Plaque reduction
Improved endothelial cell formation
Reduced thrombotic risk

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Q

Describe the side effects of Fibric Acid derivatives

A

SE – GI Upset (8%) (x1/2), Cholelithiasis (x1/2), myositis (x1/2), Abnormal LFTs (x 1/2)

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Q

Describe the contraindications of Fibric Acid derivatives

A

CI – Hepatic or Renal dysfunction (x ½), Pre-existing gallbladder disease (x ½)

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Q

Describe the adverse effects of Nicotinic Acid

A

Flushing, itching and headache
Hepatotoxicity
Activation of peptic ulcer
Hyperglycaemia and reduced insulin sensitivity

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Q

What are the contraindications of Nicotinic Acid

A

Active liver disease or unexplained LFT elevations

Peptic Ulcer disease

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Q

What top remember about exetimibe

A

Circulate enterohepatically

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Q

Name some of the DNA viruses treated with antiviral agents

A

Herpes Simplex I 
Herpes Simplex II 
Varicella-zoster  
Cytomegalovirus 
Epstein Barr Virus 
Human Herpes Virus 8 
Hepatitis B

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Q

Name some of the RNA viruses treated with antiviral agents

A

Influenza (x½)
Human Immunodeficiency Virus (x½)
Hepatitis C (x½)

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Q

Name and describe the different types of influenza virus

A

Influenza A – Multiple host species, antigenic drift and shift
Influenza B – No animal reservoir, low mortality
Influenza C – Common cold like

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Q

Name the M2 Ion Channel Inhibitors and what strain of Influenza they are good for

A

Amantadine and Rimantadine

Limited to Influenza A

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Q

Describe which M2 Ion Channel Inhibitor has a higher risk of ADR and what the ADR’s for this class of drugs are

A

Amantadine > Rimantidine
Dizziness, GI symptoms and hypotension
Confusion, Insomnia and Hallucinations

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Q

Name and compare the two current Neuramidase Inhibitors

A

Zanamivir – Given as an aerosol, low bioavailability and can only be used for treatment
Oseltamivir – Prodrug and is well absorbed by contrast, can be used for treatment and prophylaxis

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Q

What strains of Influenza can neuramindise inhbitors be used for

A

Both Influenza A and B

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Q

Describe the ADR’s associated with Neuramidase inhibitors

A

GI disturbances, Headache, Nose Bleed

Rarely respiratory depression, bronchospasm (

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Q

Describe the four different categories that phase three clinical trails of Oseltamivir informed.

A

Symptom severity and dosing – No difference in 75 and 150mg of Oseltamivir, but marked difference between administration and placebo
Initiation of treatment – Earlier treatment, shorter duration of symptoms up. Works up to 48 hours
Mortality - ~70% reduction in mortality
Prophylaxis - Treatment for six weeks with 75 mg significantly reduced incidence of flu in both healthy adults and frail elderly subjects.

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Q

What is RA?

A

An autoimmune multi-system disease
Initially localised to the synovium
Inflammatory change and proliferation of synovium leading to dissolution of cartilage and bone
Pro-inflammatory cytokines > Anti-inflammatory Cytokines

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Q

How is RA diagnosed?

A

Morning stiffness >1 hr 
Arthritis of >3 joints 
Arthritis of hand joints 
Symmetrical Arthritis 
Rheumatoid Nodules 
Serum rheumatoid factor 
X-ray changes

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What are the treatment goals in SLE and vasculitis?

Symptomatic relief Reduction in Mortality Prevention of organ damage Reduction in long term morbidity

Describe the mechanism of action of corticosteroids

Prevent IL-1 and IL-6 production by macrophages | Inhibit all stages of T-cell activation

Describe the key adverse effects of corticosteroids

Weight gain Glucose intolerance Cataracts Avascular necrosis

How is Azathioprine used in practice?

As maintenance therapy in SLE and Vasculitis Inflammatory Bowel Disease Atopic Dermatitis

Describe the main adverse effects of Azathioprine

Bone marrow suppression Increased risk of infections Emergence of malignant cell line

WHat does Calcineurin normally do

Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription

Describe the use of calcineurin inhibitors in practice

Transplant patients Inflammatory skin conditions Selective use in some RA patients

Describe the adverse effects of calcineurin inhibitors

Nephrotoxicity Hypertension Hyperlipidemia Multiple drug interactions

Describe the mechanism of action for Mycophenolate mofetil

Inhibits the enzyme inosine monophosphate dehydrogenase (required for guanosine synthesis) Impairs B and T cell proliferation Spares other rapidly dividing cells

Describe the Mycophenolate mofetil side effects

Nausea, vomiting, diarrhea | Most serious is myelosuppression

Describe the use of Mycophenolate mofetil in practice

Primarily used in transplantation | Good efficacy as induction and maintenance therapy for lupus nephritis

Describe the ADRs of Cyclophosphamide

Significant toxicity – Increased risk of bladder cancer, lymphoma and leukaemia Infertility

Describe the mechanism of action of Methotrexate

Competitively and reversibly inhibits dihydrofolate reductase (DHFR), affinity 1000x more than folate Catalyses the conversion of dihydrofolate to the active tetrahydrofolate which is the key carrier of one carbon units in purine and thymidine synthesis Therefore inhibits the synthesis of RNA, DNA and proteins Cytotoxic during S phase of cell cycle, greater toxic effect on rapidly dividing cells (x1)

Describe the adverse effects for Methotrexate

Mucositis Marrow suppression Hepatitis, cirrhosis

Describe the toxicity monitoring of methotrexate

ACR and BSR reommendations: Baseline chest xray Baseline FBC, LFT, U+E+Creatinine Monthly checks

Describe the effects of Sulfasalazine

Relieve pain and stiffness (anti-inflammatory) | And fight infection (sulphonamide)

Describe the immunological effects of Sulfasalazine

T cells – Inhibition of proliferation, possible t cell apoptosis and inhibition of IL-2 production Neutrophil – reduced chemotaxis and degranulation

Describe the absorption of sulfasalazine and how this is clinically useful

Poorly absorbed | Therefore useful for IBD

Describe the ADRs of Sulfasalazine

Myelosuppression, hepatitis, rash

Describe the pathophysiology of asthma

``` Th2-driven inflammation (x1) leading to: Mucosal oedema (x1) Bronchoconstriction and hyper responsiveness (x1) Mucus plugging (x1) ```

Describe why Beta agonists should only be used intermittently

Potential inhibition of mast cell degranulation if only used intermittently On regular use of B2 agonists, mast cell degranulation in response to allergen increases

Describe the mechanism of action of B2 agonists

Act on B2 receptors which are coupled to Gs proteins This leads to an increase in cAMP levels and consequent decrease in intracellular Ca2+ Reduces binding of Ca2+ by myosin light chain kinase Increases Ca2+ activated K+ channels Hyperpolorasis cells and augments bronchodilation

When do you begin regular preventer therapy in asthma

B2 agonists more than or equal to 3 times a week Exacerbations 3 or more times a week Waking once or more times a week Serious exacerbations requiring oral steroids in the last two years

Describe the response to ICS treatment in different types of asthma

Patients with eosinophilic asthma have a better treatment response to inhaled corticosteroids than non-eosinophilic patients

Describe the mechanism of action of Leukotriene Receptor Antagonists such as Montelukast and Zafirlukast

LTC4 release by mast cells and eosinophils can induce bronchoconstriction, mucus secretion, mucosal oedema and promote inflammatory cell recruitment LRA’s block the effect of cysteinyl leukotrienes

Describe some of the side effects of Leukotriene Receptor Antagonists

``` Angiodema Dry Mouth Anaphylaxis Arthralgia Fever Gastric Disturbances ```

Name two Methylxanthines and describe their mechanism of action

Theophylline and Aminophylline Adenosine receptor antagonists Competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and inhibits leukotriene synthesis, and reduces inflammation and innate immunity

Describe how the size of the particle determines where they end up in inhaler devices

10 micron particles – deposited in mouth and oropharynx 1-5 micron particles – Most effective as they settle in small airways 0.5 microns – Too small, inhaled into alveoli and exhaled without being deposited into the lungs

Describe acute severe asthma in adults

``` Any one of: Unable to form complete sentences Pulse greater than or equal to 110 bpm Respiration greater than or equal to 25 a minute Peak flow 33-50% of best of predicted ```

When does asthma become near fatal?

PaCO2 greater than 6kPa

Through what pathway are prostaglandins synthesized from? Describe this pathway

The arachidonic pathway Arachidonic acid is produced from phospholipids from the cell membrane mainly via phospholipase A2 Arachidonic acid can then either enter the leukotriene pathway or the prostaglandin pathway Arachidonic acid is then metabolised by COX 1 and 2 enzymes to produce PGH which can then produce specific prostaglandins

Outline the general action of Prostaglandins and the induction of a positive feedback loop

Bind to GPCRs Specific action depends on receptor type binding Autocoid release will induce the expression of COX-2 and prostaglandins themselves synergise the action of other autacoids, which mean there is a positive feedback loop present

Describe how prostaglandins act to induce pain and pyrexia

Sensitising peripheral nociception – PGE2 can bind to EP1 (Gαq-type GPCR) in C-fibres which act to inhibit K+ channels, increase Na+ channel expression and also increase neuronal sensitivity to bradykinin, resulting in an increased C-fibre activity Sensitising central nociception – PGE2 can bind to EP2 (Gαs-type GPCR) in the dorsal horn of the spinal cord The rise in cAMP and subsequent activation of PKAs causes a reduction in glycine receptor binding affinity (where glycine acts as an inhibitor of neuronal activity), leading to increased pain reception Pyrexia – Macrophage release of IL-1 at inflammatory sites acts on the hypothalamus to stimulate PGE2 release, acting on EP3 (Gαi-type GPCR) which causes a fall in cAMP which eventually causes an increase in CA2+ levels in the neurones regulating temperature, this results in both increased heat production and reduced heat loss

Describe the GI related ADR’s of NSAIDS

PGE2 stimulates mucus production and also inhibits acid secretion, thus inhibition of PGE2 production will result in damage directly to the stomach on ingestion and systemically This will lead to ulceration, haemorrhage and perforation

Describe the renal related ADR’s of NSAIDS

In susceptible individuals (i.e compromised HRH individuals) use of NSAIDS can cause reduced GFR and perfusion of the kidney due to the role PGE2 has in maintaining adequate blood flow

Describe the vascular ADR’s of NSAIDS

NSAIDS will cause an increased risk of prolonged bleeding time, increased bruising and increased risk of haemorrhage due to NSAIDS inhibiting thromboxane A2 synthesis and thus reducing platelet aggregation

What class of patients do you need to be careful when prescribing NSAIDS and why?

Asthmatics | In hypersensitivity reactions, asthmatic bronchospasm can sometimes occur

Describe how NSAIDS are used therapeutically, specifically in combination therapies. Why do you need to be careful?

NSAIDS can be used in combination with low-dose opiates, extending the therapeutic range for treating pain and will also reduce the ADRs seen with increased opiate use Use of a combination of NSAIDS can increase the risk of ADRs, as they effect one anothers binding of plasma protein

Describe specifically which drugs should be monitored carefully when used in combination with NSAIDS

Sulphonylurea – Hypoglycaemia Warfarin– Increased bleeding Methotrexate – Wide range of issues

What other therapeutic uses does aspirin have?

Athero-thrombotic disease prevention by acting as an anti-platelet as it prevents thromboxane A2 production GI cancer prophylaxes

Describe paracetamol elimination

Displays linear Pharmocokinetics (x1) 90% enters phase 2 metabolism directly (60% glucoronidation and 30% sulphonation) (x1) 10% enters phase 1 oxidation to produce NAPQI (x1)

Describe the effects of unconjugated NAPQI

Highly nucleophilic Binds with cellular macromolecules Loss of hepatic cell function and increase in subsequent cell death as well as potential renal failure

Describe the treatment for paracetamol toxicity

Treatment given within 8 hours of overdose If within 0-4 hours, activate charcoal orally can reduce uptake by 50-90% 0-36 hours, agents such as IV N-acetylcysteine or oral methionine can be used, which act to increase glutathione levels

Describe endogenous opioids

Can be used to modulate a pain response Produced from precursor molecules and all contain 4 common amino acids (tyr-gly-gly-phe-) Enkephalins – Produced from proenkephalin Endorphins – Produced from POMC Dynorphins – Produced from prodynorphin

Describe the mechanism of action of opioids

All are GPCRs that act to increase the outward flux of K+ ions to reduce excitability of the neurone Decrease the influx of Ca2+ directly by inhibiting the ion channels directly Indirectly reducing the influx of Ca2+ by reducing cAMP synthesis This fall in Ca2+ causes decreased release of neurotransmitter at the synapse

Describe how opioids are usually delivered

Enterally and parenterally IV provides the most rapid response and avoids hepatic first-pass metabolism Intrathecal route is often used for severe pain with the patient controlling the levels of analgesia

Outline the pharmacokinetics of morphine

M6G is the main active metabolite of morphine and acts to extend its analgesic effect Any hepatic or renal failure will increase its half life up to 50 hours

Describe the pharmacokinetics of diamorphine

Very lipid soluble molecule so readily crosses BBB Has to be activated by pseudocholinesterases to become activated by converting it to morphine

When may you use methadone instead of other options

May use instead of other opiods T1/2 of 15-30 hours so more suitable in chronic pain

Describe the pharmacokinetics of codeine

Opioid which is metabolised to morphine to become activated

Describe the opioid ADRs

``` Respiratory depression – MOP mediated action on CO2 sensitivity, only seen in significant use Euphoria Constipation Hypotension and bronchoconstriction ```

What else can opioids be used to treat?

Diarrhoea Heroin addiction Following an MI Naloxone is an opioid antagonist and can be used to for opioid toxicity

Define mild hypertension and how it will be treated

140-159/90-99 mmHg | Treated depending on overall cardiovascular profile, usually non-pharmacologically

When will pharmacological therapies begin?

>160/100mmHg

What is Isolated Systolic Hypertension? Who is it common in and why?

Low diastolic BP with a high systolic BP (>140mmHg) Common in increasing age occurring from the loss of compliance of elastic arteries

Describe how the treatment threshold for hypertension changes in diabetes

Threshold is 140/90mmHg | Target of <130/80mmHg

. What is a major issue in treating hypertension?

30% of patients will not take their drugs

What can individuals who cannot tolerate ACEi be given?

Angiotensin-II receptor blockers

Outline the mechanism of action of Calcium Channel Blockers

Bind specifically to the alpha subunit of L-type calcium channels, reducing calcium entry Vasodilates the peripheral, coronary and pulmonary arteries May have a rate-limiting effect on the heart rate

Outline the properties of the three groups of calcium channel blockers

Dihydropyridines - Anti Hypertnesives Benzothiazepines - Anti Arthymitics Phenylalkylamines - Anti Anginals

Dihydropyridines ADRs

ADRs include SNS activation (tachycardia and palpitations), flushing, sweating and ankle oedema. Well tolerated (x½)

Phenylalkylamines ADRs

ADR’s include constipation, bradycardia and negative inotrophy

Benzothiazepines ADRs

ADR’s include bradycardia and slight negative inotrophy

What is it important to remember about the dosing of thiazide diuretics?

Any uptitrating of levels of thiazides will not cause any increase in response (dose-blood pressure response curve flat) Will only cause an increase in ADRs

Describe the ADRs seen with thiazide diuretics

Hypokalaemia Increased urea and uric acid levels (gout) Impaired glucose tolerance Cholesterol and triglyceride levels increase

Describe the mechanism of action and ADR’s of Alpha-Blockers

Act via selective antagonism at post-synaptic apha1 adrenoreceptors and antagonise the contractile effects of noradrenaline, thus reducing TPR Postural hypotension, dizziness, headache and fatigue, oedema

Give some endocrine causes of Hypertension

Conns syndrome Bilateral Adrenal Hyperplasia Cushings Syndrome Phaeochromocytoma

Give some renal causes of Hypertension

Chronic pyelonephritis | Diabetic Renal Disease

Give some other causes of hypertension

``` Pregnancy OCP Sleep-apnoea Drug induced Aorta coartation ```

How is diagnosis of a phaeochromocytoma diagnosed? How is it initially treated?

Urinary catecholamines Imaging Non selective alpha-adrenoreceptor antagonists

Define a hypertensive emergency

>220/120mmHg

Describe treatment and goals of a hypertensive emergency and the consequences of non-treatment

BP must be reduced around 20% within 1-2 hours otherwise acute complications such as pulmonary oedema, renal failure or aortic dissection may rapidly develop Treatment is IV sodium nitroprusside, acting as an endogenous nitric oxide. This causes vasodilation and can produce rapid onset of reduction in BP

How is plasmin formed?

Circulating plasminogen binds to the fibrin strands within a thrombus Tissue Plasminogen Activations (regulated by PAI-1) converted plasminogen to plasmin following endothelial damage

Describe the mechanism of action of Streptokinase

Binds to plasminogen and induces a conformation change to plasmin

How is Streptokinase given? What is its half life? What are its ADR’s?

Given via IV infusion 15 minutes Risk of allergic response or transient hypotension

Give some examples of recombinant tPA’s. How do they work? How are they administered?

Alteplase, Reteplase and Tenecteplase Same mechanism as natural tPA’s IV bolus and infusion

Describe the contra-indications for fibrinolytic therapies

``` History of haemorrhagic stroke Active bleeding source Recent trauma or surgery CNS neoplasm Aortic Dissection Uncontrolled hypertension ```

How should serious bleeding after fibrinolytic therapy be treated?

Transfusion of blood or volume expanders Inhibition of fibrinolytics and administration of tranexamic acid (competitively inhibits the activation of plasminogen to plasmin)

Describe the mechanism of action of carbonic anhydrase inhibitors and where they act

Act at PCT Inhibit carbonic anhydrase Affects the reabsorption rate of NA+ ions

Why are carbonic anhydrase inhibitors rarely used nowadays? What are they used?

Risk of metabolic acidosis and Hypokalaemia | Used in glaucoma

When are loop diuretics used?

``` Heart failure (also have a slight venodilatory effect) Liver Failure ```

What should loop diuretics not be used in combination with and why?

Aminoglycosides – Due to the risk of ototoxicity and nephrotoxicity Digoxin or steroids – Risk of hypokalaemia

Describe the mechanism of action of Thiazide diuretics

Act on Na+-Cl- symporter | Also promotes Ca2+ reabsorption (so can be helpful in limiting calcium loss and preventing kidney stone formation)

X What are the main indications for thiazide diuretics? What else can they be used for?

Main – Heart failure Hypertension | Can also be used for kidney stones

What drugs should thiazide diuretics not be prescribed alongside?

Digoxin or steroids due to risk of hypokalaemia | Beta Blockers due to risk of hyperglycaemia, hyperlipidaemia and hyperuricaemia

Outline the mechanism of potassium sparing drugs

Act on the ENaC channel in the late DCT and collecting duct

What should potassium sparing drugs not be used alongside?

ACE inhibitors due to risk of hyperkalaemia

Outline the mechanism of action of Aldosterone antagonists

Inhibit the action of aldosterone on the mineralocorticoid receptors Affects Na+-K+-ATPase and ENaC protein synthesis

What are the main indications for Aldosterone Antagonists?

Heart failure Hypertension Liver Failure Hyperaldosteronism

Describe the mechanism of action of Warfarin

Prevents the production of vitamin K dependant clotting factors (II, VII, IX and X) Vitamin K normally acts to carboxylate certain clotting factors and it turn it itself is oxidised and so must be reduced to be re-used again Warfarin competitively antagonises the reduction of the oxidised vitamin K, meaning these clotting factors cannot be produced As it is a competitive antagonist, warfarin can be displaced by excessive Vitamin K

When is Warfarin used?

Anti-coagulant drug for deep vein thrombosis, pulmonary embolism , atrial fibrillation and mechanical prosthetic heart valves

Describe how dose levels monitored for Warfarin? Describe the targets

INR of 2.0-3.0 for DVT, PE or AF (x½) INR of 2.5-4.5 for mechanical prosthetic valves, recurrent thrombosis on Warfarin or thrombosis associated with inherited thrombophilia conditions (x½)

Describe the main ADRs of Warfarin

Haemorrhage – Especially GI | Teratogenic in first trimester of Pregnancy

Outline how Low Molecular Weight Heparin works

Inhibits only factor Xa and has no effect on thrombin

Outline the pharmacokinetics of Unfractionated Heparin

Non-linear dose-response Need to monitor with APTT test Given parentally Variable bio-availability (x1)

Outline the pharmacokinetics of Low Molecular Weight Heparin

Predictable dose-response Predictable bio-availability No monitoring needed Administered SC

Describe how monitoring of heparin occurs

APTT test Activated partial thromboplastin time Measures the efficacy of the coagulation pathway

Outline the main ADRs associated with heparin therapy in long term use!

Osteoporosis

Describe the reversal of heparin therapy

Administer Protamine Sulphate | Dissociates heparin from ATII and bind irreversibly to heparin

Describe the inhibition of Thromboxane A2

Thromboxane A2 is released from activated platelets to promote further platelet aggregation Aspiring is a COX enzyme inhibitor and so prevents thromboxane A2 production and thus prevents platelet aggregation Dipyridamole inhibits phosphodiesterase enzymes to inhibit thromboxane A2 production

Give some cardiac arrhythmias that are too fast

Atrial Fibrillation Ventricular tachycardia Torsades de Pointes

Give some cardiac arrhythmias that are too slow

Sinus Bradycardia | Heart Block

What is the most commonly used Class I anti-arrhythmic? Describe its use

Flecainide - Class Ic | Used in the treatment and prophylaxis against paroxysmal AF (x1)

When should Class II anti-arrhythmic drugs be used?

Rate-control in AF | Secondary prevention of VT or VF and heart failure

What are the contra-indications for Class II anti-arrhythmic drugs?

Asthma | AV-node block

Describe when the main Class III drug can be used and its main ADRs

Stable VT and SVT Rate control of AF when other anti-arrhythmics are contra-indicated Hepatic dysfunction, pulmonary fibrosis, peripheral neuropathy, proximal myopathy and many others

Describe the main uses of Class IV anti-arrhythmic drugs

Hypertension Angina Rate-controlled AF But only when beta blockers are contra-indicated

Describe the main contra-indications of Class IV anti-arrhythmic drugs

Heart failure Bradycardia AV node block

Describe the mechanism of action of Adenosine

Acts on the A1-receptor on the AV node Hyperpolarises the cardiac conducting tissue at the AVN Induces a transient temporary heart block

Describe the half-life and uses of Adenosine

Has a half-life of a few seconds Used to treat SVTs Can be used to distinguish SVT as if given as the tachycardia continues, then the re-entry loop is likely to occur between the atrium and the ventricles, not at the AVN

When can digoxin be used?

Used during rapid atrial fibrillation

What are the main ADRs of Digoxin?

Cardiac toxicity (x1)

What is chemotherapy?

The administration of cytotoxic drugs

Describe how Alkylating Agents work

``` Platinum compounds (eg cisplatin) Allowing covalent bonds to form between DNA strands (intra strand or interstrand) Replication cannot occur thus preventing the tumour from growing any further ```

5-Flourouracil moa

Activated to 5-FdUMP which acts to inhibit the action of thymidylate synthase , thus preventing pyramidines to be incorporated in DN

Methotrexate in chemo MOA

Inhibits dihydrofolate reductase which is necessary to form purines and thymine thus resulting in the cells unable to form DNA

Describe some of the ADRs of chemotherapy

Alopecia Pulmonary Fibrosis Cardio toxicity

What is the main dose-limiting toxicity in chemotherapy and also the most frequent cause of death from toxicity?

Haematological toxicity | Sepsis associated with haematological suppression is the most common cause

How is chemotherapy monitored?

Radiological imaging Tumour marker blood tests Bone marrow tests Drug levels monitored and organ damage should be checked for

Define a seizure

A convulsion or transient abnormal event from episodic discharge of high frequency electrical activity in the brain

Define epilepsy

The continuing tendency to have seizures, even if a long interval separates attacks

Describe the mechanism of a seizure

``` Large groups of neurones are activated repetitively, unrestrictedly and hyper synchronously, with inhibitory neurones failing A partial (focal) seizure is confined to one area of the cortex, yet can spread to cause a secondary generalisation Generalised seizures can also occur as a focal seizure, this can also be a primary generalised major convulsion ```

Describe a tonic-clonic seizure (grand mal seizure)

Warning signs Tonic phase commences – Body becomes rigid and patient falls to the floor, tongue is bitten, incontinence of urine and faeces Clonic phase begins – Generalised convulsion, frothing at the mouth and rhythmic jerking of the muscles Normally self-limiting and followed by drowsiness, confusion or a coma for several hours

Describe a Typical Absence Seizure (petit mal seizure)

Generalised epilepsy that occurs in childhood Patient will stare, eyelids may twitch and a few muscles jerk Normal activity resumes Children with typical absence attacks are more likely to develop generalised grand mal seizures as adults

Give some examples of other partial seizure types

Jacksonian (focal motor seizures) | Temporal Lobe Seizures (jamais vu or déjà vu)

Describe status epilepticus.

Continuous seizures without a recovery period of consciousness Defined as a single convulsion lasting more than 30 minutes or convulsions occurring back to back with no recoqvery between them High mortality rate 50% of cases occur without previous history of epilepsy

How does untreated status epilepticus cause damage?

Physical injury relating to a fall/crash Hypoxia SUDEP (Sudden Death in Epilepsy) Other dangers can include varying degrees of brain dysfunction, cognitive impairment, serious psychiatric disease

What are the two main classes of prescribed AEDs and give some examples of each

Voltage-Gated Sodium Channel Blockers – Carbamazepine, Phenytoin and Lamotrigine Enhanced GABA Mediated Inhibition – Valproate Sodium and Benzodiazepines (x1)

Describe the action of Voltage-Gated Sodium Channel Blockers

Bind to the internal face of an inactivated sodium channel Act preferentially on the neurones causing the high-frequency discharge that occurs in an epileptic fit, whilst not interfering with the low-frequency firing neurones in their normal state Depolarisation of a neurone increases the proportion of the sodium channels in the activated state, and VGSC blockers bind preferentially to the channels in this state, preventing them from returning to a resting state where they could continue to depolarise the neurone (x1) Thus reducing the number of functional channels available to generate action potentials

Describe the pharmacokinetic profile of Carbamazepine

Strong inducer of CYP450, which metabolises it, so initial t1/2 is 30 hrs, yet with repeated use the t1/2 becomes 15hrs (x1)

Describe the ADRs of Carbamazepine

CNS – drowsiness, dizziness, ataxia, motor disturbances, paraesthesia, anaesthesia GI – nausea and vomiting CVS – variation in BP Other – Rashes and bone marrow suppression

Describe the pharmacokinetic profile of phenytoin

Acts as a CYP450 inducer | Has non-linear PK at therapeutic levels

Describe the ADRs of Phenytoin

CNS – dizziness, ataxia, headaches and nystagmus Gingival hyperplasia (20%) Hypersensitivity rashes

Describe the Drug-Drug Interactions of phenytoin

Competitive binding with Valproate to increase plasma levels Reduce levels of oral contraceptive Increase cimetidine levels

Describe the ADRs of Lamotrigine

CNS effects – Dizziness, Ataxia and Somnolence Nausea Potential for skin rashes

Describe the drug-drug interactions of Lamotrigine

Adjunct therapy with other AEDs Oral contraceptives reduce Lamotrigine plasma levels Valproate increases levels in plasma due to competitive binding

Describe the ADRs of Valproate Sodium

CNS – Ataxia and tremor | Hepatic – Increases transaminases

Describe the DDIs of Valproate Sodium

Aspirin binds against it | Antidepressants and antipsychotics antagonise the action of valproate

Outline the mechanism of Benzodiazepines and what are its uses

Used for status epilepticus and absence seizures

Why are Benzodiazepines not used in first line therapy?

Wide range of ADRs Include sedation, tolerance with chronic use, confusion, impaired coordination, aggression, act as abrupt withdrawal seizure triggers and respiratory and CNS depression

Describe the basic management steps of epilepsy

Valproate Sodium as first line therapy from primary generalise seizures Carbamezepine for partial seizures (although can be used for general) Lamotrigine can be used for both generalised and partial seizures and is probably drug of choice for woman of childbearing age (due to reduced teratogenic effects and effects on OCP) Benzodiazeines or Phenytoin for acute life-threatening status epilepticus

Describe the classic triad of Idiopathic Parkinsons Disease

Tremor Rigidity Bradykinesia

Describe how Myasthenia Gravis is treated and what over treatment can lead to, as well as side effects of the treatment

Treated with acetylcholinesterase inhibitors Acute exacerbations can cause a Myasthenic crisis Over treatment can lead to a cholinergic crisis (a flaccid paralysis and respiratory failure) Side effects = SSLUDGE = Salivtion, Sweating, Lacrimation, Urinary Incontinence, Diarrhoea, GI hypermobility and Emesis (x1)

Describe the synthesis of dopamine

Synthesised in the cytosol of neurones (mainly in their cell body) L-Tyrosine → L-DOPA (x1) → Dopamine (→ Noradrenaline → Adrenaline)

Describe how Levodopa works, and why it has minimal effect in advanced IPD. How is it ensured that Levodopa is crosses the BBB and has minimal peripheral effects?

Dopamine cannot cross the BBB directly, L-DOPA can and can be taken up by dopaminergic cells in the Substantia Nigra and converted to dopamine In advanced IPD, not enough dopaminergic neurones are left so does not work Commonly administered with a peripheral DOPA decarboxylase inhibitor so more L-DOPA crosses the BBB, rather than getting broken down

Side effects of L-Dopa

side effects (N&V, hypotension, psychosis or tachycardia) Causes involuntary movements and can cause motor complications

Describe how Anticholinergics effect L-DOPA

Acetylcholine may have an antagonistic effect to dopamine Therefore anticholinergics can have a minor role in the treatment of IPD, especially treating a tremor No effect on bradykinesia and have side effects of confusion, drowsiness and anti-cholinergic side effects (

What are the three core symptoms of depression?

Low mood Anhedonia (lacking pleasure from anything) Decreased energy

Name some Selective Serotonin Reuptake Inhibitors (SSRIs) and outline how they work

Fluoxetine, Citalopram, Paroxetine Act by preventing the reuptake of serotonin by the presynaptic membrane, increasing the serotonin concentration in the synaptic cleft

Describe the main ADRs of SSRIs

Anorexia Nausea Diarrhoea Mania and extrapyramidal syndromes

Give some examples of Tricyclic Antidepressents and outline their mechanism of action

Amitriptyline or Clomipramine | Blocking both the re-uptake of serotonin and noradrenaline at the presynaptic membranes

Why do TCAs have limited clinical use?

Affect multiple systems and cause multiple side effects CNS – Sedation and impaired psychomotor function Max. Mark ANS – Reduced glandular secretions and eye accommodation block (x1) CVS – Tachycardia, postural hypotension and sudden cardiac death (x1)

Name a Serotonin-Noradrenaline Reuptake Inhibitor and describe how they work

Venlafxine | Cause reuptake of noradrenaline too

Describe the ADRs of SNRIs

Same ADRs as SSRIs + Sleep disturbances, increased BP, dry mouth and hyponatraemia Relatively short half life so may produce a withdrawal syndrome on discontinuation

Name the positive symptoms of Schizophrenia

Hallucinations (a perception in the absence of an external auditory or olfactory and visual stimulus) Disturbances of thinking Delusions Behavioural changes

Name the negative symptoms of Schizophrenia

Social withdrawal | Unusual speech and thought

Name the cognitive symptoms of Schizophrenia

Selective attention Poor memory Reduced abstract thought

Name the affective symptoms of Schizophrenia

Anxiety | Depression

What is the main pathophysiological theory behind the onset of Schizophrenia at the moment? What are the main CNS pathways?

Excess of dopamine being released by the brain Meso-limbic pathways Meso-cortical pathway Nigrostiatal pathways Tubero-hypophyseal pathways

X What is the main method of schizophrenia medication? Describe the effects

D2 antagonism, blocking pathways | Therapeutic responses, alongside enhanced negative and cognitive symptoms, potential dyskinesia and hyperprolactinaemia

Give some examples of typical anti-psychotics, and describe why they are not used much clinically. When are they used?

Haloperidal and Chloropromazine Regularly cause extra-pyramidal symptoms and tardive dyskinesia, thus are not used much now clinically Haloperidal is used in acute emergency setting for sedation and tranquilisation

Name some Atypical Anti-Psychotics

Olanzipine, Ripseridone, Clozapine and Quetiapine

What will all the anti-psychotics produce in a few hours after administration?

Sedation and tranquilisation

What are the main ADRs of antipsychotics?

Excessive weight gain – Olanzapine Increased prolactin secretion – Ripseridone Extra-pyramidal side effects – (Typical Anti-Psychotics) Postural hypotension and Cardiac Toxicity leading to long QT syndrome

How do benzodiazepines work? Why are they rarely prescribed?

Act on GABA receptors Significant dependence, drowsiness, dizziness, psychomotor impairment, toxic during pregnancy Overdose is rare but can be treated with Flumazenil

What are the main drugs to treat bipolar?

Lithium (main) | Sodium valproate and carbamazepine

Describe some of the ADRs of the main treatment and prophylaxis of bipolar

Memory problems, thirst, polyuria, tremor and acts as a nephrotoxin

Describe the signaling involved and the process of acid secretion in the stomach

Acid secretion occurs at the parietal cells, which contain proton pumps on their apical membranes and act to pump H+ ions into the canaliculus Stimulated by the action of gastrin on CCK-B receptors Histamine on H2 receptors Ach on M3 Muscarinic receptors

What will happen if one of the receptors involved in acid secretion are blocked?

The others will be upregulated | Except if you block H2 receptors

Describe how H+ ions are produced and moved.

Carbonic anhydrase produces HCO3- an H+ from CO2 + H2O Produced in mitochondria of the cell Proton pump is H+K+ATPase HCO3- ions are transported out the basolateral membrane in exchange for Cl- ions, producing a slight elevation in blood pH

Name the primary four H2-Receptor Antagonists

Cimetidine, Ranitidine, Famotidine and nizatidine

ADRs H2-Receptor Antagonists

cause diarrhoea, dizziness, muscle pain and rashes Cimetidine associated with gynaecomastia

Name the primary four Proton Pump Inhibitors

Omeprazole, Ianzaprazole, Rabeprazole and

Describe the ADRs of PPIs

Headache, Diarrhoea and rashes | Increased levels of Gastrin

Describe the treatment of Helicobacter Pylori

1 week of clarithromycin, amoxicillin and omeprazole | Stop any NSAIDS and re-endoscopy and biopsy 6 weeks later

Describe the process behind emesis (Vomiting)

Closing of the pyloric sphincter Relaxing of cardia and oesophagus Closure of glottis and elevation of the palate to prevent entry of the gastric contents into the trachea or nasopharynx respectively Gastric contents being propelled by the contraction of the abdominal wall muscles and diaphragm (x1)

Describe the neurotransmitters involved in emesis control and where they can be found

Vestibular Apparatus – ACh and H1 Medullary Centre – ACh, H1 and 5-HT Vomiting Centre - Dopamine

Describe the classification of anti-emetic drugs

``` Dopamine D2 receptor antagonists 5-HT3-receptor antagonist Anti-muscarinics H1-receptor antagonists Other ```

What class does Domperidone belong to? Describe its mechanism of action. Describe its use and ADRs

Dopamine D2 receptor antagonist Acts on the postrema on the floor of the 4th ventricle and also on the stomach to increase gastric emptying Used in acute nausea and vomiting episodes Main ADR is excessive prolactin release, producing galactorrhoea

What class does Ondansetron belong to? Describe its mechanism of action. Describe its use and ADRs

5-HT3-receptor antagonist Acts on medullary centres and reducing vagal afferent nerves from the GI tract Given via IV administration, indicated in radiation sickness and chemotherapy treatment ADRs are headaches, constipation and flushing

What class does Metoclopramide belong to? Describe its mechanism of action. Describe its use and ADRs

D2 antagonist Acting on the postrema on the floor of the 4th ventricle, as well as some anti-cholinergic effects and blocks vagal afferents Normally considered first line and is safe and easy to administer Main ADR is extra-pyramidal reactions, so should be avoided in PD

What class does Cyclizine belong to? Describe its mechanism of action. Describe its use and ADRs

H1-Receptor Antagonist Acute nausea and vomiting Can be administered via Oral, IV or IM ADR of prolonging QT interval

Describe the two different types of constipation and how they will be treated

Soft faeces – Stimulant laxative | Hard faeces – Osmotic laxative or bulk laxative

What could excessive use of laxatives lead to?

Hypokalaemia

Describe how Bulk Laxatives work. Describe its main ADR and contra-indications

Bulk Laxatives – Act as a non-degradable fibre, giving bulk to the gut in order to aid peristalsic action Takes a few days to work Main ADR is flatulence Should not be given to any patients with any ulcerations or adhesions

Describe how Osmotically Active Laxatives work and give an example. When are they used?

Movicol Cause water retention in the small and large bowel to increase peristalsis Normally given PR and can act quickly and severely, so should be only be used for any ‘resistant’ constipation or urgent relief

Describe how stimulant laxatives work and give an example. Describe when they are used. What can abuse lead to?

Senna, Bisacodyl Excite the sensory nerve ending leading to water and electrolyte retention and thus a peristalsic action Used for rapid treatment such as faecal impaction or surgical preparation. Act within 6-8 hrs so are administered overnight Any abuse can lead to melanosis coli

Describe how Anti-Motility Drugs work in the pharmacological treatment of Diarrhoea. Give an example and when it is used and its contraindication

Loperamide Opiate analogue to reduce GI motility Good for chronic diarrhoea Should be avoided in IBD due to risk of toxic megacolon

Describe how Bulk Formin Agents work in the pharmacological treatment of Diarrhoea. Give an example and when it is used.

Ispaghula Increase water absorption by the gut to influence the faecal composition Particularly useful for patients with IBS and those with an ileostomy