stats/pharm Flashcards
malignant hyperthermia
Malignant hyperthermia (MH) or malignant hyperpyrexia is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia; specifically, the volatile anesthetic agents and the neuromuscular blocking agent, succinylcholine.
In susceptible individuals, these drugs can induce a drastic and uncontrolled increase in skeletal muscle oxidative metabolism, which overwhelms the body’s capacity to supply oxygen, remove carbon dioxide, and regulate body temperature, eventually leading to circulatory collapse and death if not treated quickly.
Malignant hyperthermia is most commonly due to volatile anesthetic gases, such as halothane, sevoflurane, desflurane or the depolarizing muscle relaxant succinylcholine used primarily in general anesthesia
Malignant hyperthermia’s inheritance is autosomal dominant.
The propensity for malignant hyperthermia is due to a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum (SR)
A 1994 consensus conference led to the formulation of a set of diagnostic criteria. The higher the score (above 6), the more likely a reaction constituted MH:
- Respiratory acidosis (end-tidal CO2 above 55 mmHg/7.32 kPa or arterial pCO2 above 60 mmHg/7.98 kPa)
- Heart involvement (unexplained sinus tachycardia, ventricular tachycardia or ventricular fibrillation)
- Metabolic acidosis (base excess lower than -8, pH <7.25)
- Muscle rigidity (generalized rigidity including severe masseter muscle rigidity)
- Muscle breakdown (CK >20,000/L units, cola colored urine or excess myoglobin in urine or serum, potassium above 6 mmol/l)
- Temperature increase (rapidly increasing temperature, T >38.8C)
- Other (rapid reversal of MH signs with dantrolene, elevated resting serum CK levels)
- Family history (autosomal dominant pattern)
Treatment:
1) Treatment of choice is intravenous administration of dantrolene, the only known antidote.
2) Discontinuation of triggering agents
3) Supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction.
Dantrolene is a muscle relaxant that appears to work directly on the ryanodine receptor to prevent the release of calcium. After the widespread introduction of treatment with dantrolene, the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%. Dantrolene remains as the only drug known to be effective in the treatment of MH
macrolide
Macrolide causes airway modulation by 3 main mechanisms:
1) Anti-inflammatory activity is mediated by inhibition of neutrophil chemotaxis, reduction of neutrophil elastase and modification of pro-inflammatory cytokines with suppression of interleukin IL-1ß, IL-6, IL-8 and tumour necrosis factor (TNF) production.
2) Macrolides may reduce sputum viscoelasticity, airway adhesion of P. aeruginosa, and increase the killing of mucoid P. aeruginosa, by their ability to disrupt the integrity of the protective biofilm and impair the transformation of non-mucoid P. aeruginosa to the more virulent mucoid phenotype
3) Low dose azithromycin has been shown to improve macrophage function, reduce neutrophil counts in the bronchial lavage fluid and reduce pulmonary tissue damage by impairing superoxide generation by activated neutrophils.
omeprazole
hypomagnesaemia
Protein binding may be lower in the following situations
1) neonates and hyperbilirubinaemic infants
2) hypoalbuminaemia as seen in chronic liver failure
3) uraemia as seen in chronic renal failure
4) acute trauma
5) pregnancy.
formulas
Volume of distribution determines loading dose
(Loading dose = Vd x Target plasma concentration)
Clearance determines maintenance dose
(Maintenance dose= Clearance x Steady state drug concentration)
Bioavailability = 1 – hepatic extraction ratio (HER) HER = total clearance of drug by liver / total liver blood flow
Half life(T 1/2)= 0.693 x Vd/Cl. Cl= 0.693 x Vd/half life. Vd= dose/peak plasma concentration
reverse hysteresis loop or reverse tachyphylaxis (anti-clockwise)
This can be due to either the
- drug having active metabolites like codeine or
- there is increase delivery of the drug to the tissues like with Digoxin.
Hysteresis loop.(Clockwise)
Concept of tachyphylaxis is a term used to describe a rapid decrease in the response to a drug due to previous (long term) exposure to that drug.
Increasing the dose of the drug will not increase the pharmacological response.
In other words, over time, the person will get less effect for the same concentration of drug.
Usually seen in drug of abuse such as amphetamine,cocaine or pseudoephedrine.
serotonin syndrome
1) hyperpyrexia
2) impaired conscious level or agitation
3) Increased muscle tone and clonus.
4) often associated with an elevated creatine kinase level.
Features of serotonin toxicity may also occur if the patient has co-ingested other drugs that increase the effect of serotonin, or is taking one of these drugs therapeutically.
Such drugs include selective serotonin reuptake inhibitors (SSRIs), venlafaxine, monoamine oxidase inhibitors, amphetamines, cocaine, MDMA (ecstasy), linezolid, tramadaol, or triptans.
Neuroleptic malignant syndrome
A mnemonic used to remember the features of NMS is FALTER:
- F – Fever
- A – Autonomic instability
- L – Leukocytosis
- T – Tremor
- E – Elevated enzymes (elevated CPK)
- R – Rigidity of muscles
Neuroleptic malignant syndrome (NMS) is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. It generally presents with muscle rigidity, fever, autonomic instability and cognitive changes such as delirium, and is associated with elevated creatine phosphokinase (CPK)
It has been reported that individuals using haloperidol and chlorpromazine are at greatest risk.
The mechanism is thought to depend on decreased levels of dopamine activity due to Dopamine receptor blockade and Genetically reduced function of dopamine receptor D2.
NMS is an emergency, and can lead to death if untreated.
Treatment: – stop neuroleptic drugs – treat hyperthermia aggressively – use Benzodiazepines to control agitation – aggressive hydration
NAC ; PCM Overdose
NAC should also be started immediately or empirically when:
- patients present 8 hours or more after ingestion
- serum paracetamol level is not available within an 8-hour time window
- there is uncertainty as to the timing of the overdose
- patients are unconscious or have a suspected overdose
High-risk factors are those that may exacerbate paracetamol toxicity and include ethanol use, liver disease, CYP 450 inductors, malnutrition, HIV infection, and cystic fibrosis.
level of evidence
Ia- evidence from meta-analysis of randomised controlled trials
Ib- evidence from at least one randomised controlled trial
IIa- evidence from at least one well designed controlled trial which is not randomised.
IIb- evidence from at least one well designed experimental trial
III- evidence from case, correlation and comparative studies.
IV- evidence from a panel of experts.
Grade of recommendations:
Grade A- based on evidence from at least once RCT (Ia,Ib)
Grade B- based on evidence from non-RCT (IIa,IIb,III)
Grade C- based on evidence from a panel of experts (IV).
Intention-To-Treat Analysis
minimise selection bias from cross-over
- Therefore ITT analysis ALWAYS under-estimates any treatment effect
error
A type I error (also known as alpha) is the probability of incorrectly concluding that there is a statistically significant difference in a dataset.Alpha is the number after a p-value
Thus a statistically significant difference reported as p
A type II error (also known as beta) is the probability of incorrectly concluding that there was no statistically significant difference in a dataset.
This error often reflects insufficient power of the study.
The term power(calculated as 1- beta) refers to the ability of a study to detect a true difference.
Negative findings in a study may reflect that the study was underpowered to detect a difference.
Power increases with increase in sample size.
Formulas
Vd = given dose / plasma conc
Vd = (cl * t1/2) / 0.7
Cl = (Vd * 0.7) / t 1/2
t 1/2 = (Vd * 0. 7) / Cl
