Clinical pharmacology Flashcards
What is the mechanism of action of Quinolones?
Quinolones (e.g. ciprofloxacin) - inhibits DNA synthesis
Inhibit bacterial DNA duplication through inhibition of topoisomerase
What class of antiarrhtymic is disopramide?
Class Ia agent
What are examples of class 1a antiarrthmics?
Quinidine
Procainamide
Disopyramide
Mechanism of action of class Ia antiarrhythmics?
Block sodium channels
Increases AP duration
What are examples of class Ib antiarrhythmics?
Lidocaine
Mexiletine
Tocainide
Mechanism of action of Ib antiarryhtmics?
Block sodium channels
Decreases AP duration
Examples of calss Ic antiarrhythmics?
And mechanism of action
Flecainide
Encainide
Propafenone
Block sodium channels
No effect on AP duration
Mechanism of action of class II antiarrhythmics and mechanism of action?
Propranolol
Atenolol
Bisoprolol
Metoprolol
Beta-adrenoceptor antagonists
Examples of class III antiarrhtymics and mechanism of action ?
Amiodarone
Sotalol
Ibutilide
Bretylium
Block potassium channels
Mechanism of action of class IV antiarrhythmics? and examples?
Verapamil
Diltiazem
Calcium channel blcockers
Mechanism of action of digoxin?
decreases conduction through the atrioventricular node which slows the ventricular rate in atrial fibrillation and flutter
increases the force of cardiac muscle contraction due to inhibition of the Na+/K+ ATPase pump. Also stimulates vagus nerve
digoxin has a narrow therapeutic index
How should digoxin be monitored?
digoxin level is not monitored routinely, except in suspected toxicity
if toxicity is suspected, digoxin concentrations should be measured within 8 to 12 hours of the last dose
Features of digoxin toxicity?
generally unwell, lethargy, nausea & vomiting, anorexia, confusion, yellow-green vision
arrhythmias (e.g. AV block, bradycardia)
gynaecomastia
precipitating factors for digoxin toxicity?
classically: hypokalaemia
digoxin normally binds to the ATPase pump on the same site as potassium. Hypokalaemia → digoxin more easily bind to the ATPase pump → increased inhibitory effects
increasing age
renal failure
myocardial ischaemia
hypomagnesaemia, hypercalcaemia, hypernatraemia, acidosis
hypoalbuminaemia
hypothermia
hypothyroidism
drugs: amiodarone, quinidine, verapamil, diltiazem, spironolactone (competes for secretion in distal convoluted tubule therefore reduce excretion), ciclosporin. Also drugs which cause hypokalaemia e.g. thiazides and loop diuretics
management of digoxin toxicity?
Digibind
correct arrhythmias
monitor potassium
what types of caustic substance may be ingested?
Oxidising agents, e.g. hydrogen peroxide, sodium hypochlorite (found in household bleach)
Strong alkali, e.g. sodium hydroxide, potassium hydroxide (found in dishwasher cleaner, industrial cleaners) -> liquefactive necrosis, more commonly resulting in oesophageal injury
Strong acid, e.g. hydrochloric, nitric acid (found in car batteries, WC cleaner) -> coagulative necrosis, more commonly resulting in gastric injury
How is Caustic substance ingestion managed?
Acute management
A-E assessment
Urgent uppeer GI surgical referral if signs of perforation present (surgical emphysema, medistinal widening on CXR)
Neutralisation of ingested substance (e.g. with milk) should be avoided as the resulting exothermic reaction will release heat and may cause further injury
High dose IV PPI
Symptomatic ingestion (drooling, vomiting, dysphagia, odynophagia, chest pain) requires urgent assessment with upper GI endoscopy to assess the degree of ulceration (Zargar classification). Extensive injury on endoscopy should prompt consideration of urgent surgical exploration
Asymptomatic ingestion can usually be discharged after a trial of oral fluid and a period of observation
Acute complications after caustic substance ingestion?
Upper GI ulceration, perforation
Upper airway injury and compromise
Aspiration pneumonitis
Infection
Electrolyte disturbance (e.g. hypocalcaemia in hydrofluoric acid ingestion)
Acute complications after caustic substance ingestion?Chronic
Strictures, fistulae, gastric outlet obstruction
Upper GI carcinoma (estimated 1000-3000 fold increased risk)
Features of Mercury Poisoning?
paraesthesia
visual field defects
hearing loss
irritability
What is an oculogyric crisis?
A dystonic reaction to certain drugs or medical conditions
Characterized by involuntary upward eye movement
What are the features of an oculogyric crisis?
- Restlessness
- Agitation
- Involuntary upward deviation of the eyes
What are some causes of an oculogyric crisis?
- Antipsychotics
- Metoclopramide
- Postencephalitic Parkinson’s disease
What is the first step in managing an oculogyric crisis?
Cessation of causative medication if possible
Which intravenous antimuscarinic agents can be used in the management of an oculogyric crisis?
- Benztropine
- Procyclidine
What are common symptoms of mercury poisoning?
Visual field defects, hearing loss, paraesthesia
Mercury poisoning often results from ingestion via contaminated food, especially fish and whale.
What is the most common cause of mercury poisoning?
Ingestion via foodstuffs, particularly fish and whale
Fish and whale are known to accumulate mercury in their tissues.
Lead poisoning typically presents with which symptoms?
Abdominal pain, constipation, headaches
These symptoms are indicative of lead exposure and toxicity.
What are the typical symptoms of ethylene glycol poisoning?
Nausea, vomiting, headaches, intoxication, seizures
Ethylene glycol is commonly found in antifreeze and can be highly toxic.
Carbon monoxide poisoning typically presents with which symptoms?
Headache, dizziness, weakness, vomiting, chest pain, confusion
Carbon monoxide is a colorless, odorless gas that can be lethal.
What might an ibuprofen overdose present with?
Abdominal pain, nausea, vomiting, drowsiness, dizziness, headache, ear ringing, nystagmus
Ibuprofen is a common over-the-counter pain reliever.
What are the symptoms associated with lead poisoning?
Abdominal pain, constipation, headaches
These symptoms can vary in severity based on the level of exposure.
Features of Tricyclic overdose?
Early features relate to anticholinergic properties: dry mouth, dilated pupils, agitation, sinus tachycardia, blurred vision.
Features of severe poisoning include:
arrhythmias
seizures
metabolic acidosis
coma
ECG changes in Tricyclic overdose?
ECG changes include:
sinus tachycardia
widening of QRS
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 of Tricyclic overdose?
IV bicarbonate (first line for hypotension or arrhythmias, indications include widening of the QRS interval >100 msec or a ventricular arrhythmia)
intravenous lipid emulsion is increasingly used to bind free drug and reduce toxicity
dialysis is ineffective in removing tricyclics
Methanol poisoning features?
Methanol poisoning causes both the effects associated with alcohol (intoxication, nausea etc) and also 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 of methanol poisoning?
fomepizole (competitive inhibitor of alcohol dehydrogenase) or ethanol
haemodialysis
cofactor therapy with folinic acid to reduce ophthalmological complications
What drugs may cause cataracts?
steroids
what drugs mau cause corneal opacities?
amiodarone
indomethacin
What drugs may cause optic neuritis?
ethambutol
amiodarone
metronidazole
what drugs may cause retinopathy?
chloroquine, quinine
what ocular problems may sildenafil cause?
Sildenafil can cause both blue discolouration and non-arteritic anterior ischaemic neuropathy
Adrenoceptor antagonists?
Alpha antagonists
alpha-1: doxazosin
alpha-1a: tamsulosin - acts mainly on urogenital tract
alpha-2: yohimbine
non-selective: phenoxybenzamine (previously used in peripheral arterial disease)
Beta antagonists
beta-1: atenolol
non-selective: propranolol
Carvedilol and labetalol are mixed alpha and beta antagonists
Examples of alpha antagonists?
alpha-1: doxazosin
alpha-1a: tamsulosin - acts mainly on urogenital tract
alpha-2: yohimbine
non-selective: phenoxybenzamine (previously used in peripheral arterial disease)
Examples of beta antagnoists?
beta-1: atenolol
non-selective: propranolol
examples of mixed alpha and beta antagonists?
Carvedilol and labetalol are mixed alpha and beta antagonists
Paracetamol overdose metabolic pathway?
The liver normally conjugates paracetamol with glucuronic acid/sulphate. 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)
Normally glutathione acts as a defence mechanism by conjugating with the toxin forming the non-toxic mercapturic acid. If glutathione stores run-out, the toxin forms covalent bonds with cell proteins, denaturing them and leading to cell death. This occurs not only in hepatocytes but also in the renal tubules
How doe NAC work in paracetamol overdose?
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
What are the two types of biochemical reactions involved in drug metabolism?
Phase I and Phase II reactions
Phase I reactions include oxidation, reduction, and hydrolysis, while Phase II involves conjugation.
What are the main processes involved in phase I reactions?
Oxidation, reduction, hydrolysis
Mainly performed by P450 enzymes, but some drugs are metabolized by specific enzymes.
What types of products do phase I reactions typically produce?
More active and potentially toxic products
These products can contribute to drug effects and side effects.
What is the main process in phase II reactions?
Conjugation
Products of phase II reactions are typically inactive and excreted.
Where do the majority of phase I and phase II reactions take place?
In the liver
The liver is the primary site for drug metabolism.
What is first-pass metabolism?
A phenomenon where drug concentration is reduced before reaching systemic circulation
This occurs due to hepatic metabolism.
Why do larger oral doses of some drugs need to be administered compared to other routes?
Due to first-pass metabolism
Many drugs undergo significant metabolism before entering systemic circulation.
Name drugs affected by first-pass metabolism.
- Aspirin
- Isosorbide dinitrate
- Glyceryl trinitrate
- lignocaine
- propranolol
- verapamil
- isoprenaline
- testosterone
- hydrocortisone
Many other drugs are also affected.
What is zero-order kinetics?
Metabolism independent of reactant concentration
It occurs when metabolic pathways become saturated.
What is a consequence of zero-order kinetics?
A constant amount of drug is eliminated per unit time
This can affect drug testing results.
Name a drug that exhibits zero-order kinetics.
- Phenytoin
- Salicylates (e.g., high-dose aspirin)
- Heparin
- Ethanol
These drugs show unique elimination patterns.
What percentage of the UK population is deficient in hepatic N-acetyltransferase?
50%
This status affects drug metabolism in certain individuals.
Name a drug affected by acetylator status.
- Isoniazid
- Procainamide
- Hydralazine
- Dapsone
- Sulfasalazine
These drugs can have altered effects based on acetylator status.
Mechanism of action and side effects of Rifampicin?
mechanism of action: inhibits bacterial DNA dependent RNA polymerase preventing transcription of DNA into mRNA
potent liver enzyme inducer
hepatitis, orange secretions
flu-like symptoms
Mechanism of action and sife effects of Isoniazid?
mechanism of action: inhibits mycolic acid synthesis
peripheral neuropathy: prevent with pyridoxine (Vitamin B6)
hepatitis, agranulocytosis
liver enzyme inhibitor
Mechanism of action and side effects of pyrazinamide?
mechanism of action: converted by pyrazinamidase into pyrazinoic acid which in turn inhibits fatty acid synthase (FAS) I
hyperuricaemia causing gout
arthralgia, myalgia
hepatitis
Mechanism of action and side effects of ethambutol ?
mechanism of action: inhibits the enzyme arabinosyl transferase which polymerizes arabinose into arabinan
optic neuritis: check visual acuity before and during treatment
dose needs adjusting in patients with renal impairment
TB management side effects?
What is the mechanism of action of ocreatide?
long-acting analogue of somatostatin
somatostatin is released from D cells of pancreas and inhibits the release of growth hormone, glucagon and insulin
What is ocreotide used for?
acute treatment of variceal haemorrhage
acromegaly
carcinoid syndrome
prevent complications following pancreatic surgery
VIPomas
refractory diarrhoea
Adverse effects of ocreotide?
gallstones (secondary to biliary stasis)
Heprin vs LMWH
Administration
duration of action
mechanism of action
Side effects
monitoring
What is Trastuzumab ?
Trastuzumab (Herceptin) is a monoclonal antibody directed against the HER2/neu receptor. It is used mainly in metastatic breast cancer although some patients with early disease are now also given trastuzumab.
What are the adverse effects of Trastuzumab?
Adverse effects
flu-like symptoms and diarrhoea are common
cardiotoxicity
more common when anthracyclines have also been used
an echo is usually performed before starting treatment
What is Acute intermittent porphyria?
Acute intermittent porphyria (AIP) is an autosomal dominant condition caused by a defect in porphobilinogen deaminase, an enzyme involved in the biosynthesis of haem. It characteristically presents with abdominal and neuropsychiatric symptoms in 20-40 year olds. AIP is more common in females (5:1)
What drugs may precipitate and attack of acute intermittent porphyria?
barbiturates
halothane
benzodiazepines
alcohol
oral contraceptive pill
sulphonamides
