Drug Therapy Flashcards
Define the term Pharmaceutical Process
Getting the drug into the patient
Define the term pharmacokinetic process.
getting the drug to the site of action
Define the term pharmacodynamic process.
Producing the pharmacological effect
Define the term therapeutic process.
Producing the therapeutic effect.
What are the four basic factors that determine drug pharmacokinetics?
ADME
Absorption
Distribution
Metabolism
Elimination
Define the term absorption
The process of movement of unchanged drug from the site of administration to the systemic circulation
Define Tmax
The time to peak concentration
Define Cmax
The peak concentration
Complete the sentence: The more rapid the rate of absorption the …
… earlier the Tmax
What effect does increase dose have on Cmax
Increases Cmax
What does area under the drug concentration-time curve show?
Total drug absorbed into the systemic circulation
How is bio-availability of a formulation calculated?
AUC for formulation compared to that of IV
Drug given IV has 100% availability
What factors would contribute to a drug’s ability to pass physiological barrier which would affect its bio-availability?
Particle size
Lipid solubility
-Drug must be in solution and lipid soluble, ability to cross lipid membrane determined by lipid-water partition coefficient
pH and ionisation
- Ionised drugs do NOT cross the membrane
- Most drugs acids/bases so ionisation depends on pH
- Changes in pH will affect rate of absorption (eg PPI use)
What gastrointestinal effects would affect a drug’s bio-availability?
Gut motility
- Affect speed at which drug reaches site of action
- Can be affected by: food/drink, other drugs, illness (eg Coeliac and malabsorption, migraine reduces stomach emptying)
What is first pass metabolism?
Metabolism of a drug prior to reaching systemic circulation
(Drug absorbed by digestive system and reaches liver before rest of body. Most drug metabolised on this first pass through the liver)
Discuss how different routes of administration can affect bio-availability
(SC/IM, SL/Bucca, PR, Inhalation/Nasal, Transdermal)
SC/IM
- Can change rate of absoption with different formulations
- Dependent on blood flow to site
- Avoids first pass metabolism
Sublingual/Buccal
- Bypasses first pass metabolism
- Enters circulation directly
Rectal
- Bypasses first pass metabolism
- Slow absorption
Inhalation/Nasal -Dependent on: >type of delivery system >Pt technique >Particle size -Relatively rapid action -Good for topical effect
Transdermal
-Avoids first pass metabolism
State factors affecting drug distribution. (7)
Plasma protein binding Tissue perfusion Membrane characteristics (blood-brain, blood-testes/ovary) Transport Mechanisms Disease Other drugs Elimination
Why do plasma proteins affect drug distribution?
Many drugs bind to plasma proteins (eg albumin)
Only the UNBOUND drug is active
Binding is reversible
What can affect the amount of drug bound to a plasma protein?
Renal failure Hypoabluminaema Pregnancy Other drugs -(eg NSAID displacing Warfarin)
What is apparent volume of distribution?
the theoretical volume in which the amount of drug would be uniformly distributed in to produce the observed blood concentration
How is Vd calculated?
Volume of distribution = total amount of drug in the body / drug blood plasma concentration
Complete the sentence: the greater the Vd the …
… greater the ability of the drug to diffuse through membranes
What would a Vd of 8L reflect?
A high degree of plasma protein binding
What would a Vd of around 30L represent
Distribution in total body water
What would a Vd of 15000L reflect?
A highly lipophilic molecule which distributes into total body fat
What is clearance?
the theoretical volume of fluid from which a drug is completely removed from over a period of time
(is a measure of elimination)
What is renal clearance dependent on?
Concentration and urine flow rate
What is hepatic clearance dependent on?
Metabolism and biliary excretion
What is half life?
The time taken for the blood drug concentration to decrease by half
What will the effect of a prolonged half life be?
Increased toxicity
What is drug elimination?
The removal of the active drug and metabolites from the body
What does elimination determine?
The length of action of a drug
Where does drug metabolism normally occur
Liver
Where can drug excretion occur?
!Kidney
Biliary system/Gut
Lung
Milk
What are the three principle mechanisms involved in excretion?
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
Discuss passive tubular reabsoption
As filtrate moves down the renal tubule any drug present is concentrated
Passive diffusion allows drug to be reabsorbed into the circulation.
However only unionised drugs are reabsorbed
Discuss active tubular secretion
Some drugs (acidic and basic compounds) are actively secreted into the proximal tubule. Important for the elimination of protein bound charged drugs.
What is drug metabolism?
The biochemical modification of pharmaceutical substances by living organisms usually through specialised enzymatic acitivity
What does metabolism do to a drug (broadly speaking)?
Makes the water soluble to be excreted
List the important sites of metabolism
!Liver
Lining of the gut
Kidneys
Lungs
What are prodrugs?
Drugs that are activated following metabolism
Give two examples of prodrugs
Codeine
Enalapril
What does Phase 1 of metabolism do?
Increases the polarity of a compound
Involves hydrolysis, oxidation, or reduction.
What is the most important family of metabolic enzymes?
Cytochrome p-450 enzymes
What is determined by the isoform of cytochrome p-450?
Drug specificity of the enzyme
Discuss CYP3A4
Major constantly produced enzyme in the liver, contributes to metabolism of a wide range of drugs
Also found in the gut and is responsible for pre-systemic metabolism of several drugs
Example drugs metabolised by CYP3A4: Diazepam, Methadone, Simvastatin
Discuss CYP2D6
Responsible for the metabolism of: some antidepressants, some antipsychotics, codeine to morphine
Is absent or reduced in 5-10% of the population: hence immune to analgesic action of codeine
Is induced by cigarette smoke: hence important to consider in psychiatric patients
What does phase 2 metabolism do?
Increases water solubility and enhances excretion of compound
Conjugation
What is the mechanism of phase 2 metabolism?
Attachment of one of the following to the phase 1 metabolite: Glucuronic acid Glutathione Suphate Acetate
State eight factors which affect drug metabolism
Other drugs/herbals Genetics Hepatic blood flow Liver disease Age Sex Ethnicity Pregnancy
What is the consequence of enzyme induction?
Decreased effect due to increased metabolism
State five of the most common enzyme inducers.
Alcohol Cigarette smoke St Johns Wort Carbamazepine Rifampicin
What is a possible consequence of enzyme inhibition?
Toxicity
State six common enzyme inhibitors.
Cimetidine Erythromycin Clarithromycin Ketoconazole Grapefruit Calcium channel blockers
List different drug formulations (general) (13)
Tablets Capsules Solutions Suspensions Ointments Creams Lotions Topical solution Inhalation Injection Suppository Pessary Transdermal patch
Consider different tablet formulations
MR/SR/PR
GR/EC
Why are some tablets enteric coated?
To protect drug from stomach acid (eg Omperazole)
To protect the stomach from the drug (eg Aspirin ec gr)
Give an example of when IM administration may be contraindicated?
Pt on warfarin (bleed into muscle)
What is an adverse drug reaction?
any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or treatment
What is classed as an acute onset ADR and what would a typical symptom be?
Occurs within 60 mins
Bronchoconstriction
What is classed as a subacute onset ADR and what would a typical symptom be?
Occurswithin 1-24 hours
Rash, serum sickness
What is classed as a latent onset ADR and what would a typical symptom be?
Occurs more than 2 days later
Eczematous eruptions
What is a mild ADR?
Give an example
A bothersome reaction, no change in therapy is needed
Metallic taste associated with metronidazole
What is a moderate ADR?
Give an example
An ADR requiring a change in therapy, additional treatment or hospitalisation
Amphotericin induced hypokalaemia
What is a severe ADR?
Give an example
An ADR which is disabling or life threatening
Kidney failure
What is a type A ADR?
An augmented response which is predictable and dose related
Eg. bradycardia with beta-blockers
What is a type B ADR?
A bizarre reaction which can cause serious illness or death
Can go unidentified for years
What is a type C ADR?
○ Chronic ○ Semi-predictable ○ Examples § Steroid induced osteoporosis Opiate dependence
What is a type D ADR?
○ Delayed
○ In children of treated patients
○ In treated patients many years after treatment stopped
○ Examples
§ Second cancers in those treated with alkylating agents
Malformations in children whose mothers took certain drugs
What is a type E ADR?
○ End of treatment (sudden)
○ Examples
§ Unstable angina and hypertension when β-blockers stopped
Addisonian crisis when long term steroids stopped
What is a type F ADR?
○ Failure of therapy
○ Commonly caused by drug interactions
○ Examples
Failure of oral contraceptives when given with hepatic enzyme inducers/antibiotics
What are some predisposing factors to ADRs?
Polypharmacy Age (elderly, neonates) Sex (more common in women) Disease (renal or hepatic impairment) Race and genetics
What is a drug interaction?
the modification of a drugs effect by prior of concomitant administration of another drug, herb, foodstuff or drink
What is an object drug?
The drug whose activity is affected by the interaction
What is a precipitant? (in the context of interactions)
the agent which precipitates the interaction
Which patients are particularly susceptible to interactions?
Those on multiple drugs Elderly Young Critically ill Those undergoing complex surgery Those with chronic conditions such as -Liver disease -Renal impairment -Diabetes mellitus -Epilepsy -Asthma
Give an example of a direct anatgonistic pharmacodynamic interaction
Beta blockers block action of bronchodilators (Propranolol and salbutamol)
Give an example of an indirect antagonistic pharmacodynamic interaction
NSAIDs and antihypertensives
List different was drug interactions can affect absorption
Formation of insoluble complexes (eg tetracycline and erythromycin complex with iron, calcium and magnesium)
Altered pH affecting ionisation (PPIs H2 antagonists, antacids)
Altered bacterial flora (may lead to failure of oral contraceptives or digoxin toxicity)
Altered GI motility (most drugs absorbed in small intestine, gastric emptying is rate limiting step)
How can interactions affect distribution?
Protein binding displacement
Gives examples of drugs which inhibit cytochrome p450 enzymes
Erythromycin Clarithromycin Ketoconazole Fluconazole Omeprazole Calcium channel blockers
Give examples of drugs that induce cytochrome p450 enzymes
Barbiturates Carbamazapine Phenytoin Rifampacin Tobacco smoke
Discuss how drug interactions can affect elimination
changes in GFR or tubular secretion
§ Example:
□ Calcium channel blockers and digoxin
® CCBs inhibit excretion, digoxin is toxic
□ Loop diuretics and lithium
® Loop diuretics increase tubular reabsorption, lithium is toxic
Discuss the stages of a clinical trial
• Preclinical development
○ Tissue Culture
○ Animal pharmacology
§ Dose
§ Adverse effects
○ Animal toxicology
§ Teratogenicity
§ Fertility
§ Mutagenicity
• Phase I (volunteer studies)
○ Pharmacology in normal volunteers
○ Give pharmacokinetic, metabolic and pharmacodynamic data
○ Usually around 100 subjects
○ Certain drugs (eg cytotoxics bypass this phase)
• Phase II
○ Investigations to confirm kinetics and dynamics in patients
○ Gives some evidence of efficacy and likely dosage
○ Involves up to 500 patients
• Phase III
○ Formal therapeutic trial establishing efficacy and safety
○ Involves 1000-15,000 patients
○ After this stage application for a license is submitted
• Phase IV
○ Postmarketing surveillance for evidence of long term safety
○ May involve hundreds of thousands of patients worldwide
Contrast placebo controlled and comparison studies
○ Placebo controlled study
§ 100 pts, 50 get active drug 50 get placebo
§ Does the drug work?
○ Comparison with other therapy
§ 100 pts, 50 take drug in study and 50 get another therapy
Is the drug better than the existing therapy?
Contrast parallel studies with crossover studies
○ Parallel § Participants get either A or B ○ Crossover § Half of participants get A half get B § Wash out period Cohorts swap and get other treatment
