Clinical Pharmacology Flashcards
What are inhibitors of the p450 enzyme system?
Inhibitors of the P450 system include
antibiotics: ciprofloxacin, erythromycin
isoniazid
cimetidine,omeprazole
amiodarone
allopurinol
imidazoles: ketoconazole, fluconazole
SSRIs: fluoxetine, sertraline
ritonavir
sodium valproate
acute alcohol intake
quinupristin
What are inducers of the P450 enzyme system?
Induction usually requires prolonged exposure to the inducing drug, as opposed to P450 inhibitors where effects are seen rapidly
Inducers of the P450 system include
antiepileptics: phenytoin, carbamazepine
barbiturates: phenobarbitone
rifampicin
St John’s Wort
chronic alcohol intake
griseofulvin
smoking (affects CYP1A2, reason why smokers require more aminophylline)
How does carbamazepine reduce the efficiency of the COC pill?
Carbamazepine is a P450 enzyme inducer. Ethinylestradiol is used in the combined oral contraceptive (COC) pill and is a substrate of the CYP3A4 P450 isoenzyme system. Inducers of the P450 enzymes increase the speed of the breakdown of ethinylestradiol and reduce the efficacy of the COC pill.
what is Ethylene glycol and what are the stages of toxicity ?
Ethylene 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 kidney injury
What is the management of Ethylene Glycol toxicity?
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
fomepizole, an inhibitor of alcohol dehydrogenase, is now used first-line in preference to ethanol
haemodialysis also has a role in refractory cases
How does fomepizole work in Ethylene glycol toxicity?
fomepizole acts as a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase is the primary enzyme responsible for metabolising ethylene glycol into its toxic metabolites, including glycoaldehyde and glycolic acid. By competitively inhibiting this enzyme, fomepizole prevents the formation of these harmful substances and allows the body to excrete unmetabolised ethylene glycol via renal elimination.
which antibiotics inhibit cell wall formation?
> peptidoglycan cross-linking: penicillins, cephalosporins, carbopenems
> peptidoglycan synthesis: glycopeptides (e.g. vancomycin)
Which antibiotics inhibit protein synthesis?
> 50S subunit: macrolides, chloramphenicol, clindamycin, linezolid, streptogrammins
30S subunit: aminoglycosides, tetracyclines
What antibiotics inhibit DNA synthesis?
quinolones (e.g. ciprofloxacin)
What antibiotic damage DNA?
Metronidazole
What antibiotics inhibit folic acid formation ?
sulpohonamides
trimethoprim
What antibiotics inhibit RNA synthesis?
Rifampicin
what is the mechanism of action of teicoplanin?
Teicoplanin is similar to vancomycin (e.g. a glycopeptide antibiotic), but has a significantly longer duration of action, allowing once daily administration after the loading dose
what is the criteria for liver transplantation in paracetamol liver failure?
Arterial pH < 7.3, 24 hours after ingestion
or all of the following:
prothrombin time > 100 seconds
creatinine > 300 µmol/l
grade III or IV encephalopathy
How is paracetamol overdose managed?
The minority of patients who present within 1 hour may benefit from activated charcoal to reduce absorption of the drug.
Acetylcysteine should be given if:
the plasma paracetamol concentration is on or above a single treatment line joining points of 100 mg/L at 4 hours and 15 mg/L at 15 hours, regardless of risk factors of hepatotoxicity
there is a staggered overdose* or there is doubt over the time of paracetamol ingestion, regardless of the plasma paracetamol concentration; or
patients who present 8-24 hours after ingestion of an acute overdose of more than 150 mg/kg of paracetamol even if the plasma-paracetamol concentration is not yet available
patients who present > 24 hours if they are clearly jaundiced or have hepatic tenderness, their ALT is above the upper limit of normal
acetylcysteine should be continued if the paracetamol concentration or ALT remains elevated whilst seeking specialist advice
Why is acetycysteine given over 1 hour now instead of 15 minutes?
Acetylcysteine is now infused over 1 hour (rather than the previous 15 minutes) to reduce the number of adverse effects.
What is the common reaction to Acetylcysteine?
Acetylcysteine commonly causes an anaphylactoid reaction (non-IgE mediated mast cell release). Anaphylactoid reactions to IV acetylcysteine are generally treated by stopping the infusion, then restarting at a slower rate.
Why should you not give hypotonic intravenous fluids to children?
In paediatric patients, there are at higher risk of hyponatraemic encephalopathy. This is most noted in those who receive hypotonic intravenous fluids such as 0.45% sodium chloride.
what drugs commonly cause urticaria?
aspirin
penicillin
NSAIDs
Opiates
what is the mechanism of action of unfractionated heparin?
Unfractionated heparin activates antithrombin III, forms a complex that inhibits thrombin, factors Xa, Ixa, Xia and XIIa
What’s the action of LMWH?
increases the action of antithrombin III on factor Xa
What is HIT?
Heparin-induced thrombocytopaenia (HIT)
> immune mediated - antibodies form against complexes of platelet factor 4 (PF4) and heparin
> these antibodies bind to the PF4-heparin complexes on the platelet surface and induce platelet activation by cross-linking FcγIIA receptors
> usually does not develop until after 5-10 days of treatment
> despite being associated with low platelets HIT is actually a prothrombotic condition
> features include a greater than 50% reduction in platelets, thrombosis and skin allergy
> address need for ongoing anticoagulation:
direct thrombin inhibitor e.g. argatroban
danaparoid
How can heparin overdose be reversed?
Heparin overdose may be reversed by protamine sulphate, although this only partially reverses the effect of LMWH.
What is IVIG used for?
primary and secondary immunodeficiency
idiopathic thrombocytopenic purpura
myasthenia gravis
Guillain-Barre syndrome
Kawasaki disease
toxic epidermal necrolysis
pneumonitis induced by CMV following transplantation
low serum IgG levels following haematopoietic stem cell transplant for malignancy
dermatomyositis
chronic inflammatory demyelinating polyradiculopathy
What antibiotic is contraindicated in G6PD deficiency?
Ciprofloxacin is contraindicated in G6PD deficiency.
It can lead to potentially fatal haemolytic anaemia
What is the target of rituximab?
What is it effective in treating?
Rituximab - monoclonal antibody against CD20 antigen on B lymphocytes.
It binds to the CD20 molecules on the surface of these cells leading to cell death either through complement-dependant cytoxicity or antibody-dependant cellular toxicity.
his makes rituximab effective in treating diseases characterised by excessive, malignant, or dysfunctional B cells such as non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia.
It is also used in the treatment of rheumatoid arthritis
How are monoclonal antibodies manufactured?
somatic cell hybridisation
this involves the fusion of myeloma cells with spleen cells from a mouse that has be immunised with the desired antigen. The resulting fused cells are termed a hybridoma and act as a factory for producing monoclonal antibodies
what is one limitation of monoclonal antibodies?
The main limitation to this is that mouse antibodies are immunogenic leading to the formation of human anti-mouse antibodies. This problem is overcome by a process known as humanising. One method involves combining the variable region from the mouse body with the constant region from a human antibody.
What is the action of Infliximab and what is it used in ?
infliximab (anti-TNF): used in rheumatoid arthritis and Crohn’s
What is the action of cetuximab and what is it used in?
cetuximab (epidermal growth factor receptor antagonist): used in metastatic colorectal cancer and head and neck cancer
what is the action of trastuzumab and what is it used in?
trastuzumab (HER2/neu receptor antagonist): used in metastatic breast cancer
what is the action of alemtuzumab and what is used in?
alemtuzumab (anti-CD52): used in chronic lymphocytic leukaemia
what is the action of abciximab and what is it used in?
abciximab (glycoprotein IIb/IIIa receptor antagonist): prevention of ischaemic events in patients undergoing percutaneous coronary interventions
what is the action of OKT3 and what is it used in?
OKT3 (anti-CD3): used to prevent organ rejection
Which patients are at risk of developing hepatoxocity following paracetamol overdose?
patients taking liver enzyme-inducing drugs (rifampicin, phenytoin, carbamazepine, chronic alcohol excess, St John’s Wort)
malnourished patients (e.g. anorexia nervosa) or patients who have not eaten for a few days
what may actually be protective against developing hepatotoxicity?
Interestingly, acute alcohol intake, as opposed to chronic alcohol excess, is not associated with an increased risk of developing hepatotoxicity and may actually be protective.
how does metformin cause b12 deficiency?
by altering small bowel motility, leading to bacterial overgrowth and deconjugation of bile salts, which in turn impairs B12 absorption.
what is the mechanism of action of metformin?
acts by activation of the AMP-activated protein kinase (AMPK)
increases insulin sensitivity
decreases hepatic gluconeogenesis
may also reduce gastrointestinal absorption of carbohydrates
what are the adverse effects of metformin?
gastrointestinal upsets are common (nausea, anorexia, diarrhoea), intolerable in 20%
reduced vitamin B12 absorption - rarely a clinical problem
lactic acidosis with severe liver disease or renal failure
it is now increasingly recognised that lactic acidosis secondary to metformin is rare, although it remains important in the context of exams
what are the contraindications to metformin?
CKD - it should be reviewed if creatinine is > 130ummol/l or eGFR < 45 and stopped if the creatinine is > 150 µmol/l (or eGFR < 30 ml/min)
metformin may cause lactic acidosis if taken during a period where there is tissue hypoxia. Examples include a recent myocardial infarction, sepsis, acute kidney injury and severe dehydration
iodine-containing x-ray contrast media: examples include peripheral arterial angiography, coronary angiography, intravenous pyelography (IVP); there is an increasing risk of provoking renal impairment due to contrast nephropathy; metformin should be discontinued on the day of the procedure and for 48 hours thereafter
alcohol abuse is a relative contraindication
What are the clinical features of ecstasy poisoning?
neurological: agitation, anxiety, confusion, ataxia
cardiovascular: tachycardia, hypertension
hyponatraemia
this may result from either syndrome of inappropriate ADH secretion or excessive water consumption whilst taking MDMA
hyperthermia
rhabdomyolysis
Hyperthermia
How does Ecstasy cause hyperthermia?
occurs due to increased serotonin release in the hypothalamus, which regulates body temperature. Additionally, the use of ecstasy in club settings where users are dancing and overheating can exacerbate this effect.
How is ecstasy poisoning managed?
supportive
dantrolene may be used for hyperthermia if simple measures fail
What is the pathophysiology of carbon monoxide poisoning?
Carbon monoxide has a high affinity for haemoglobin and myoglobin resulting in a left-shift of the oxygen dissociation curve and tissue hypoxia.
Pathophysiology
carbon monoxide binds readily to haemoglobin, forming carboxyhaemoglobin → reduced oxygen-carrying capacity
in carbon monoxide poisoning the oxygen saturation of haemoglobin decreases leading to an early plateau in the oxygen dissociation curve
What are the features of carbon monoxide poisoning?
headache: 90% of cases
nausea and vomiting: 50%
vertigo: 50%
confusion: 30%
subjective weakness: 20%
severe toxicity: ‘pink’ skin and mucosae, hyperpyrexia, arrhythmias, extrapyramidal features, coma, death
How do you investigate for carbon monoxide poisoning?
pulse oximetry may be falsely high due to similarities between oxyhaemoglobin and carboxyhaemoglobin
therefore a venous or arterial blood gas should be taken
typical carboxyhaemoglobin levels
< 3% non-smokers
< 10% smokers
10 - 30% symptomatic: headache, vomiting
> 30% severe toxicity
an ECG is a useful supplementary investgation to look for cardiac ischaemia
How do you manage carbon monoxide poisoning?
100% high-flow oxygen via a non-rebreather mask
from a physiological perspective, this decreases the half-life of carboxyhemoglobin (COHb)
should be administered as soon as possible, with treatment continuing for a minimum of six hours
target oxygen saturations are 100%
treatment is generally continued until all symptoms have resolved, rather than monitoring CO levels
hyperbaric oxygen
due to the small number of cases the evidence base is limited, but there is some evidence that long-term outcomes may be better than standard oxygen therapy for more severe cases
therefore, discussion with a specialist should be considered for more severe cases (e.g. levels > 25%)
in 2008, the Department of Health publication ‘Recognising Carbon Monoxide Poisoning’ also listed loss of consciousness at any point, neurological signs other than headache, myocardial ischaemia or arrhythmia and pregnancy as indications for hyperbaric oxygen
What is the mechanism of action of Aspirin?
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
Why can rifampicin decrease the INR in patients taking warfarin
Rifampicin is a potent inducer of the cytochrome P450 enzyme system, which is responsible for the metabolism of warfarin. This induction leads to an increased clearance of warfarin and thus, a decreased INR.
Side effects of calcium channel blockers?
- Headache
- Flushing
- Ankle oedema
Verapamil also commonly causes constipation
what are the side effects of beta blockers?
- Bronchospasm (especially in asthmatics)
- Fatigue
- Cold peripheries
- Sleep disturbances
Side effects of nitrates?
Headache
* Postural hypotension
* Tachycardia
Side effects of Nicorandil?
- Headache
- Flushing
- Anal ulceration
What is MDMA?
Ecstasy (MDMA, 3,4-Methylenedioxymethamphetamine) use became popular in the 1990’s during the emergence of dance music culture.
Clinical features of Ecstasy poisoning?
Clinical features
neurological: agitation, anxiety, confusion, ataxia
cardiovascular: tachycardia, hypertension
hyponatraemia
this may result from either syndrome of inappropriate ADH secretion or excessive water consumption whilst taking MDMA
hyperthermia
rhabdomyolysis
Management of Ecstasy Poisoning?
Management
supportive
dantrolene may be used for hyperthermia if simple measures fail
What is a muscarinic agonist eye drop?
Pilocarpine - used in glaucoma
P450 enzyme system inducers - lower concentrations of warfarin?
antiepileptics: phenytoin, carbamazepine
barbiturates: phenobarbitone
rifampicin
St John’s Wort
chronic alcohol intake
griseofulvin
smoking (affects CYP1A2, reason why smokers require more aminophylline)
P450 enzyme system inhibitors - increase concentrations of warfarin?
antibiotics: ciprofloxacin, erythromycin
isoniazid
cimetidine,omeprazole
amiodarone
allopurinol
imidazoles: ketoconazole, fluconazole
SSRIs: fluoxetine, sertraline
ritonavir
sodium valproate
acute alcohol intake
quinupristin
Drugs to avoid in renal failure?
antibiotics: tetracycline, nitrofurantoin
NSAIDs
lithium
metformin
Drugs that will accumulate in CKD - may need dose adjustment?
most antibiotics including penicillins, cephalosporins, vancomycin, gentamicin, streptomycin
digoxin, atenolol
methotrexate
sulphonylureas
furosemide
opioids
mechanism of action of standard heparin and LMHWH?
Heparin:
Activates antithrombin III. Forms a complex that inhibits thrombin, factors Xa, IXa, Xia and XIIa
LMWH
Activates antithrombin III. Forms a complex that inhibits factor Xa
mechanisms of action of allopurinol?
Allopurinol is used in the prevention of gout. It works by inhibiting xanthine oxidase.
when is allopurinol indicated?
the British Society of Rheumatology Guidelines now advocate offering urate-lowering therapy to all patients after their first attack of gout
ULT is particularly recommended if:
>= 2 attacks in 12 months
tophi
renal disease
uric acid renal stones
prophylaxis if on cytotoxics or diuretics
patients with Lesch-Nyhan syndrome often take allopurinol for life
Adverse effects of allopurinol?
The most significant adverse effects are dermatological and patients should be warned to stop allopurinol immediately if they develop a rash:
severe cutaneous adverse reaction (SCAR)
drug reaction with eosinophilia and systemic symptoms (DRESS)
Stevens-Johnson syndrome
Certain ethnic groups such as the Chinese, Korean and Thai people seem to be at an increased risk of these dermatological reactions.
Patients at a high risk of severe cutaneous adverse reaction should be screened for the HLA-B *5801 allele.
What medications does allopurinol interact with?
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
Cyclophosphamide - allopurinol reduces renal clearance, therefore may cause marrow toxicity
Theophylline - allopurinol causes an increase in plasma concentration of theophylline by inhibiting its breakdown
Mechanism of action of ketamine?
NMDA receptor antagonist
Uses of Ketamine?
May be used for induction of anaesthesia
Has moderate to strong analgesic properties
Produces little myocardial depression making it a suitable agent for anaesthesia in those who are haemodynamically unstable
May induce state of dissociative anaesthesia resulting in nightmares
Mechanism of action of propofol?
GABA receptor antagonist
when may sodium thiopentone be used ?
Extremely rapid onset of action making it the agent of choice for rapid sequence of induction
Marked myocardial depression may occur
Metabolites build up quickly
Unsuitable for maintenance infusion
Little analgesic effects
What is heparin induced thrombocytopenia?
immune mediated - antibodies form against complexes of platelet factor 4 (PF4) and heparin
these antibodies bind to the PF4-heparin complexes on the platelet surface and induce platelet activation by cross-linking FcγIIA receptors
usually does not develop until after 5-10 days of treatment
despite being associated with low platelets HIT is actually a prothrombotic condition
features include a greater than 50% reduction in platelets, thrombosis and skin allergy
address need for ongoing anticoagulation:
direct thrombin inhibitor e.g. argatroban
danaparoid
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
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
why does rifampicin reduce effectiveness of COCP?
Rifampicin is correct. Of this patient’s regular medications, rifampicin is the only enzyme inducer. Induction of the P450 enzyme system results in faster metabolism and clearance of the contraceptive pill, reducing its effectiveness.
what are the different types of amiodarone induced thyroxicosis ?
AIT type 1 - Excess iodine-induced thyroid hormone synthesis, Goitre present
Management - Carbimazole or potassium perchlorate
AIT type 2 - Amiodarone-related destructive thyroiditis
Goitre - absent
Management - corticosteroids
pathophysiology of amiodarone induced hypothyroidism?
The pathophysiology of amiodarone-induced hypothyroidism (AIH) is thought to be due to the high iodine content of amiodarone causing a Wolff-Chaikoff effect - an autoregulatory phenomenon where thyroxine formation is inhibited due to high levels of circulating iodide
Amiodarone may be continued if this is desirable
what drugs commonly cause urticaria?
aspirin
penicillins
NSAIDs
opiates
What are phosphodiesterase type V inhibitors?
Phosphodiesterase type V (PDE5) inhibitors are used in the treatment of erectile dysfunction. They are also used in the management of pulmonary hypertension. PDE5 inhibitors cause vasodilation through an increase in cGMP leading to smooth muscle relaxation in blood vessels supplying the corpus cavernosum.
Examples
sildenafil (Viagra)
this was the first phosphodiesterase type V inhibitor
short-acting - usually taken 1 hour before sexual activity
tadalafil (Cialis)
longer acting than sildenafil, may be taken on a regular basis (e.g. once daily)
vardenafil (Levitra)
What are the contraindications of phosphodiesterase type V inhibitors?
patients taking nitrates and related drugs such as nicorandil
hypotension
recent stroke or myocardial infarction (NICE recommend waiting 6 months)
Side effects of Phosphodiesterase type V (PDE5) inhibitors
visual disturbances
blue discolouration
non-arteritic anterior ischaemic neuropathy
nasal congestion
flushing
gastrointestinal side-effects
headache
priapism
Motion sickness - management?
occurs when an apparent discrepancy exists between visually perceived movement and the vestibular systems sense of movement
Management
the BNF recommends hyoscine (e.g. transdermal patch) as being the most effective treatment. Use is limited due to side-effects
non-sedating antihistamines such as cyclizine or cinnarizine are recommended in preference to sedating preparation such as promethazine
Antiarrhythmics: Vaughan Williams classification
Ia - quinidine, Procainamide, Disopyramide (blocks sodium channels - increases AP duration)
Ib - lidocaine, Mexiletine, Tocainide (Block sodium channels - decreases AP duration)
Ic - flecainide, Ecainid, propafenone (block sodium channels - no effect onAP duration)
II - propranolol, atenolol, bisoprolol, metoprolol (Beta-adrenoceptor antagonists)
III - amioderone, sotalol, Ibutilide, Bretylium (block potassium channels)
IV - Verapamil, Diltiazem (CCB)
