Drug Metabolism and Interactions (adverse effects) Flashcards
What are the statistics for death from adverse drug effects?
4th leading cause of death. Drug poisoning accounting for 65.8 deaths per 1 million population in 2016 in UK. 1 in 7 deaths among people in their 20s and 30s.
In hospitalisation, what is the incidence of adverse effects?
2.9 - 3.7% of hospitalisations involve adverse events Adverse events occur in 10-20% of hospitalized patients. 7% of those in ambulatory setting
What are type A and type B adverse drug reactions?
TYPE A = pharmacological or toxic effect
TYPE B = idiosyncrasy or drug allergy
What is typical pharmacopeia (drugs) in the dental practice? (4)
sedative
LA
analgesic
antibiotic
What is the therapeutic index?
It compares the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity
The therapeutic effects of a drug are found in all doses between the minimum effective concentration and the minimum toxic concentration.
Below the minimum effective conc the drug gives sub-therapeutic effects, and above the minimum toxic conc it gives toxic effects.
Is the therapeutic index consistent among substances?
No it varies widely.
What are some drugs with low therapeutic index? (3)
Anticoagulant (i.e. warfarin) Aminoglycoside antibiotics (i.e. gentamicin) Anticonvulsants (i.e. phenytoin)
Can the therapeutic index vary among opioid analgesics?
YES Remifentanyl = 33000:1 Morphine = 70:1
What are the factors that can cause adverse drug effects?
Circumstances: accidental or deliberate overdose. These give normal therapy side effects
Site of Action: Localized aspirin ( can cause mouth ulcers, GI irritation). Systemic Majority of reactions.
Time Course
- Acute toxicity- single intake/rapid onset
- Narcotics (i.e. respiratory depression)
- Sub-acute toxicity-repeated exposure (hours/days)
- Tetracycline (i.e. renal impairment)
- Chronic toxicity- repeated exposure (months/years)
- Chemical carcinogenesis
Mechanisms
- type A (for augmented)
- type B (for bizarre)
What can localised aspirin intake cause?
Mouth ulcers and GI irritation
What can tetracycline cause after repeated exposure?
renal impairment
Explain the difference between type A and type B mechanisms and their adverse consequences?
Type A (for Augmented - exaggerated response)
- Exaggerated therapeutic responses
- Secondary unwanted actions
- More predictable or anticipated effects
Type B (for Bizarre)
- Pharmacologically unexpected, unpredictable, or idiosyncratic adverse reactions
- Can be immunologic (Allergic or anaphylactic)
- Can be idiosyncratic (Qualitatively abnormal adverse reactions that occur in a given individual and whose mechanism is not yet understood)
What are the major and minor concerns with type A reactions? Which drugs are most lilely to cause these concerns?
Major concerns
- Respiratory depression (i.e. narcotic agents)
- Cardiac toxicity (i.e. overdose of intravascular injection of local anesthetic)
Minor concerns
- Diarrhea (Broad spectrum antibiotics)
- Dry mouth (Anticholinergics i.e. antidepressant)
- Drowsiness (CNS drugs i.e. benzodiazepines)
With type A reactions, what is the link between dose and risk of side effects?
Higher dose = higher possibility of side effects.
Which patient situations are risk situations for type A reactions to occur?
- Childhood
- Elderly
- Pregnancy
- Lactation
- Renal failure
- Haemodialysis
What stage of pharmacokinetics (ADME) can type A reactions occur at?
ALL OF THEM - each step is a target for adverse effect
Describe the effects of tetracycline on the absorption and distribution stages of pharmacokinetics?
Absorption reduced by chelation of drugs/food/vitamins/divalent cations (i.e. milk)
Distribution sequestration of tetracycline in bone (tissue binding) leading to depression of bone growth in children and irreversible staining of tooth enamel
So, who should tetracycline NOT be prescribed to?
pregnant women and children under 12
What should you take tetracycline with instead of on an empty stomach?
Al(OH)3 gel or with milk
Antiacids and iron preparation decrease absorption by chelation
How can the metabolism stage of pharmacokinetics be affected by drugs?
Some important preventable drug interactions are due to their effects on drug metabolizing enzymes, resulting in either inhibition of the enzyme or induction of the enzyme.
Diseases may alter drug metabolism (i.e. renal and hepatic dysfunction)
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation
Polypharmacy introduces the risk of drug interactions
How can the renal excretion phase of pharmacokinetics be affected by drugs?
Renal excretion of drugs mainly controlled by: glomerular filtration, tubular secretion and tubular reabsorption.
Factors affecting renal excretion of drugs include: kidney function, protein binding, urine pH and urine flow.
Impaired renal function may lead to clinically significant accumulation of drugs eliminated by the kidneys.
What are some examples of type B reactions?
Anaphylaxis, Stevens-Johnson syndrome, Blood dyscrasias, Hepatitis.
What are the features of a type B adverse reaction?
- No dose relationship
- Unexpected
- Mechanism uncertain
- Causality uncertain
- Not reproducible
- Characteristic, serious
- Suggestive time relationship
- Low background frequency
- Immunoallergic reactions
- Pseudoallergy
- Metabolic intolerance
- Idiosyncrasy
Is type A or type B reaction pharmacologically predictable?
type A
Is type A or type B reaction dose dependent?
type A
Is it type A or type B reaction with a high incidence and morbidity?
type A
Is it type A or type B reaction with a high mortality?
Type B
What are the treatments if type A / B reactions occur?
type A = decrease dose
type B = stop the drug
What are many type A or type B reactions due to?
the conversion of drugs in active metabolites
What is valproic acid used for? What are its effects in pregnant women?
It is an antiepileptic used to control certain types of seizures.
Can cause fetal valproate syndrome (FVS) - baby born has broad forehead, flat nasal bridge, long philtrum, thin upper lip, short anteverted nose and epicanthal folds.
What are the characteristics of a drug allergy?
- Delay after initial exposure
- Caused with small doses of drug
- Does not resemble normal pharmacology
- Classical symptoms of allergic response
Which 2 factors can cause drug allergy? Give examples of each factor?
Drug-related factors
- Nature of the drug
- Degree of exposure (dose, duration, frequency and repeated administration)
- Route of administration (i.e. allergic reactions to penicillins occur more frequently parenteral rather than oral administration)
- Cross sensitisation (reactivity either to drugs with a close structural chemical relationship or to immunochemically similar metabolites)
Host related factors
- Age (between 20 and 49 at higher risk of allergic reactions)
- Sex (slightly more common in women)
- Genetic factors
- Diseases
- Previous exposure
What is anaphylaxis and its incidence?
An acute response that is potentially fatal.
Incidence: drug related 3 per 100000 (1800 in UK). Deaths 1-2 per 100000
Mechanisms: release of inflammatory mediators from mast cells to tissue oedema/damage
What are the signs and symptoms of anaphylaxis?
In dentistry, what are the majority of deaths by anaphylaxis from?
penicillin (75% of anaphylactic deaths)
aspirin
LA (rare)
What are the treatment options of anaphylaxis? (4)
Adrenaline (intramuscular)
Antihistamine (chlorphenamine)
Steroids (hydrocortisone)
Bronchodilator (β agonist/aminophylline)
What can be the cause of Stephen-Johnson syndrome?
- Anti-gout medications, (allopurinol)
- Pain relievers acetaminophen (i.e.Tylenol), ibuprofen (Advil, Motrin IB), naproxen sodium (Aleve)
- Antibiotic penicillin
- Medications to treat seizures or mental illness (i.e anticonvulsants and antipsychotics)
- Radiation therapy
Is drug toxicity in dentistry common?
no
What are the outcomes of drug-drug interactions? What food can affect drug activity?
If you take 2 drugs at the same time there could be interactions.
Fruit can affect how the drug is metabolisted.
3 scenarios are faced: no effect, toxic effect or beneficial effect.
What are the factors affecting drug-drug interactions mechanisms?
- Pharmaceutical
- Pharmacodynamic
- Pharmacokinetic (Absorption Distribution Metabolism Excretion)
Give an e.g. of an LA and vasoconstrictor combo?
lidocaine and adrenaline
What does adrenaline do to the therapeutic effect of lidocaine? What are the outcomes of this?
Adrenaline enhances the therapeutic effect of lidocaine by slowing absorption from site of action into systemic circulation
- Prolonged more intense anaesthesia
- Reduced bleeding
- Reduced systemic toxicity
What are the pharmacodynamics of warfarin?
Increased risk of anticoagulation (negatively interacts with vitamin K)
Warfarin antagonises the recycling of vitamin K by depleting active vitamin K in the liver.
What are the dangers of grapefruit juice? With which drug is this a danger?
A glass of grapefruit juice doubles plasma concentration of midazolam.
RISK = oversedation, airway obstruction
Which drugs are not affected by adverse metabolism reactions?
Water soluble drugs aren’t really affected by metabolism because they can be directly excreted
What do enzyme inhibitors and enzyme inducers do?
enzyme inhibitors increase blood levels (i.e. antibiotics)
enzyme inducers reduce blood levels
Is penicillin water soluble or insoluble?
water soluble
Which enzymes in the liver are used to metabolise drugs?
cytochrome P450 enzymes (i.e. for sedatives and analgesics)
What are the different inducers of cytochrome CYP3A?
- Carbamazepine
- Phenytoin
- Rifampicin
- Glucocorticoids
- St. John’s Wort (plant that helps depression)
What are the different substrates of cytochrome CYP3A?
- Midazolam or other benzodiazepines
- Cyclosporin
- Methadone
- Statins
- HIV protease
- Inhibitors
What are the inhibitors of cytochrome CYP3A?
- Erythromycin
- Ketaconazole
- Itraconazole
- Grapefruit juice
- Omeprazole
Which drugs does erythromycin (an antibiotic) increase the effect of and how?
increases the effect of:
- warfarin
- carbamazepine
- theophylline
- cyclosporin
It does this by the inhibition of CYP 450
What is St John’s Wort? What does it interact with which give a risk?
An extract of leaf and golden flowers from hypericum perforatum.
It enhances the metabolism of drugs, reducing their plasma levels by inducing CYP3A
Can react with oral contraceptive (risk of pregnancy) and immunosuppressants (risk of organ rejection).
Can also interact with midazolam, methadone and others.
What if alcohol is consumed when taking metronidazole?
If alcohol and metronidazole are taken together: nausea, vomiting, flushing, tachycardia, shortness of breath, headache
This is due to increased levels of acetaldehyde through inhibition of acetaldehyde dehydrogenase
(Non CYP interaction)
Why may dental treatment with antibiotics/antifungals have a higher risk of interactions?
because the duration of drug use in dentistry is often more prolonged than other treatments = increased risk of interactions - liver enzyme inhibitors
What is the link between cytochrome P450 enzymes and CYP3A4 enzyme?
CYP3A4 is an enzyme of the cytochrome P450 family.
Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, with CYP3A4 responsible for about half of this metabolism
How does hepatic blood flow affect CYP3A4 substrate (e.g. lidocaine)?
What drug can reduce hepatic blood flow?
What drug can inhibit hepatic enzyme metabolism?
Clearance is limited by hepatic blood flow rather than metabolism (45 min half life)
Hepatic blood flow reduced by propanolol
Hepatic enzyme metabolism inhibited by cimetidine
What do local anaesthetics generally do? What can excessive dosage do?
They’re generally safe - few adverse effects if used within dosage guidelines
- They inhibit neuronal activity in brain and heart.
- Initially CNS stimulation by depressing inhibitory pathways: tremor/convulsion
- Followed by CNS depression: lethargy, respiratory depression, unconsciuoness
Excessive dosage - Local anaesthetics addictive effect, care with combined use
Are maximum safe doses more rapidly reached with 3% mepivacaine OR 2% lignocaine in combination with adrenaline
3% mepivacaine
What are the adrenaline α/β agonists? What do they do?
α1 vasoconstriction – skin and mucous membrane
β2 vasodilation – skeletal muscle properties add to safety
In compromised patients, reduce the dose and test it.
What is potentiation when considering adrenaline’s activity?
the increase in strength of nerve impulses along pathways which have been used previously, either short-term or long-term.
What drugs can change our actions of adrenaline?
- Non selective β blockers
- Tetracyclin antidepressants – inhibit uptake
- Cocaine – inhibit uptake
- Ritalin – ADHA (release endogenous norepinephrine)
- Parkinson’s disease (COMT inhibitors reduce breakdown)
- Felypressin – alternative vasoconstriction
What are benzodiazepines used for? Give examples (2). Are they safe?
They’re anxiolytic - used to reduce anxiety / aid sedation.
e.g. temazepam/diazepam
They have a wide therapeutic index = relatively safe to use.
Which drugs would affect the action of benzodiazepenes?
If other drugs are being taken that act on CYP3A4 too, it can affect whether benzodiazepine is working as an anxiolytic.
