0014Clinical Pharmacology Notes 2015

8/18/2019 0014Clinical Pharmacology Notes 2015

1/84

Pharmacokinetics:MetabolismDrug metabolism usually involves two types of biochemical reactions - phase I and phase II

reactions

Phase I reactions:

• Oxidation, reduction, hydrolysis.

• Mainly performed by the P450 enzymes but some drugs are metabolised by specific

enzymes, for example alcohol dehydrogenase and xanthine oxidase.

• Products of phase I reactions are typically more active and potentially toxic

phase II reactions:

• Conjugation.

• Products are typically inactive and excreted in urine or bile.• Glucuronyl, acetyl, methyl, sulphate and other groups are typically involved

The majority of phase I and phase II reactions take place in the liver

First-pass metabolism

• This is a phenomenon where the concentration of a drug is greatly reduced before it

reaches the systemic circulation due to hepatic metabolism.• As a consequence much larger doses are need orally than if given by other routes.

• This effect is seen in many drugs, including:

1)aspirin

2)isosorbide dinitrate

3)glyceryl trinitrate

4)lignocaine

5)propranolol

6)verapamil

7)isoprenaline

8)testosterone

9)hydrocortisone

Questions concerning zero-order kinetics and acetylator status are also common in the exam

Zero-order kinetics

• Zero-order kinetics describes metabolism which is independent of the concentration of thereactant.

1


2/84


3/84

4)amiodarone

5)allopurinol

6)imidazoles: ketoconazole, fluconazole

7)SSRIs: fluoxetine, sertraline

8)ritonavir

9)sodium valproate

10) acute alcohol intake

11) quinupristin

P450 drug interactions: more detailWhilst you are expected to know in broad terms what are the main inhibitors and inducers of

the P450 system it is unlikely that you will be asked detailed questions about the individual

enzyme systems.

It is worthwhile noting that the most important and common reason for drug interactions is the

P450CYP3A4 system.

The table below shows the main enzyme systems that are affected by common drugs. There

is clearly a lot of overlap within the various P450 enzymes.

P450system Substrates Inhibitors Inducers

CYP3A4 MacrolidesAntiretroviralsCalcium channel

blockers

MacrolidesProtease inhibitors(including ritonavir)Imidazoles

CarbamazepinePhenytoinPhenobarbitoneRifampicint !ohn"s #ort

CYP2D6 $ricyclicantidepressants

RIsRitonavir

3


4/84

P450system Substrates Inhibitors Inducers

Antipsychotics

CYP2C9 #arfarinulfonylureas

ImidazolesAmiodarone

odium valproate

Rifampicin

CYP1A2 $heophylline Ciproflo%acin moking&meprazole

CYP21 Alcohol ChronicalcoholIsoniazid

!"#$ %&'(

!"#$%&$ '()'*

#*+,- ./ + + 7,8,$! :!;+* ?@$! B8) E(Q) XRQ) KW$!% &$;,$!

+,- ./0123 4-56 ,7849: 49; :5-?@,/B,-D=EFG/H59: GJ6K1L+,$!

FG019: N,* OQ G-,0 S93 .T; S7@ UL V40 WTXQ 4YZ; [/1\19: >:,]^: G01_ S93 :5`Q B:

4

http://void%280%29/http://www.aljazeera.net/home/getpage/f2543b4a-bc1a-44bb-9be3-0cdcb2096083/0b5251c2-e1f2-44a5-a8fc-ee1ccf0093bchttp://www.aljazeera.net/home/getpage/f2543b4a-bc1a-44bb-9be3-0cdcb2096083/0b5251c2-e1f2-44a5-a8fc-ee1ccf0093bchttp://void%280%29/


5/84

279: -579: .9: ] (>1959:) W9: OQ 6 4Y1L j,9: 6 B; :,]^: G019 G/B1959: G7`9: [1q

F519 1Q \9: 4q 50 >,/B195L G1JXQ V:3 O1L :,0 >8 18

FG//:523 G859 L GYX1L w: /L G/] S0 U718K1L G919:; GB/x9L GQ,`K9: QUZL >1959: 6 5U7*:6 GT]; G9;49: q: WUB Q 6 \9: {Q [Q 4-49: 8 18 |X/2 F}/9: +5*; V?/9:;

4-49L +4YZ 18 W9: OQ 6 ~,_; ] >/L; G@3 W •€ G\1]; L:,72: [/\1] [Q 58‚L Q4YZ 9 .2 ƒ ; F[/B:,Y9: -Q [Q

V,„ 6 ./0123 4-56 '* 8; 5-X- .H [\9: .]: F•19: G-UB 6 G\9:

arid Ismaif

ghe date and face o birth" !une


6/84

—e succeeded in –inning a seat in Parliament during the ninth legislative term from


7/84

• Whilst it is common that non-hypoxic patients receive oxygen therapy there is little

evidence to support this approach.

• The 2008 British Thoracic Society oxygen therapy guidelines advise not giving oxygen

unless the patient is hypoxic.

B)Antithrombin treatment:

• Fondaparinux should be offered to patients who are not at a high risk of bleeding and

who are not having angiography within the next 24 hours.

• If angiography is likely within 24 hours or a patient’s creatinine is > 265umol/l

unfractionated heparin should be given.

C)Clopidogrel 300mg should be given toall patients and continued for 12 months.

D)Intravenous glycoprotein IIb/IIIa receptor antagonists

• Eptifibatide or tirofiban

• It should be given to:

1)Patients who have an intermediate or higher risk of adverse cardiovascular events(predicted 6-month mortality above 3.0%), and

2)Who are scheduled to undergo angiography within 96 hours of hospital admission

E)Coronary angiography:

• Should be considered within 96 hours of first admission to hospital to patients who

have a predicted 6-month mortality above 3.0%.

• It should also be performed as soon as possible in patients who are clinically unstable.

Mechanism of action of drugs commonly used in the management of acute coronary syndrome:

ledication lechanism o action

Asirin Antiplatelet inhibits the production of thrombo%ane A<

Cfoidoref Antiplatelet inhibits A™P binding to its platelet receptor

noaarin Activates antithrombin III’ –hich in turn potentiates the inhibition of coagulationfactors œa

ondaarinu Activates antithrombin III’ –hich in turn potentiates the inhibition of coagulation

factors œaipafirudin Reversible direct thrombin inhibitor

)sirin• Aspirin works by blocking the action of both cyclooxygenase-1 and 2.

• Cyclooxygenase is responsible for prostaglandin, prostacyclin and thromboxane synthesis.

• The blocking of thromboxane A2 formation in platelets reduces the ability of platelets to

aggregate which has lead to the widespread use of low-dose aspirin in cardiovascular

disease.


8/84

• Until recent guidelines changed all patients with established cardiovascular disease took

aspirin if there was no contraindication. Following the 2010 technology appraisal of

clopidogrel this is no longer the case*.

• Two recent trials (the Aspirin for Asymptomatic Atherosclerosis and the Antithrombotic

Trialists Collaboration) have cast doubt on the use of aspirin in primary prevention of

cardiovascular disease.• Guidelines have not yet changed to reflect this. However the Medicines and Healthcare

products Regulatory Agency (MHRA) issued a drug safety update in January 2010

reminding prescribers that aspirin is not licensed for primary prevention.

What do the current guidelines recommend?

• first-line for patients with ischaemic heart disease

Potentiates

• oral hypoglycaemics

• warfarin

• steroids

*NICE now recommend clopidogrel first-line following an ischaemic stroke and for peripheral

arterial disease. For TIAs the situation is more complex. Recent Royal College of Physician

(RCP) guidelines support the use of clopidogrel in TIAs. However the older NICE guidelines

still recommend aspirin + dipyridamole - a position the RCP state is 'illogical'

iyridamole• Dipyridamole is an antiplatelet mainly used in combination with aspirin after an ischaemic

stroke or transient ischaemic attack.

Mechanism of action:

• inhibits phosphodiesterase, elevating platelet cAMP levels which in turn reduce

intracellular calcium levels

• other actions include reducing cellular uptake of adenosine and inhibition of

thromboxane synthase


9/84

Familial Hypercholesterolaemia

• FH is an autosomal dominant condition that is thought to affect around 1 in 500 people.

• It results in high levels of LDL-cholesterol which, if untreated, may cause early cardiovascular

disease (CVD).• FH is caused by mutations in the gene which encodes the LDL-receptor protein.

Clinical diagnosis is now based on theSimon Broome criteria

The Simon Broome criteria:

1)in adults total cholesterol (TC) > 7.5 mmol/l and LDL-C > 4.9 mmol/l or

Children TC > 6.7 mmol/l and LDL-C > 4.0 mmol/l,

plus:

1)For definite FH:

• tendon xanthoma in patients or

• 1st or 2nd degree relatives or

• DNA-based evidence of FH

2)For possible FH:family history of myocardial infarction:

• below age 50 years in 2nd degree relative,

• below age 60 in 1st degree relative, or

• a family history of raised cholesterol levels

Management

• the use of CVD risk estimation using standard tables is not appropriate in FH as they do not

accurately reflect the risk of CVD

• referral to a specialist lipid clinic is usually required

the maximum dose of potent statins are usually required

• First-degree relatives have a 50% chance of having the disorder and should therefore be

offered screening. This includes children who should be screened by the age of 10 years if

there is one affected parent

• statins should be discontinued in women 3 months before conceptiondue to the risk

of congenital defects

yerliidaemia: mechanism o* action and ad6ersee7ects

The following table compares the side-effects of drugs used in hyperlipidaemia:

8


10/84

Drus lechanism o action Adperse eects

tatins —M˜ CoA reductase inhibitors Myositis’ deranged $s

“zetimibe ™ecreases cholesterol absorption in the small intestine —eadache

šicotinic acid ™ecreases hepatic ž™ secretion lushing’ myositis

ibrates Agonist of PPARalpha therefore increases lipoproteinlipase e%pression

Myositis’ pruritus’cholestasis

Cholestyramine

™ecreases bile acid reabsorption in the small intestine’upregulating the amount of cholesterol that isconverted to bile acid

˜I sideeffects

,tatinsStatins inhibit the action of HMG-CoA reductase, the rate-limiting enzyme in hepatic

cholesterol synthesis

Adverse effects:

1) Myopathy:

• Includes myalgia, myositis, rhabdomyolysis and asymptomatic raised creatine

kinase.

•

Risks factors for myopathy include advanced age, female sex, low body massindex and presence of multisystem disease such as diabetes mellitus.

• Myopathy is more common in lipophilic statins (simvastatin, atorvastatin) than

relatively hydrophilic statins (rosuvastatin, pravastatin, fluvastatin)

2) Liver impairment:

• The 2014 NICE guidelines recommend checking LFTs at baseline, 3 months

and 12 months.

• Treatment should be discontinued if serum transaminase concentrations rise to

and persist at 3 times the upper limit of the reference range

3)There is some evidence that statins mayincrease the risk of intracerebral

haemorrhage in patients who've previously had a stroke. This effect is not seen in

primary prevention. For this reason the Royal College of Physicians recommend

avoiding statins in patients with a history of intracerebral haemorrhage

Who should receive a statin?

10


11/84


12/84

eart *ailure:rug managementA number of drugs have been shown to improve mortality in patients with chronic heart

failure:

1)ACE inhibitors (SAVE, SOLVD, CONSENSUS)

2)spironolactone (RALES)

3)beta-blockers (CIBIS)4)hydralazine with nitrates (VHEFT-1)

No long-term reduction in mortality has been demonstrated for loop diuretics such as

furosemide.

NICE issued updated guidelines on management in 2010, key points include:

1)first-line treatment for all patients is both an ACE-inhibitor and a beta-blocker2)second-line treatment is now either an aldosterone antagonist, angiotensin II receptor

blocker or a hydralazine in combination with a nitrate

12


13/84

3)if symptoms persist cardiac resynchronisation therapy or digoxin* should be considered

4)diuretics should be given for fluid overload

5)offer annual influenza vaccine

6)offer one-off** pneumococcal vaccine

*digoxin has also not been proven to reduce mortality in patients with heart failure. It may

however improve symptoms due to its inotropic properties. Digoxin is strongly indicated if

there is coexistent atrial fibrillation

**adults usually require just one dose but those with asplenia, splenic dysfunction or chronic

kidney disease need a booster every 5 years

igo9in and digo9in to9icity• Digoxin is a cardiac glycoside now mainly used for rate control in the management of atrial

fibrillation.

• As it has positive inotropic properties it is sometimes used for improving symptoms (but

not mortality) in patients with heart failure.


1)decreases conduction through the atrioventricular node which slows the ventricular rate

in atrial fibrillation and flutter

2)Increases the force of cardiac muscle contraction due to inhibition of the Na+ /K+ATPase

pump.

3)Also stimulates vagus nerve

Digoxin toxicity

• Plasma concentration alone does not determine whether a patient has developed digoxin

toxicity.

• The BNF advises that the likelihood of toxicity increases progressively from 1.5 to 3 mcg/l.

Features:

1)generally unwell, lethargy, nausea & vomiting, anorexia, confusion, yellow-green vision

13


14/84

2)arrhythmias (e.g. AV block, bradycardia)

Precipitating factors:

1)classically: hypokalaemia*

2)increasing age

3)renal failure

4)myocardial ischaemia

5)hypomagnesaemia,

6)hypercalcaemia, hypernatraemia, acidosis

7)hypoalbuminaemia

8)hypothermia

9)hypothyroidism

10) Drugs: amiodarone, quinidine, verapamil, diltiazem, spironolactone (competesfor secretion in distal convoluted tubule therefore reduce excretion), ciclosporin. Also

drugs which cause hypokalaemia e.g. thiazides and loop diuretics

Management:

1)Digibind

2)correct arrhythmias

3)monitor potassium

*hyperkalaemia may also worsen digoxin toxicity, although this is very small print

Prescribing in atients ith heart *ailureThe following medications may exacerbate heart failure:

1)thiazolidinediones*: pioglitazone is contraindicated as it causes fluid retention

2)verapamil: negative inotropic effect

3)NSAIDs**/glucocorticoids: should be used with caution as they cause fluid retention

4)class I antiarrhythmics; flecainide (negative inotropic and proarrhythmic effect)

*pioglitazone is now the only thiazolidinedione on the market

**low-dose aspirin is an exception - many patients will have coexistent cardiovascular disease

and the benefits of taking aspirin easily outweigh the risks

14


15/84

;endro


16/84

Adverse effects:

1)hypotension

2)hyponatraemia

3)hypokalaemia

4)hypochloraemic alkalosis

5)ototoxicity

6)hypocalcaemia

7)renal impairment (from dehydration + direct toxic effect)

8)hyperglycaemia (less common than with thiazides)

9)gout

;eta>blocker o6erdoseFeatures:

• bradycardia

• hypotension

• heart failure

• syncope

Management:

• if bradycardic then atropine• in resistant cases glucagon may be used

Haemodialysis is not effective in beta-blocker overdose

?alcium channel blockers• Calcium channel blockers are primarily used in the management of cardiovascular

disease.• Voltage-gated calcium channels are present in:

1)myocardial cells,

2)cells of the conduction system

3)the vascular smooth muscle cells

The various types of calcium channel blockers have varying effects on these three areas and

it is therefore important to differentiate their uses and actions.

1


17/84

amfes Indications notes Sideeects and cautions

veraamif ) Angina’ hypertension’ arrhythmias• —ighly negatively inotropic• hould not be given –ith betablockers as

may cause heart block • hould not be given in ventricular

tachcardia

) —eart failure’


18/84

Cfass amfes lechanism o action xotes

Atenolol”isoprololMetoprolol

antagonists

III AmiodaroneotalolIbutilide”retylium

”lock potassium channels

Iž žerapamil™iltiazem

Calcium channel blockers

1


19/84


20/84

Clecainide• Flecainide is a Vaughan Williams class 1c antiarrhythmic.

• It slows conduction of the action potential by acting as a potent sodium channel blocker.

• This may be reflected by widening of the QRS complex and prolongation of the PR interval

• The Cardiac Arrhythmia Suppression Trial (CAST, 1989) investigated the use of agents to

treat asymptomatic or mildly symptomatic premature ventricular complexes (PVCs) post

myocardial infarction. The hypothesis was that this would reduce deaths from ventricular

arrhythmias.Flecainide was actually shown to increase mortality post myocardial

infarction and is therefore contraindicated in this situation

Indications:

• atrial fibrillation

• SVT associated with accessory pathway e.g. Wolf-Parkinson-White syndrome

Adverse effects

1)negatively inotropic

2)bradycardia

3)proarrhythmic

4)oral paraesthesia5)visual disturbances

20


21/84


22/84

AIg tye 1 AIg tye 2

Pathophysiology

“%cess iodineinduced thyroidhormone synthesis

Amiodaronerelated destructivethyroiditis

˜oitre Present Absent

Management Carbimazole or potassium perchlorate Corticosteroids

Unlike in AIH, amiodarone should be stopped if possible in patients who develop AIT

)denosine

The effects of adenosine are:⇒ Enhanced by dipyridamole (anti-platelet agent) and

⇒ blocked by theophyllines

• It should be avoided in asthmatics due to possible bronchospasm.


1)causes transient heart block in the AV node

2)agonist of the A1 receptor which inhibits adenylyl cyclase thus reducing cAMP and

causing hyperpolarization by increasing outward potassium flux

3)adenosine has a very short half-life of about 8-10 seconds

Adverse effects:

1)chest pain

2)bronchospasm

3)can enhance conduction down accessory pathways, resulting in increased ventricular

rate (e.g. WPW syndrome)

22


23/84

)drenalineAdrenaline is a sympathomimetic amine with both alpha and beta adrenergic stimulating

properties

Indications:

• anaphylaxis

• cardiac arrest

Recommend Adult Life Support (ALS) adrenaline doses:

1)anaphylaxis: 0.5ml 1:1,000 IM

2)cardiac arrest:

⇒ 1ml of 1:1000 IV

⇒ 10ml 1:10,000 IV

Management of accidental injection:

• local infiltration of phentolamine

)drenocetor antagonistsAlpha antagonists

• alpha-1: doxazosin

• alpha-1a: tamsulosin - acts mainly on urogenital tract

• alpha-2: yohimbine

• non-selective: phenoxybenzamine (previously used in peripheral arterial disease)

23


24/84


25/84

⇒ the British Society for Rheumatology recommend 'In uncomplicated gout uric

acid lowering drug therapy should be started if a second attack, or further

attacks occur within 1 year'

2)tophi

3)renal disease

4)uric acid renal stones

5)prophylaxis if on cytotoxics or diuretics

*patients with Lesch-Nyhan syndrome often take allopurinol for life

Interactions

1)Azathioprine:

•

Azathioprine metabolised to active compound 6-mercaptopurine• xanthine oxidase is responsible for the oxidation of 6-mercaptopurine to 6-thiouric acid

• allopurinol can therefore lead to high levels of 6-mercaptopurine

• a much reduced dose (e.g. 25%) must therefore be used if the combination cannot be

avoided

2) Cyclophosphamide

• allopurinol reduces renal clearance, therefore may cause marrow toxicity

)ntihistamines• Antihistamines (H1 inhibitors) are of value in the treatment of allergic rhinitis and urticaria.

Examples of sedating antihistamines:

• chlorpheniramine

25


26/84

• As well as being sedating these antihistamines have some antimuscarinic properties

(e.g. urinary retention, dry mouth).

Examples of non-sedating antihistamines

• loratidine

• cetirizine

Of the non-sedating antihistamines there is some evidence that cetirizine may cause more

drowsiness than other drugs in the class.

rugs hich act on serotonin recetors• Below is a summary of drugs which are known to act via modulation of the serotonin (5-

HT) system.

• It should be noted that 5-HT receptor agonists are used in the acute treatment of migrainewhilst 5-HT receptor antagonists are used in prophylaxis

Agonists:

• sumatriptan is a 5-HT1D receptor agonist which is used in the acute treatment of

migraine

• ergotamine is a partial agonist of 5-HT1 receptors

Antagonists:

• Pizotifen is a 5-HT2 receptor antagonist used in the prophylaxis of migraine attacks.

• Methysergide is another antagonist of the 5-HT2 receptor but is rarely used due to the

risk ofretroperitoneal fibrosis

• cyproheptadine is a 5-HT2 receptor antagonist which is used tocontrol diarrhoea in

patients with carcinoid syndrome

• ondansetron is a 5-HT3 receptor antagonist and is used as an antiemetic

5>-3 antagonists• 5-HT3 antagonists are antiemetics used mainly in the management of chemotherapy

related nausea.

• They mainly act in the chemoreceptor trigger zone area of the medulla oblongata.

Examples:

• ondansetron• granisetron

Adverse effects:

2


27/84

• constipation is common

Motion sickness• Motion sickness describes the nausea and vomiting which occurs when an apparent

discrepancy exists between visually perceived movement and the vestibular systems

sense of movement

Management:

1)The BNF recommends hyoscine (e.g. transdermal patch) as being the most effective

treatment. Use is limited due to side-effects

2)non-sedating antihistamines such as cyclizine or cinnarizine are recommended in

preference to sedating preparation such as promethazine

Proton um inhibitors• Proton pump inhibitors (PPI) are a group of drugs which profoundly reduce acid secretion

in the stomach.

• They irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme

system (the H+/K+ ATPase) of the gastric parietal cell

• Examples include omeprazole and lansoprazole

2


28/84

,teroid dosesEquivalence

• 1mg prednisolone = 4mg hydrocortisone

• 1mg dexamethasone = 7mg prednisolone = 28 mg hydrocortisone

)zathiorine• Azathioprine is metabolised to the active compound mercaptopurine, a purine analogue

that inhibits purine synthesis.

• A thiopurine methyltransferase (TPMT) test may be needed to look for individuals prone to

azathioprine toxicity.

• A significant interaction may occur with allopurinol and hence lower doses of azathioprine

should be used.

Adverse effects include:

1)bone marrow depression

2)nausea/vomiting

3)pancreatitis

?iclosorin• Ciclosporin is an immunosuppressant which decreases clonal proliferation of T cells by

reducing IL-2 release.

• It acts by binding to cyclophilin forming a complex which inhibits calcineurin, a

phosphotase that activates various transcription factors in T cells

Adverse effects: (note how everything is increased - fluid, BP, K+, hair, gums, glucose)

1)nephrotoxicity

2)hepatotoxicity

3)fluid retention4)hypertension

5)hyperkalaemia

2


29/84

6)hypertrichosis

7)gingival hyperplasia

8)tremor

9)impaired glucose tolerance

10) hyperlipidaemia

11) increased susceptibility to severe infection

Interestingly for an immunosuppressant, ciclosporin is noted by the BNF to be 'virtually non-

myelotoxic'.

Indications:

1)following organ transplantation

2)rheumatoid arthritis

3)psoriasis (has a direct effect on keratinocytes as well as modulating T cell function)4)ulcerative colitis

5)pure red cell aplasia

-acrolimus• Tacrolimus is a macrolide used as an immunosuppressant to prevent transplant rejection.

• It has a very similar action to ciclosporin

• The action of tacrolimus differs in that it binds to a protein called FKBP rather than

cyclophilin

• Tacrolimus is more potent than ciclosporin and hence the incidence of organ rejection is

less. However, nephrotoxicity and impaired glucose tolerance is more common

28


30/84

oamine recetor agonists• e.g.bromocriptine, ropinirole, cabergoline, apomorphine

•

Ergot-derived dopamine receptor agonists (bromocriptine, cabergoline, pergolide*) havebeen associated with pulmonary, retroperitoneal and cardiac fibrosis.

• The Committee on Safety of Medicines advice that an ESR, creatinine and chest x-ray

should be obtained prior to treatment and patients should be closely monitored

Indications:

1)Parkinson's disease

2)prolactinoma/galactorrhoea

3)cyclical breast disease

4)acromegaly

Currently accepted practice in the management of patients with Parkinson's disease is to

delay treatment until the onset of disabling symptoms and then to introduce a dopamine

receptor agonist. If the patient is elderly, L-dopa is sometimes used as an initial treatment

Adverse effects:

1)nausea/vomiting

30


31/84

2)postural hypotension

3)hallucinations

4)daytime somnolence

*pergolide was withdrawn from the US market in March 2007 due to concern regarding

increased incidence of valvular dysfunction

EctreotideOverview

• long-acting analogue of somatostatin

• somatostatin is released from D cells of pancreas and inhibits the release of growth

hormone, glucagon and insulin

Uses:

1)acute treatment of variceal haemorrhage

2)acromegaly

3)carcinoid syndrome

4)prevent complications following pancreatic surgery

5)VIPomas

6)refractory diarrhoea

Adverse effects:

• gallstones (secondary to biliary stasis)

Monoamine o9idase inhibitors• serotonin and noradrenaline are metabolised by monoamine oxidase in the presynaptic

cell

Non-selective monoamine oxidase inhibitors

• e.g. tranylcypromine, phenelzine

• used in the treatment of atypical depression (e.g. hyperphagia) and other psychiatric

disorder

• not used frequently due to side-effects

Adverse effects of non-selective monoamine oxidase inhibitors:

• hypertensive reactions with tyramine containing foods

31


32/84

e.g. cheese, pickled herring,GB59: Bovril, Oxo, Marmite, broad beans

• anticholinergic effects

-ricyclic o6erdose• Overdose of tricyclic antidepressants is a common presentation to emergency

departments

• Amitriptyline and dosulepin (dothiepin) are particularly dangerous in overdose.

Early features relate to anticholinergic properties:

1)dry mouth,

32


33/84

2)dilated pupils,

3)agitation,

4)sinus tachycardia,

5)blurred vision

Features of severe poisoning include:

1)arrhythmias

2)seizures

3)metabolic acidosis

4)coma

ECG changes include:

1)sinus tachycardia

2)widening of QRS

3)prolongation of QT interval

Widening of QRS > 100ms is associated with an increased risk of seizures

whilst QRS > 160ms is associated with ventricular arrhythmias

Management:

1)IV bicarbonate may reduce the risk of seizures and arrhythmias in severe toxicity

2)arrhythmias:

⇒ Response to lignocaine is variable and it should be emphasized that correction of

acidosis is the first line in management of tricyclic induced arrhythmias

⇒ Class 1a (e.g. Quinidine) and class Ic antiarrhythmics (e.g. Flecainide) are

contraindicated as they prolong depolarisation.

⇒ Class III drugs such as amiodarone should also be avoided as they prolong the QT

interval.3)intravenous lipid emulsion is increasingly used to bind free drug and reduce toxicity

4)dialysis is ineffective in removing tricyclics

33


34/84

,t FohnGs AortOverview

• shown to be as effective as tricyclic antidepressants in the treatment of mild-moderate

depression

• mechanism: thought to be similar to SSRIs (although noradrenaline uptake inhibition has

also been demonstrated)

• NICE advise 'may be of benefit in mild or moderate depression, but its use should not be

prescribed or advised because of uncertainty about appropriate doses, variation in the

nature of preparations, and potential serious interactions with other drugs'

Adverse effects:

1)profile in trials similar to placebo

2)can cause serotonin syndrome

3)Inducer of P450 system, therefore:

⇒ Decreased levels of drugs such as warfarin, ciclosporin.

⇒ The effectiveness of the combined oral contraceptive pill may also be reduced

34


35/84


36/84

Eculogyric crisisAn oculogyric crisis is a dystonic reaction to certain drugs or medical conditions

Features:

• restlessness, agitation

• involuntary upward deviation of the eyes

Causes:

1)phenothiazines

2)haloperidol

3)metoclopramide

4)postencephalitic Parkinson's disease

Management:

• procyclidine

Eioid misuse• Opioids are substances which bind to opioid receptors.

• This includes both naturally occurring opiates such as morphine and synthetic opioids

such as buprenorphine and methadone.

Features of opioid misuse:

1)rhinorrhoea

2)needle track marks

3)pinpoint pupils

4)drowsiness

5)watering eyes

6)yawning

Complications of opioid misuse:

1)viral infection secondary to sharing needles: HIV, hepatitis B & C

2)bacterial infection secondary to injection: infective endocarditis, septic arthritis,

septicaemia, necrotising fasciitis

3)venous thromboembolism

4)overdose may lead to respiratory depression and death

5)psychological problems: craving

6)social problems: crime, prostitution, homelessness

Emergency management of opioid overdose:

3


37/84

• IV or IM naloxone: has a rapid onset and relatively short duration of action

Harm reduction interventions may include:

1)needle exchange

2)offering testing for HIV, hepatitis B & C

Management of opioid dependence

1)patients are usually managed by specialist drug dependence clinics although some GPs

with a specialist interest offer similar services

2)patients may be offered maintenance therapy or detoxification

3)NICE recommend methadone or buprenorphine as the first-line treatment in opioid

detoxification

4)compliance is monitored using urinalysis

5)detoxification should normally last up to 4 weeks in an inpatient/residential setting and up

to 12 weeks in the community

?ocaine:• Cocaine is an alkaloid derived from the coca plant.

• It is widely used as a recreational stimulant.

• The price of cocaine has fallen sharply in the past decade resulting in cocaine toxicity

becoming a much more frequent clinical problem.

• This increase has made cocaine a favourite topic of question writers.


• cocaine blocks the uptake of dopamine, noradrenaline and serotonin

The use of cocaine is associated with a wide variety of adverse effects:

Cardiovascular effects:

1)myocardial infarction

2)both tachycardia and bradycardia may occur3)hypertension

4)QRS widening and QT prolongation

3


38/84

5)aortic dissection

Neurological effects:

1)seizures

2)mydriasis

3)hypertonia

4)hyperreflexia

Psychiatric effects:

1)agitation

2)psychosis

3)hallucinations

Others:1)hyperthermia

2)metabolic acidosis

3)rhabdomyolysis

Management of cocaine toxicity

1)in general benzodiazipines are generally first-line for most cocaine related problems

2)Chest pain: benzodiazipines + glyceryl trinitrate.

3)If myocardial infarction develops then primary percutaneous coronary intervention

4)hypertension: benzodiazipines + sodium nitroprusside

The use of beta-blockers in cocaine-induced cardiovascular problems is a controversial

issue.

The American Heart Association issued a statement in 2008 warning against the use of

beta-blockers (due to the risk of unopposed alpha-mediated coronary vasospasm) but

many cardiologists since have questioned whether this is valid. If a reasonable alternative

is given in an exam it is probably wise to choose it

.cstasy oisoning• Ecstasy (MDMA, 3, 4-Methylenedioxymethamphetamine)

• Its use became popular in the 1990's during the emergence of dance music culture

Clinical features:

1)neurological: agitation, anxiety, confusion, ataxia

3


39/84


40/84

• chronic alcohol consumption:

1)enhances GABA mediated inhibition in the CNS (similar to benzodiazepines) and

2)inhibits NMDA-type glutamate receptors

• alcohol withdrawal is thought to be lead to the opposite (decreased inhibitory GABA and

increased NMDA glutamate transmission)

Features:

• symptoms start at 6-12 hours

• peak incidence of seizures at 36 hours

• peak incidence of delirium tremens is at 72 hours

Management:

1)benzodiazepines

2)carbamazepine also effective in treatment of alcohol withdrawal

3)phenytoin is said not to be as effective in the treatment of alcohol withdrawal seizures

)lcohol > roblem drinking: managementNutritional support

•

SIGN recommends alcoholic patients should receive oral thiamine if their 'diet may bedeficient'

Drugs used

1)benzodiazepines for acute withdrawal

2)disulfram:

• Promotes abstinence

• alcohol intake causes severe reaction due to inhibition of acetaldehyde

dehydrogenase

• Patients should be aware that even small amounts of alcohol (e.g. In perfumes,

foods, mouthwashes) can produce severe symptoms.

• Contraindications include ischaemic heart disease and psychosis

3)acamprosate:

• reduces craving,• known to be a weak antagonist of NMDA receptors,

• improves abstinence in placebo controlled trials

40


41/84

.thylene glycol to9icityEthylene glycol is a type of alcohol used as a coolant or antifreeze

Features of toxicity are divided into 3 stages:

Stage 1: symptoms similar to alcohol intoxication: confusion, slurred speech, dizziness

Stage 2:

• metabolic acidosis with high anion gap and high osmolar gap

• Also tachycardia, hypertension

Stage 3: acute renal failure

Management has changed in recent times

1)Fomepizole,

• an inhibitor of alcohol dehydrogenase

• now used first-line in preference to ethanol

2)ethanol:• has been used for many years

• works by competing with ethylene glycol for the enzyme alcohol dehydrogenase

• this limits the formation of toxic metabolites (e.g. glycoaldehyde and glycolic acid)

which are responsible for the haemodynamic/metabolic features of poisoning

3)haemodialysis also has a role in refractory cases

Methanol oisoning• Methanol poisoning causes both:

1)the effects associated with alcohol (intoxication, nausea etc) and also

2)Specific visual problems, including blindness.

• These effects are thought to be secondary to the accumulation of formic acid.

• The actual pathophysiology of methanol-associated visual loss is not fully understood but

it is thought to be caused by a form of optic neuropathy

Management:1)fomepizole or

2)ethanol

41


42/84


43/84


44/84

-heohylline• Theophylline, like caffeine, is one of the naturally occurring methylxanthines.

• The main use of theophyllines in clinical medicine is as a bronchodilator in the

management of asthma and COPD

• The exact mechanism of action has yet to be discovered.

• One theory suggests theophyllines may be a non-specific inhibitor of phosphodiesteraseresulting in an increase in cAMP. Other proposed mechanisms include antagonism of

adenosine and prostaglandin inhibition

Theophylline poisoning

Features:

• acidosis, hypokalaemia

•

vomiting• tachycardia, arrhythmias

• seizures

Management:

• activated charcoal

• charcoal haemoperfusion is preferable to haemodialysis

Paracetamol o6erdose: risk *actorsThe following groups of patients are at an increased risk of developing hepatotoxicityfollowing a paracetamol overdose:

1)patients taking liver enzyme-inducing drugs (rifampicin, phenytoin, carbamazepine,

chronic alcohol excess, St John's Wort)

2)malnourished patients (e.g. anorexia or bulimia, cystic fibrosis, hepatitis C, alcoholism,

HIV

3)patients who have not eaten for a few days

44


45/84

Paracetamol o6erdose: metabolic athays1)The liver normally conjugates paracetamol with glucuronic acid/sulphate.

2)During an overdose the conjugation system becomes saturated leading to oxidation by

P450 mixed function oxidases*. This produces a toxic metabolite (N-acetyl-B-

benzoquinone imine)

3)Normally glutathione acts as a defence mechanism by conjugating with the toxin

forming the non-toxic mercapturic acid.

4)If glutathione stores run-out, the toxin forms covalent bonds with cell proteins,

denaturing them and leading to cell death.

5)This occurs not only in hepatocytes but also in the renal tubules

6)N-acetyl cysteine is used in the management of paracetamol overdose as it is a

precursor of glutathione and hence can increase hepatic glutathione production

*this explains why there is a lower threshold for treating patients who take P450

inducing medications e.g. phenytoin or rifampicin

,alicylate o6erdose• A key concept for the exam is to understand that salicylate overdose leads to a mixed

respiratory alkalosis and metabolic acidosis.

• Early stimulation of the respiratory centre leads to a respiratory alkalosis

• whilst later the direct acid effects of salicylates (combined with acute renal failure) may

lead to an acidosis

45


46/84

• In children metabolic acidosis tends to predominate

Features:

1)hyperventilation (centrally stimulates respiration)

2)tinnitus

3)lethargy

4)sweating, pyrexia*

5)nausea/vomiting

6)hyperglycaemia and hypoglycaemia

7)seizures

8)coma

Treatment:1)general (ABC, charcoal)

2)urinary alkalinization

3)haemodialysis

Indications for haemodialysis in salicylate overdose

1)serum concentration > 700mg/L

2)metabolic acidosis resistant to treatment

3)acute renal failure

4)pulmonary oedema

5)seizures

6)coma

*salicylates cause the uncoupling of oxidative phosphorylation leading to decreased

adenosine triphosphate production, increased oxygen consumption and increased carbon

dioxide and heat production

4


47/84

Mercury oisoningFeatures

1)paraesthesia

2)visual field defects

3)hearing loss

4)irritability

5)renal tubular acidosis

=ead oisoning• Along with acute intermittent porphyria, lead poisoning should be considered in questions

giving a combination of abdominal pain and neurological signs

Features:

1)abdominal pain

2)peripheral neuropathy (mainly motor)

3)fatigue

4)constipation

5)blue lines on gum margin (only 20% of adult patients, very rare in children)

Investigations:

1)The blood lead level is usually used for diagnosis. Levels greater than 10 mcg/dl are

considered significant

2)Full blood count: microcytic anaemia. Blood film shows red cell abnormalities including

basophilic stippling and clover-leaf morphology

3)raised serum and urine levels of delta aminolaevulinic acid may be seen making it

sometimes difficult to differentiate from acute intermittent porphyria4)urinary coproporphyrin is also increased (urinary porphobilinogen and uroporphyrin

levels are normal to slightly increased)

Management - various chelating agents are currently used:

1)dimercaptosuccinic acid (DMSA)

2)D-penicillamine

3)EDTA

4)dimercaprol

4


48/84

=ithium• Lithium is mood stabilising drug used most commonly prophylatically in bipolar disorder

but also as an adjunct in refractory depression.

• It has a very narrow therapeutic range (0.4-1.0 mmol/L) and a long plasma half-life being

excreted primarily by the kidneys.

Mechanism of action - not fully understood, two theories:

1)interferes with inositol triphosphate formation

2)interferes with cAMP formation

Adverse effects:

1)nausea/vomiting, diarrhoea

2)fine tremor

3)polyuria (secondary to nephrogenic diabetes insipidus)

4)thyroid enlargement, may lead to hypothyroidism

5)ECG: T wave flattening/inversion

6)weight gain

Monitoring of patients on lithium therapy:

1)Inadequate monitoring of patients taking lithium is common - NICE and the National

Patient Safety Agency (NPSA) have issued guidance to try and address this. As a result it

is often an exam hot topic

2)Lithium blood level should 'normally' be checked every 3 months. Levels should be taken

12 hours post-dose

3)thyroid and renal function should be checked every 6 months

4)patients should be issued with an information booklet, alert card and record book

4


49/84

=ithium to9icity• Lithium toxicity generally occurs following concentrations > 1.5 mmol/L.

• Toxicity may be precipitated by:

1)dehydration, diuretics (especially bendroflumethiazide)

2)renal failure,

3)ACE inhibitors4)Metronidazole

Features of toxicity

1)coarse tremor (a fine tremor is seen in therapeutic levels)

2)acute confusion

3)seizure

4)coma

Management:

1)mild-moderate toxicity may respond to volume resuscitation with normal saline

2)haemodialysis may be needed in severe toxicity

3)Sodium bicarbonate is sometimes used but there is limited evidence to support this. By

increasing the alkalinity of the urine it promotes lithium excretion

Methaemoglobinaemia• Methaemoglobinaemia describes haemoglobin which has been oxidised from Fe2+(ferrous

iron)to Fe3+(ferric iron).

• This is normally regulated by NADH methaemoglobin reductase, which transfers electrons

from NADH to methaemoglobin resulting in the reduction of methaemoglobin to

haemoglobin.

• There is tissue hypoxia as Fe3+ cannot bind oxygen, and hence the oxidation dissociation

curve is moved to the left

Congenital causes:

1)haemoglobin chain variants: HbM, HbH

2)NADH methaemoglobin reductase deficiency

Acquired causes:

1)drugs:

1.sulphonamides,

2.nitrates, , sodium nitroprusside,3.primaquine

4.dapsone

48


50/84

2)chemicals: aniline dyes

Features:

1)'chocolate' cyanosis

2)dyspnoea, anxiety, headache

3)severe: acidosis, arrhythmias, seizures, coma

4)normal pO2 but decreased oxygen saturation

Management:

1)NADH - methaemoglobinaemia reductase deficiency: ascorbic acid

2)IV methylene blue if acquired

?yanide oisoning• Cyanide may be used in insecticides, photograph development and the production of

certain metals.

• Toxicity results from reversibleinhibition of cellular oxidising enzymes

Presentation:

1)'classical' features: brick-red skin, smell of bitter almonds519: j,9:

2)acute: hypoxia, hypotension, headache, confusion

3)chronic: ataxia, peripheral neuropathy, dermatitis

Management:

1)supportive measures: 100% oxygen

50


51/84

2)definitive:

⇒ hydroxocobalamin (intravenously), also

⇒ combination of amyl nitrite (inhaled), sodium nitrite (intravenously), and sodium

thiosulfate (intravenously)

?arbon mono9ide oisoning• Carbon monoxide has high affinity for haemoglobin and myoglobin resulting in a left-shiftof the oxygen dissociation curve and tissue hypoxia.

• There are approximately 50 per year deaths from accidental carbon monoxide poisoning in

the UK

• Questions may hint at badly maintained housing e.g. student houses

Features of carbon monoxide toxicity :

1)headache: 90% of cases

2)nausea and vomiting: 50%

3)vertigo: 50%

4)confusion: 30%

5)subjective weakness: 20%

6)severe toxicity: 'pink' skin and mucosae, hyperpyrexia, arrhythmias, extrapyramidal

features, coma, death

Typical carboxyhaemoglobin levels

• < 3% non-smokers

• < 10% smokers

• 10 - 30% symptomatic: headache, vomiting

• > 30% severe toxicity

Management

• 100% oxygen

• hyperbaric oxygen

Indications for hyperbaric oxygen*1)loss of consciousness at any point

2)neurological signs other than headache

3)myocardial ischaemia or arrhythmia

4)pregnancy

*as stated in the 2008 Department of Health publication 'Recognising Carbon Monoxide

Poisoning'

Erganohoshate insecticide oisoning

51


52/84

One of the effects of organophosphate poisoning is inhibition of acetylcholinesterase

Features can be predicted by the accumulation of acetylcholine (mnemonic =SLUD)

• Salivation

• Lacrimation

• Urination

• Defecation/diarrhoea

• cardiovascular: hypotension, bradycardia

• also: small pupils, muscle fasciculation

Management:

• atropine

• the role of pralidoxime is still unclear - meta-analyses to date have failed to show anyclear benefit

52


53/84

aemodialysis in o6erdoseDrugs that can be cleared with haemodialysis - mnemonic: BLAST

1)Barbiturate2)Lithium

3)Alcohol (inc methanol, ethylene glycol)

4)Salicylates

5)Theophyllines (charcoal haemoperfusion is preferable)

Drugs which cannot be cleared with haemodialysis include

1)tricyclics2)benzodiazepines

3)dextropropoxyphene (Co-proxamol)

4)digoxin

5)beta-blockers

-heraeutic drug monitoring

Lithium• range = 0.4 - 1.0 mmol/l

• take 12 hrs post-dose

Digoxin

• at least 6 hrs post-dose

Phenytoin

• trough levels immediately before dose

Ciclosporin

• trough levels immediately before dose

53


54/84


55/84

rug causes o* urticariaThe following drugs commonly cause urticaria:

1)aspirin

2)penicillins

3)NSAIDs

4)opiates

rug>induced imaired glucose toleranceDrugs which are known to cause impaired glucose tolerance include:

1)thiazides, furosemide (less common)2)steroids

3)tacrolimus, ciclosporin

4)interferon-alpha

5)nicotinic acid

6)atypical antipsychotics e.g. olanzapine

Beta-blockers cause a slight impairment of glucose tolerance. They should also be used with

caution in diabetics as they can interfere with the metabolic and autonomic responses to

hypoglycaemia

rugs causing ocular roblemsCataracts

• steroids

Corneal opacities

1)amiodarone

55


56/84


57/84

3)anabolic steroids, testosterones

4)phenothiazines: chlorpromazine, prochlorperazine

5)sulphonylureas

6)fibrates

7)rare reported causes: nifedipine

Liver cirrhosis:

1)methotrexate

2)methyldopa

3)amiodarone

*risk may be reduced with erythromycin stearate

rug>induced ancytoaenia1)cytotoxics

2)antibiotics: trimethoprim, chloramphenicol

3)anti-rheumatoid: gold, penicillamine

4)carbimazole*

5)anti-epileptics: carbamazepine

6)sulphonylureas: tolbutamide

*causes both agranulocytosis and pancytopaenia

rug>induced thrombocytoenia (Probable immune mediated)

5


58/84

1)quinine

2)Abciximab

3)NSAIDS

4)diuretics: furosemide

5)antibiotics: penicillins, sulphonamides, rifampicin

6)anticonvulsants: carbamazepine, valproate

7)heparin

Osteoporosis management:

• NICE guidelines were updated in 2008 on the secondary prevention of osteoporotic fractures in

postmenopausal women.

• Key points include:

Treatment is indicated following osteoporotic fragility fractures in postmenopausal women

who are confirmed to have osteoporosis (a T-score of - 2.5 SD or below).

In women aged 75 years or older, a DEXA scan may not be required 'if the responsible

clinician considers it to be clinically inappropriate or unfeasible'

vitamin D and calcium supplementation should be offered to all women unless the clinician

is confident they have adequate calcium intake and are vitamin D replete

5


59/84

alendronate is first-line

Around 25% of patients cannot tolerate alendronate, usually due to upper gastrointestinal

problems. These patients should be offeredrisedronate oretidronate (see treatment

criteria below)

strontium ranelate andraloxifeneare recommended if patients cannot tolerate

bisphosphonates (see treatment criteria below)

Treatment criteria for patients not taking alendronate:

• Unfortunately, a number of complicated treatment cut-off tables have been produced in the

latest guidelines for patients who do not tolerate alendronate

• These take into account a patients age, their T-score and the number of risk factors they have

from the following list:

1)parental history of hip fracture

2)alcohol intake of 4 or more units per day

3)rheumatoid arthritis

The most important thing to remember is:

1)the T-score criteria for risedronate or etidronate are less than the others implying that

these are the second line drugs

2)if alendronate, risedronate or etidronate cannot be taken then strontium ranelate or

raloxifene may be given based on quite strict T-scores (e.g. a 60-year-old woman would

need a T-score < -3.5)

3)the strictest criteria are for denosumab

A Bisphosphonates:

1)alendronate, risedronate and etidronate are all licensed for the prevention and treatment

of post-menopausaland glucocorticoid-induced osteoporosis

2)all three have been shown toreduce the risk of both vertebral and non-vertebral

fractures although alendronate, risedronate may be superior to etidronate in preventing hip

fractures

3)ibandronate is aonce-monthly oral bisphosphonate

Vitamin D and calcium:

• poor evidence base to suggest reduced fracture rates in the general population at risk of

osteoporotic fractures - may reduce rates in frail, housebound patients

C)Raloxifene:

58


60/84

selective oestrogen receptor modulator (SERM)

• has been shown to prevent bone loss and toreduce the risk of vertebral fractures, but

hasnot yet been shown to reduce the risk of non-vertebral fractures

has been shown toincrease bone density in the spine and proximal femur

• may worsen menopausal symptoms

increased risk of thromboembolic events• maydecrease risk of breast cancer

D Strontium ranelate :

• dual action bone agent:

increases deposition of new bone by osteoblasts (promotes differentiation of pre-

osteoblast to osteoblast) and

reduces the resorption of bone by inhibiting osteoclasts

• Concerns regarding the safety profile of strontium have been raised recently.

• It should only be prescribed by a specialist in secondary care

due to these concerns the European Medicines Agency in 2014 said itshould only be

used by people for whom there are no other treatments for osteoporosis

Adverse Effects:

1) increased risk of cardiovascular events: any history of cardiovascular disease or

significant risk of cardiovascular disease is a contraindication2) increased risk of thromboembolic events:a Drug Safety Update in 2012 recommended it

is not used in patients with a history of venous thromboembolism

3) may cause serious skin reactions such asStevens Johnson syndrome

E) Denosumab:

human monoclonal antibody

• inhibits RANK ligand, which in turninhibits the maturation of osteoclasts

• given as asingle subcutaneous injection every 6 months

• initial trial data suggests that it is effective and well tolerated

Teriparatide:

recombinant form of parathyroid hormone

very effective at increasing bone mineral density butrole in the management of

osteoporosis yet to be clearly defined

z Hormone replacement therapy:

0


61/84

• has been shown toreduce the incidence of vertebral fracture and non-vertebral

fractures

• due to concerns aboutincreased rates of cardiovascular disease and breast cancer it is

no longer recommended for primary or secondary prevention of osteoporosis

unless the woman is suffering from vasomotor symptoms

{ Hip protectors:

• evidence to suggest significantly reduce hip fractures in nursing home patients

• compliance is a problem

I Falls risk assessment:

• no evidence to suggest reduced fracture rates

• however, do reduce rate of falls and should be considered in management of high risk

patients

;ishoshonates• Bisphosphonates are analogues of pyrophosphate, a molecule which decreases

demineralisation in bone.

• They inhibit osteoclasts by reducing recruitment and promoting apoptosis.

Clinical uses:

1)prevention and treatment of osteoporosis

2)hypercalcaemia

3)Paget's disease

4)pain from bone metatases

Adverse effects

1)oesophageal reactions: oesophagitis, oesophageal ulcers (especially alendronate)

2)osteonecrosis of the jaw

3)increased risk of atypical stress fractures of the proximal femoral shaft in patients

taking alendronate

The BNF suggests the following counselling for patients taking oral bisphosphonates• 'Tablets should be swallowed whole with plenty of water while sitting or standing; to be

given on an empty stomach at least 30 minutes before breakfast (or another oral

1


62/84

medication); patient should stand or sit upright for at least 30 minutes after taking

tablet'

PhenytoinPhenytoin is used to in the management of seizures.

Mechanism of action

• sodium channel blocker, decreasing the sodium influx into neurons which in turn

decreases excitability

Adverse effects:

Phenytoin is associated with a large number of adverse effects. These may be divided into

acute, chronic, idiosyncratic and teratogenic

Acute:

1)initially: dizziness, diplopia, nystagmus, slurred speech, ataxia

2)later: confusion, seizures

Chronic:

1)common:

1.gingival hyperplasia (secondary to increased expression of platelet derived

growth factor, PDGF),

2.hirsutism,

3.coarsening of facial features,

4.drowsiness2)megaloblastic anaemia (secondary to altered folate metabolism)

3)peripheral neuropathy

2


63/84

4)enhanced vitamin D metabolism causing osteomalacia

5)lymphadenopathy

6)dyskinesia

Idiosyncratic:

1)fever

2)rashes, including severe reactions such as toxic epidermal necrolysis

3)hepatitis

4)Dupuytren's contracture*

5)aplastic anaemia

6)drug-induced lupus

Teratogenic:• associated with cleft palate and congenital heart disease

*although not listed in the BNF

,odium 6alroateSodium valproate is used in the management of epilepsy and is first line therapy for

generalised seizures. It works by increasing GABA activity.

Adverse effects:1)gastrointestinal: nausea

2)increased appetite and weight gain

3)alopecia: regrowth may be curly

4)ataxia

5)tremor

6)hepatitis

7)pancreatitis

8)thromobcytopaenia

9)teratogenic

3


64/84

10) hyponatraemia

+ehrotic syndrome: causesPrimary glomerulonephritis accounts for around 80% of cases

• minimal change glomerulonephritis (causes 80% in children, 30% in adults)

• membranous glomerulonephritis

4


65/84

• focal segmental glomerulosclerosis

• membranoproliferative glomerulonephritis

Systemic disease (about 20%)

• diabetes mellitus

• systemic lupus erythematosus

• amyloidosis

Drugs

• gold (sodium aurothiomalate), penicillamine

Others

• congenital• neoplasia: carcinoma, lymphoma, leukaemia, myeloma

• infection: bacterial endocarditis, hepatitis B, malaria

Prescribing in atients ith renal *ailureQuestions regarding which drugs to avoid in renal failure are common

Drugs to avoid in renal failure:

1)antibiotics: tetracycline, nitrofurantoin

2)NSAIDs

3)lithium

4)metformin

Drugs likely to accumulate in chronic kidney disease - need dose adjustment

1)most antibiotics including penicillins, cephalosporins, vancomycin, gentamicin,

streptomycin2)digoxin, atenolol

3)methotrexate

4)sulphonylureas

5)furosemide

6)opioids

Drugs relatively safe - can sometimes use normal dose depending on the degree of chronickidney disease:

• antibiotics: erythromycin, rifampicin

5


66/84


67/84

,ildenaBlSildenafil is a phosphodiesterase type V inhibitor used in the treatment of impotence.

Contraindications:

1)patients taking nitrates and related drugs such as nicorandil

2)hypotension

3)recent stroke or myocardial infarction (NICE recommend waiting 6 months)

4)non-arteritic anterior ischaemic optic neuropathy

Side-effects:

1)visual disturbances e.g. blue discolouration, non-arteritic anterior ischaemic opticneuropathy

2)nasal congestion

3)flushing

4)gastrointestinal side-effects

5)headache


68/84


69/84

Prescribing in regnant atients• Very few drugs are known to be completely safe in pregnancy.

• Some countries have developed a grading system - see the link.

• The list below largely comprises of those known to be harmful:

Antibiotics

• tetracyclines

• aminoglycosides

• sulphonamides and trimethoprim

• quinolones: the BNF advises to avoid due to arthropathy in some animal studies

Other drugs• ACE inhibitors, angiotensin II receptor antagonists

• statins

• warfarin

• sulfonylureas

• retinoids (including topical)

• cytotoxic agents

The majority of antiepileptics including valproate, carbamazepine and phenytoin are known to

8


70/84

be potentially harmful. The decision to stop such treatments however is difficult as

uncontrolled epilepsy is also a risk

.clamsia• Eclampsia may be defined as the development of seizures in association pre-eclampsia.

• To recap, pre-eclampsia is defined as:

1)condition seen after 20 weeks gestation

2)pregnancy-induced hypertension

3)proteinuria

Magnesium sulphate is used to both prevent seizures in patients with severe pre-eclampsia

and treat seizures once they develop. Guidelines on its use suggest the following:

1)should be given once a decision to deliver has been made

2)in eclampsia an IV bolus of 4g over 5-10 minutes should be given followed by an

infusion of 1g / hour

3)urine output, reflexes, respiratory rate and oxygen saturations should be monitored

during treatment

4)treatment should continue for 24 hours after last seizure or delivery (around 40% of

seizures occur post-partum)

Other important aspects of treating severe pre-eclampsia/eclampsia include fluid restriction to

avoid the potentially serious consequences of fluid overload

;reast *eeding: contraindicationsThe major breastfeeding contraindications tested in exams relate to drugs (see below). Other

contraindications of note include:

1)galactosaemia

2)viral infections - this is controversial with respect to HIV in the developing world. This is

because there is such an increased infant mortality and morbidity associated with

bottle feeding that some doctors think the benefits outweigh the risk of HIV

transmission

Drug contraindications

The following drugs can be given to mothers who are breast feeding:

0


71/84

1)antibiotics: penicillins, cephalosporins, trimethoprim

2)endocrine: glucocorticoids (avoid high doses), levothyroxine*

3)epilepsy: sodium valproate, carbamazepine

4)asthma: salbutamol, theophyllines

5)psychiatric drugs: tricyclic antidepressants, antipsychotics**

6)hypertension: beta-blockers, hydralazine, methyldopa

7)anticoagulants: warfarin, heparin

8)digoxin

The following drugs should be avoided:

• antibiotics: ciprofloxacin, tetracycline, chloramphenicol, sulphonamides

• psychiatric drugs: lithium, benzodiazepines

•

aspirin• carbimazole

• sulphonylureas

• cytotoxic drugs

• amiodarone

*the BNF advises that the amount is too small to affect neonatal hypothyroidism screening

**clozapine should be avoided

ormone relacement theray: indicationsHormone replacement therapy (HRT) involves the use of a small dose of oestrogen,

combined with a progestogen (in women with a uterus), to help alleviate menopausal

1


72/84

symptoms.

The indications for HRT have changed significantly over the past ten years as the long-term

risks became apparent, primarily as a result of the Women's Health Initiative (WHI) study.

Indications:

1)vasomotor symptoms such as flushing, insomnia and headaches

2)premature menopause: should be continued until the age of 50 years

3)osteoporosis: but should only be used as second-line treatment

The main indication is the control of vasomotor symptoms. The other indications such as

reversal of vaginal atrophy and prevention of osteoporosis should be treated with other agents

as first-line therapies

Other benefits include a reduced incidence of colorectal cancer

?ombined oral contraceti6e ill: contraindicationsThe decision of whether to start a women on the combined oral contraceptive pill is now

guided by the UK Medical Eligibility Criteria (UKMEC). This scale categorises the potential

cautions and contraindications according to a four point scale, as detailed below:

UKMEC 1: a condition for which there is no restriction for the use of the contraceptive method

UKMEC 2: advantages generally outweigh the disadvantages

UKMEC 3: disadvantages generally outweigh the advantages

UKMEC 4: represents an unacceptable health risk

Examples of UKMEC 3 conditions include

1)more than 35 years old and smoking less than 15 cigarettes/day

2)BMI > 35 kg/m̂ 2*

3)migraine without aura and more than 35 years old

4)family history of thromboembolic disease in first degree relatives < 45 years

5)controlled hypertension

6)immobility e.g. wheel chair use

7)breast feeding 6 weeks - 6 months postpartum

Examples of UKMEC 4 conditions include

• more than 35 years old and smoking more than 15 cigarettes/day

• migraine with aura

• history of thromboembolic disease or thrombogenic mutation

• history of stroke or ischaemic heart disease

• breast feeding < 6 weeks post-partum

2


73/84

• uncontrolled hypertension

• breast cancer

• major surgery with prolonged immobilisation

Diabetes mellitus diagnosed > 20 years ago is classified as UKMEC 3 or 4 depending on

severity

*The UKMEC 4 rating for a BMI > 40 kg/m̂ 2 was removed in 2009.

Progestogen only ill:Advantages

• highly effective (failure rate = 1 per 100 woman years)

• doesn't interfere with sex

• contraceptive effects reversible upon stopping

• can be used whilst breast-feeding

• can be used in situations where the combined oral contraceptive pill is contraindicatede.g. in smokers > 35 years of age and women with a history of venous thromboembolic

disease

Disadvantages

1)Irregular periods: some users may not have periods whilst others may have irregular or light

periods. This is the most common adverse effect

2)Doesn’t protect against sexually transmitted infections.

3)increased incidence of functional ovarian cysts

4)Common side-effects include breast tenderness, weight gain, acne and headaches. These

symptoms generally subside after the first few months

-amo9i*en• Tamoxifen is a selective estrogen receptor modulator (SERM) which acts as an oestrogen

receptor antagonist and partial agonist.• It is used in the management of oestrogen receptor positive breast cancer

Adverse effects

• menstrual disturbance: vaginal bleeding, amenorrhoea

• hot flushes

• venous thromboembolism

•

endometrial cancer

Tamoxifen is typically used for 5 years following removal of the tumour.

3


74/84

Raloxifene is a pure oestrogen receptor antagonist, and carries a lower risk of endometrial

cancer

)ntibiotics: bactericidal 6sJ bacteriostaticBactericidal antibiotics:

1)penicillins

2)cephalosporins

3)aminoglycosides

4)nitrofurantoin

5)metronidazole

6)quinolones7)rifampicin

8)isoniazid

Bacteriostatic antibiotics

1)chloramphenicol

2)macrolides

3)sulphonamides4)tetracyclines

5)trimethoprim

)ntibiotics: mechanisms o* actionThe lists below summarise the site of action of the commonly used antibiotics

Inhibit cell wall formation:

1)penicillins

2)cephalosporins

4


75/84

Inhibit protein synthesis:

1)aminoglycosides (cause misreading of mRNA)

2)chloramphenicol

3)macrolides (e.g. erythromycin)

4)tetracyclines

5)fusidic acid

Inhibit DNA synthesis:

1)quinolones (e.g. ciprofloxacin)

2)metronidazole

3)sulphonamides

4)trimethoprim

Inhibit RNA synthesis

• rifampicin

Macrolides• Erythromycin was the first macrolide used clinically.

• Newer examples include clarithromycin and azithromycin.

• Macrolides act by inhibiting bacterial protein synthesis.

• If pushed to give an answer they are bacteriostatic in nature, but in reality this depends on

the dose and type of organism being treated.

Adverse effects:

1)Gastrointestinal side-effects are common. Nausea is less common with clarithromycin

than erythromycin

2)cholestatic jaundice: risk may be reduced if erythromycin stearate is used

3)P450 inhibitor (see below)

Common interactions:

5


76/84

Statins should be stopped whilst taking a course of macrolides:

⇒ Macrolides inhibit the cytochrome P450 isoenzyme CYP3A4 that metabolises

statins.

⇒ Taking macrolides concurrently with statins significantly increases the risk of

myopathy and rhabdomyolysis.

Kuinolones• Quinolones are a group of antibiotics which work by inhibiting DNA synthesis.

• They are bactericidal in nature. Examples include:

1)ciprofloxacin

2)levofloxacin


• inhibit topoisomeras II (DNA gyrase) and topoisomerase IV

Adverse effects:

1)lower seizure threshold in patients with epilepsy

2)tendon damage (including rupture) - the risk is increased in patients also taking steroids

3)cartilage damage has been demonstrated in animal models and for this reason quinolones

are generally avoided (but not necessarily contraindicated) in children

Kuinuristin L dal*oristin antibiotics• injectable streptogrammin antibiotic

• combination of group A and group B streptogrammin

• inhibits bacterial protein synthesis by blocking tRNA complexes binding to the ribosome

Spectrum:

• most Gram positive bacteria

• exception: Enterococcus faecalis*

Adverse effects

1)thrombophlebitis (give via a central line)

2)arthralgia

3)P450 inhibitor

*not to be confused with Enterococcus faecium, which is sensitive to Quinupristin & dalfopristin

Antibiotic guidelines

The following is based on current BNF guidelines:

Respiratory system


77/84

Condition Recommended treatment

Exacerbations of chronic

bronchitis

Amoxicillin or tetracycline or clarithromycin

Uncomplicated

community-acquired

pneumonia

Amoxicillin (Doxycycline or clarithromycin in penicillin allergic,

add flucloxacillin if staphylococci suspected e.g. In influenza)

Pneumonia possibly

caused by atypical

pathogens

Clarithromycin

Hospital-acquired

pneumonia

Within 5 days of admission: co-amoxiclav or cefuroxime

More than 5 days after admission: piperacillin with tazobactam

OR a broad-spectrum cephalosporin (e.g. ceftazidime) OR a

quinolone (e.g. ciprofloxacin)

Urinary tract


Lower urinary tractinfection

Trimethoprim or nitrofurantoin. Alternative: amoxicillin orcephalosporin

Acute pyelonephritis Broad-spectrum cephalosporin or quinolone

Acute prostatitis Quinolone or trimethoprim

Skin


Impetigo Topical fusidic acid, oral flucloxacillin or erythromycin if widespread

Cellulitis Flucloxacillin

(clarithromycin or clindomycin if penicillin-allergic)

Erysipelas Phenoxymethylpenicillin (erythromycin if penicillin-allergic)

Animal or human bite Co-amoxiclav (doxycycline + metronidazole if penicillin-allergic)

Mastitis during Flucloxacillin


78/84


79/84


Clostridium difficile First episode: metronidazole

Second or subsequent episode of infection: vancomycin

Campylobacter enteritis Clarithromycin

Salmonella (non-typhoid) Ciprofloxacin

Shigellosis Ciprofloxacin

*a combined topical antibiotic and corticosteroid is generally used for mild/moderate cases of

otitis externa

)nti6iral agentsDru lechanism o action Indications Adperse eectstoicity

Acicfopir • ˜uanosine analog’• phosphorylated by thymidine kinase

–hich in turn inhibits the viral ™šA polymerase

—ž’ ž›ž Crystalline nephropathy

zancicfopir • ˜uanosine analog’• phosphorylated by thymidine kinase

–hich in turn inhibits the viral ™šA polymerase

CMž Myelosuppressionagranulocytosis

|ibapirin • ˜uanosine analog• inhibits inosine monophosphate (IMP)

dehydrogenase’• interferes –ith the capping of viral

Mrna

Chronic hepatitisC’ Rž

—aemolytic anaemia

Amantadine • Inhibits uncoating (M< protein) of

virus in cellF• Also releases dopamine from nerve

endings

Influenza’Parkinson"sdisease

Confusion’ata%ia’slurred speech

}seftamipir Inhibits neuraminidase Influenza

oscarnet • Pyrophosphate analog –hich• inhibits viral ™šA polymerase

CMž’

—ž if notresponding to

šephroto%icity’

hypocalcaemia’hypomagnesaemia’

8


80/84


81/84


82/84

Mesna binds to these metabolites through its sulfhydryl-moieties and reduces the

incidence of haemorrhagic cystitis

2)myelosuppression

3)transitional cell carcinoma

Cytotoxic antibiotics

Cytotoxic Mechanism of action Adverse effects

Bleomycin Degrades preformed DNA Lung fibrosis

Doxorubicin • Stabilizes DNA-topoisomerase II complex

• inhibits DNA & RNA synthesis

Cardiomyopathy

Antimetabolites


Methotrexate • Inhibits dihydrofolate reductase and

• thymidylate synthesis

1)Myelosuppression,

2)mucositis,

3)liver fibrosis,

4)lung fibrosis

Fluorouracil

(5-FU)

• Pyrimidine analogue

• inducing cell cycle arrest and apoptosis by blocking

thymidylatesynthase (works during S phase)

1)Myelosuppression,

2)mucositis,

3)dermatitis

6-

mercaptopurine

• Purine analogue

• activated by HGPRTase, decreasing purine

synthesis

Myelosuppression

Cytarabine • Pyrimidine antagonist.

• Interferes with DNA synthesis specifically at the S-

phase of the cell cycle and inhibits DNA polymerase

1)Myelosuppression,

2)ataxia

Acts on microtubules

2


83/84


Vincristine,

vinblastine

Inhibits formation of microtubules Vincristine:

1)Peripheral neuropathy (reversible) ,

2)paralytic ileus

Vinblastine: myelosuppression

Docetaxel Prevents microtubule

depolymerisation & disassembly,

decreasing free tubulin

Neutropaenia

Other cytotoxic drugsCytotoxic Mechanism of action Adverse effects

Cisplatin Causes cross-linking in DNA 1)Ototoxicity,

2)peripheral neuropathy,

3)hypomagnesaemia

Hydroxyurea

(hydroxycarbamide)

Inhibits ribonucleotide reductase,

decreasing DNA synthesis

Myelosuppression

3


84/84

Documents

0014Clinical Pharmacology Notes 2015