Drug interactions - adverse effects Flashcards
Adverse drug effects statistics
2.9 - 3.7% of hospitalizations involve adverse events
4th leading cause of death
Drug poisoning accounting for 1 in 7 deaths among
people in their 20s and 30s in 2014 in UK
Majority of deaths in males
Adverse events occur in 10-20% of hospitalized patients.
7% of those in ambulatory setting
Type A reactions
pharmacological or toxic effect
Type B reactions
iodiosyncrasy and drug allergy
Typical pharmacopeia in dental practice
Sedative
Local anesthetic
Analgesic
Antibiotics
Therapeutic index
The therapeutic index varies widely among substances
GRAPH
Know the TI for drugs we use
Therapeutic index remifentanyl
Opioid analgesic
33000:1
Therapeutic index diazepam
Benzodiazepine sedative, muscle relaxant
100:1
Therapeutic index morphine
Opioid analgesic
70:1
Drugs with low therapeutic index
Anticoagulant i.e. warfarin
Aminoglycoside antibiotics i.e. gentamicin
Anticonvulsants i.e. phenytoin
Circumstances
Accidental or deliberate overdose
Normal therapy -side effects
Site of action
Localized
-aspirin (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
- exaggerated therapeutic responses
- secondary unwanted actions
- more predictable or anticipated effects
Mechanisms - type B
For bizarre
Pharmacologically unexpected, unpredictable, or idiosyncratic
adverse reactions
-immunologic (Allergic or anaphylactic)
-idiosyncratic (Qualitatively abnormal adverse reactions
that occur in a given individual and whose mechanism
is not yet understood)
Type A reactions - major concerns
Respiratory depression (i.e. narcotic agents) Cardiac toxicity (i.e. overdose of intravascular injection of local anesthetic)
Type A reactions - minor concerns
Diarrhea (Broad spectrum antibiotics)
Dry mouth (Anticholinergics i.e. antidepressant)
Drowsiness (CNS drugs i.e. benzodiazepines)
Higher dose –>
Higher possibility of side effects
Type A reactions - risk situation
Childhood
- Elderly
- Pregnancy
- Lactation
- Renal failure
- Haemodialysis
Type A reactions - pharmacokinetics
Absorption Distribution Metabolism Excretion -each step is a target for adverse effect
Type A reactions - absorption/ distribution (tetracycline)
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
No to be prescribed in pregnant women and children under 12
Type A reactions - absorption GRAPH
Antiacids and iron preparation
decrease absorption by
chelation
Type A reactions - metabolism
Some important preventable drug interactions are due to their
effects on drug metabolizing enzymes, resulting in inhibition of
enzyme or induction of 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 risk of drug interactions
Type A reactions - excretion
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
Type B 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
Type B reaction examples
Anaphylaxis, Stevens-Johnson syndrome, Blood
dyscrasias, Hepatitis
Type A vs Type B reaction
Pharmacalogically predictable - A Dose dependent - A Incidence and morbidity -A high -B low Mortality -A low -B high Treatment -A decrease dose -B stop Many are due to conversion of drugs in active metabolites
Valproic acid in pregnant women
Antiepileptic used to control certain types of seizures Fetal valproate syndrome: facial features -broad forehead -epicanthal folds -flat nasal brdige -short anteverted nose -long philtrum -thin upper lip
Drug allergy characteristics
Delay after initial exposure (up to a week)
Precipitated with small doses of drug
Does not resemble normal pharmacology
Classical symptoms of allergic response
Drug allergy dependent on
Drug related factors
Host related factors
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
Anaphylaxis plus incidence
Acute response
Potentially fatal
Incidence: drug related 3 per 100000 (1800 in UK). Deaths
1-2 per 100000
Anaphylaxis mechanism
release of inflammatory mediators from mast
cells to tissue oedema/damage
Anaphylaxis: signs and symptoms
Welling of conjunctiva Runny nose Swelling of lips, tongue and/ or throat Heart rate fast/ slow, low BP Hives, itchiness, flushing Pelvic pain Loss of bladder control Crampy abdo pain, diarrhoea, vomiting Shortness of breath, wheezes or stridor, hoarseness, pan with swallowing, cough Lightheadedness, confusion, headache, anxiety
Anaphylaxis in dentistry - deaths from
Penicinillin (75% of anaphylactic deaths)
Aspirin
Local anaesthetics: procaine, lidocaine (rare)
Anaphylaxis in dentistry - treatment
Adrenaline (im)
Antihistamine (chlorphenamine)
Steroids (hydrocortisone)
Bronchodilator (β agonist/aminophylline)
Stephen/ Johnson syndrome can be caused by
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
Drug toxicity in dentistry
A limited range but regularly used drug
Probably injected more drugs than average GP
Most drugs on dental list are safe
Unlikely to see much toxicology (recognition)
Important to recognise, treat/report adverse drug reactions
Drug-drug interactions
No effect
Beneficial effect
Toxic
Drug-drug interactions mechanisms
Pharmaceutical Pharmacodynamic Pharmacokinetic Absorption -distribution -metabolism -excretion
LA and vasoconstrictor
LIDOCAINE + ADRENALINE
Adrenaline enhances therapeutic effect of lidocaine by slowing
absorption from site of action into systemic circulation
–>prolonged more intense anaesthesia
–>reduced bleeding
–>reduced systemic toxicity
Pharmacodynamics - warfarin
> risk of anticoagulation (negatively interacts with
vitamin K)
Warfarin antagonises the recycling of vitamin K by depleting
active vitamin K in the liver
Pharmacokinetic: metabolism
Not for water soluble drugs (i.e. penicillins)
Drugs metabolized in the liver - substrates of the cytochrome
P450 enzymes (i.e. sedative and analgesics)
Enzyme inhibitors - increase blood levels (i.e. antibiotics)
Enzyme inducers - reduce blood levels
Glass of grapefruit juice doubles
plasma concentration of midazolam
RISK oversedation, airway
obstruction
Cytochrome CYP3A**
Inducers -carbamazepine -phenytoin -rifampicin -glucocorticoids -st. John’s Wort Substrates -midazolam or other benzodiazepines -cyclosporin -methadone -statins -HIV protease Inhibitors -erythromycin -ketaconazole -itraconazole -grapefruit juice -omeprazole
Erythromycin
Increases effect of : Warfarin Carbamazepine Theophylline Cyclosporin -by inhibition of CYP 450
Midazolam (GRAPH)
Increased plasma concentration by : Erythromycin Ketoconazole ( or other antifungal) Omeprazole Grapefruit juice -CYP3A inhibition
CYP3A induction (GRAPH)
Induction of enzyme activity particularly cytochrome P450
Requires synthesis of new enzymes
St John’s Wort found in
Hypericum perforatum
Extract of leaf and golden flowers
Hyepericin (anthracene)
Hyperforin (phenol)
St John’s Wort
Enhances metabolism of drugs, reducing their plasma levels,
by inducing CYP3A
Oral contraceptive RISK unwanted pregnancies
Immunosuppressant RISK organ rejection
Can also interact with midazolam, methadone and others
Acetaldehyde dehydrogenase
Metronidazole + Alcohol
–>nausea, vomiting, flushing, tachycardia, shortness of breath,
headache
> levels of acetaldehyde through inhibition of
acetaldehyde dehydrogenase?
(Non CYP interaction)
–> No alcohol consumption
Antibiotic/ Antifungal agents
In dental practice duration more prolonged than other treatments
increasing risks of interactions – liver enzyme inhibitors
CYP1A2, CYP2C9
CYP1A2
Macrolides (erythomycin)
Substrates
-antidepressant
-major tranquilisers
CYP2C9**
Azole antifungal (metronidazole/ ketoconazole) Substrates -warfarin -phenytoin -lidocaine (no interaction) -midazolam (airway obstruction in children) Many inhibitors Major area of interactions
Lidocaine and the liver
CYP3A4 substrate
-clearance limited by hepatic blood flow rather than
metabolism (45 min half life)
-hepatic blood flow reduced by propanolol
-hepatic enzyme metabolism inhibited by cimetidine
LA
Safe - few adverse effect if used within dosage guidelines
Inhibit neuronal activity in brain and heart
Excessive dosage - Local anaesthetics addictive effect, care
with combined use
Initially CNS stimulation by depressing inhibitory pathways:
tremor/convulsion
Followed by CNS depression: lethargy, respiratory
depression, unconsciousness
Mortality due to LAs
Healthy 5 years old booked for multiple extractions
Injected 5 cartridges (270mg) of 3% mepivacaine
Convulsion occurred 10 min later followed by full
cardiopulmonary arrest
Dies four days later from anoxic brain injury secondary to
complete pulpal anaesthesia
-based on px weight, max safe dose = 72mg
-nearly 4x higher
-low safety margin for LA in children
-maximum safe doses more rapidly reached with 3%
Lidocaine and opioid sedation
Local anaesthetics – membrane depressant CNS, CVS
Maximum safe doses determined by body weight
Potential problem in pediatric dentistry
Children- body weight is NOT proportional to difference in
orofacial anatomy
Need for apparent higher doses in children
Multiple mechanisms – convulsions, respiratory,
depression and cardiac arrest
Adrenaline (alpha/ beta agonists)
α1 vasoconstriction – skin and mucous membrane
β2 vasodilation – skeletal muscle properties add to safety
Compromised patients – reduce the dose, test the dose
Adrenaline cases
Yagiela (1991) – 58 yrs man died of angina, pervious MI
received 0.18 mg of adrenaline
Campbell (1996) 70 yrs patient no adverse effects
arrhythmia + CVS medication, received 0/04 mg adrenaline
Adrenaline - potentiation
Non selective β blockers Tetracycline antidepressants – inhibit uptake Cocaine – inhibit uptake Ritalin – ADHA (release endogenous norepinephrine) Parkinson’s disease (COMT inhibitors reduce breakdown) Felypressin – alternative vasoconstriction
Benzodiazepines
Anxiolytic without sedation or ataxia Temazepam/diazepam Large margin safety – wide therapeutic index Liver CYP3A4 Inhibition (increased plasma levels) Calcium channel blockers /macrolide / azole antifungal/ protease inhibitors Induction (decreased plasma levels) Anti-TB, anti epileptic
