Drug metabolism and interaction - Pharmacology Flashcards
What percentage of hospitalisations involve adverse drug events?
2.9-3.7%
4th leading cause of death
Drug poisoning = 1 in 7 deaths in UK in people in their 20s
What are type A and type B adverse drug effects?
A = pharmacological or toxic effect B = idiosyncrasy and drug allergy
What are the typical pharmacopeia in dental practice?
Sedative
LA
Analgesic
Antibiotics
What drugs have a low therapeutic index?
Anticoagulant - warfarin
Aminoglycoside antibiotics - gentamicin
Anticonvulsants - phenytoin
Give the therapeutic index of remifentanyl (opioid analgesic) and diazepam
Remifentanyl - 33000:1
Diazepam - 100:1
What are the types of adverse drug effects?
Circumstances;
- Accidental/deliberate overdose
- Normal therapy - side effects
Site of action;
- Localised aspirin (mouth ulcers, GI irritation)
- Systemic - majority of rxns
Time course;
- Acute toxicity - single intake/rapid onset - Narcotics (resp depression)
- Sub-acute toxicity-repeated exposure - Tetracycline
- Chronic toxicity - repeated exposure - chemical carcinogenesis
What are the mechanisms of adverse drug effects?
Type A (for augmented)
- Exaggerated therapeutic responses
- 2ndry unwanted actions
- More predictable or anticipated effects
Type B (for Bizarre)
- Pharmacologically unexpected, unpredictable or idiosyncratic adverse rxns
- Immunological (allergic/anaphylactic)
- Idiosyncratic (qualitatively abnormal adverse rxn - mechanism not yet understood)
What are the major and minor concerns of type A reactions?
Major
- Resp depression
- Cardiac toxicity (LA)
Minor
- Diarrhoea
- Dry mouth
- Drowsiness
What does a higher dose of the drug cause?
Higher possibility of side effects
Give examples of drug risk situations in patients? (high risk of adverse drug effects)
Childhood Elderly Pregnancy Lactation Renal failure Haemodialysis
Pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
How is absorption reduced? (tetracycline)
By chelation of drugs/food/vitamins/divalent cations
What is distribution? (tetracycline)
Sequestration of tetracycline in bone (tissue
binding) leading to depression of bone growth in children and
irreversible staining of tooth enamel
Who should tetracycline not be prescribed to?
Pregnant women and children under 12
How are drugs involved in metabolism?
Effect drug metabolising enzymes = inhibition/induction of enzyme
Diseases may alter drug metabolism (renal/hepatic dysfunction)
What can cause abnormal drug metabolism?
Inherited factors of either phase I oxidation or phase II conjugation
What is renal excretion of drugs controlled by?
Glomerular filtration, tubular secretion and tubular reabsorption
What factors affect renal excretion of drugs?
Kidney function
Protein binding
Urine pH
Urine flow
What may impaired renal function result in?
Accumulation of drugs eliminated by the kidneys
Features of type B reactions?
No dose relationship Unexpected Mechanism uncertain Not reproducible Serious Low background frequency Pseudoallergic Metabolic intolerance
Give examples of type B reactions
Anaphylaxis, hepatitis, blood dycrasias
How do type A and B reactions differ?
A = pharmacologically predictable, B is not
A is dose dependent, B is not
A has high incidence and morbidity, B is low
A has low mortality, B has high mortality
A = treatment = decrease dose, B = stop
What is valproic acid?
Antiepileptic used to control certain types of seizures
Characteristics of drug allergy?
Delay after initial exposure Precipitated with small doses of drug Does not resemble normal pharmacology Classical symptoms of allergic response Due to drug related factors or host related factors
Causes of drug allergy;
Features of drug related factors?
Nature of drug
Degree of exposure (dose, duration, freq, repeated administration)
Route of administration
Cross sensitisation (reactivity to drugs with close structural chem relationship)
Causes of drug allergy:
Host related factors?
Age (20-49 = higher risk of allergic rxns) Sex (women more common) Genetic factors Diseases Previous exposure
Features of anaphylaxis?
Acute response
Potentially fatal
Drug related = 3 per 100000, deathers 1-2 per 100000
Mechanism; Release of inflam mediators from mast cells due to tissue oedema/damage
Signs and symptoms of anaphylaxis?
- Runny nose
- Light headed, loss of consciousness, confusion, headache, anxiety
- Shortness of breath, wheezes, pain with swallowing, cough
- Diarrhoea, vomitting
- Hives, itchiness, flushing
- Fast/slow HR, low BP
- Swelling of lips, tongue or throat
What causes anaphylaxis in dentistry?
Penicillin (75% of anaphylactic deaths)
Aspirin
LA - procaine, lidocaine
How to treat anaphylaxis?
Adrenaline
Antihistamine (clorphenamine)
Steroids
Bronchodilator
Medications for Stephen/Johnson syndrome?
Anti-gout medications
Pain relievers - acetaminophen, ibuprofen
Naproxen sodium
Antibiotic - penicillin
Medications to treat seizures or mental illness = anticonvulsants
Radiation therapy
Name the drug-drug interaction mechanisms?
Pharmaceutical
Pharmacodynamic
Pharmacokinetic - absorption, distribution, metabolism, excretion
What does adrenaline in LA do?
Enhances therapeutic effect of lidocaine by slowing absorption from site of action into systemic circulation = prolonged intensity of anaesthesia, reduced bleeding and systemic toxicity
Pharmodynamics - what does warfarin do?
Increased risk of anticoagulation
Antagonises recycling of vitamin K by depleting active vitamin K in the liver
Pharmacokinetic: metabolism
Not for water soluble drugs (penicillins)
Drugs metabolised in the liver - substrates of the cytochrome P450 enzymes
Enzyme inhibitors - increase blood levels
Enzyme inducers - reduce blood levels
What does grapefruit juice do?
Doubles the conc of midazolam = risk of oversedation, airway obstruction
List the inducers of cytochrome CYP3A
Carbamazepine Phenytoin Rifampicin Glucocorticoids St. John's Wort
List the substrates of cytochrome CYP3A
Midazolam/other benzodiazepines Cyclosporine Methadone Statins HIV protease Inhibitors
List the inhibitors of cytochrome CYP3A
Erythromycin
Ketaconazole
Grapefruit juice
Omeprazole
What does erythromycin increase the effects of? How?
Warfarin
Carbamazepine
Theophylline
Cyclosporin
By inhibition of CYP450
How does midazolam increase the plasma concentration? How?
Erythromycin Ketoconazole (or other antifungal) Omeprazole Grapefruit juice By CYP3A inhibition
CYP3A induction?
Induction of enzyme activity particularly cytochrome P450
Requires synthesis of new enzymes
What does St. John’s Wort do?
Enhances metabolism of drugs, reducing their plasma levels by inducing CYP3A
Oral contraceptive - risk unwanted pregnancies
Immunosuppressant - risk organ rejection
Can interact with midazolam, methadone
What causes acetaldehyde dehydrogenase?
Metronidazole and alcohol
= Nausea, vomiting, tachycardia, shortness of breath, headache
No alcohol consumption
What can antibiotic/antifungal agents in dental practice cause?
More prolonged duration than other treatments = increased risk of interactions - liver enzyme inhibitors
How are lidocaine and the liver connected?
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 (used to treat ulcers and GERD)
What does LA do?
Inhibit neuronal activity in brain and heart
Initially CNS stimulation by depressing inhibitory pathways = tremor/convulsion
Followed by CNS depression: resp depression and unconsciousness
In LA - which LA reaches the maximum safe dose more rapidly?
More rapid with mepivacaine 3% than 2% lignocaine with adrenaline
How does adrenaline work?
α1 vasoconstriction – skin and mucous membrane
• β2 vasodilation – skeletal muscle properties add to safety
Compromised pts - reduce the dose and test the dose
Adrenaline - potentiation?
- 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
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
