Lecture 1 Flashcards
What is the clinical aim of a drug?
Achieved effective drug concentration at site of action long enough to produce a therapeutic effect
What is the therapeutic index?
Ratio of a drug’s toxic level to the level that provides therapeutic benefits
What is bioavailability?
Proportion of a dose that reaches systemic circulation
What does 100% bioavailability mean?
All of the unchanged drug has reached the site of action
Positives of intravenous injections
- 100% bioavailability - rapid action
Negatives of intravenous injections
- sterile equipment - trained personnel - expensive - potentially painful
Positives of Oral Administration
- safest - most convenient - most cheap
Negatives of oral administration
- always less than 100% bioavailability - destruction by enzymes, pH, bacteria - drugs can complex with food - absorption depends on rate of passage - irritation may cause vomiting - requires patient compliance
Factors affecting passive diffusion
- size of drug molecule - ionisation of drug - lipid solubility
Which drug ionisation is better absorbed?
Unionised drugs
What is the main site of drug absorption?
small intestine
Why is the small intestine the main site of drug absorption?
- large surface area - alkali pH - large blood flow from capillaries
What are the two other sites of drug absorption?
Stomach and colon
How does formulation affect GI absorption
Drug form affects likelihood of entering hepatic portal vein
Do tablets or fine particles better enter the hepatic portal vein
Fine particles
Two factors affecting rate of absorption
- gut motility - splanchnic blood flow
Examples of orally administered drugs with potential problems
- phenomethylpenicillin (pen V) - tetracyclines - aspirin (NSAIDS)
Phenomethylpenicillin (pen v) issue
- absorbed by food - reduced bioavailability when this happens
Tetracyclines issue
Chelate metals so absorption reduced by milk, antacids, and iron preparations
Aspirin (NSAIDS) issue
- irritate the stomach= dyspepsia, nausea, vomiting and diarrhoea - gastric damage
Issues of taking antibiotics and oral contraceptives
- drug interactions - oral contraceptives undergo enterohepatic cycling
first pass metabolism
Degradation of an orally administered drug caused by enzyme metabolism in the liver and gut lumen before the drug reaches the systemic circulation
Why is a high first pass metabolism bad
- orally ineffective - a drug will be broken down before it reaches system circulation
Different routes of administration
- inhalation - transdermal - buccal and sublingual - intranasal - rectal - subcutaneous - intramuscular
Inhalation mechanisms
- absorption depends on particle size - lipid soluble anaesthetics
Transdermal mechanisms
- stratum corneum acts as a rate limiting step - lipophilic - low input rates (slow absorption)
Examples of transdermal drugs
- nicotine patches - HRT (oestrogen/progesterone) - fentanyl patches - ibuprofen gels
Buccal and sublingual mechanisms
Passive absorption, washed away by saliva
Examples of buccal and sublingual drugs
- GTN (angina) - temgesic (buprenorphine)
Intranasal mechanisms
- epithelial metabolism - passive diffusion
Examples of intranasal drugs
- GTN (angina) - desmopressin (diabetes insipidus, nocturnal enuresis)
Rectal mechanisms
- avoids first pass metabolism in the middle/lower rectum - erratic passive diffusion
Examples of rectal drugs
- diazepam rectal tubes (status epilepticus) - diclofenac suppositories (pain and inflammation)
Subcutaneous mechanisms
- passive diffusion to primary absorption capillary wall - lipophilic, water soluble - dependent on blood flow/release from dosage form - slow absorption rate
Examples of subcutaneous drugs
- insulin - heparin - growth hormone
Intramuscular mechanisms
- reliable route - quick uptake into body - good for depot preparations (long lasting) - absorption is perfusion limited- exercise
Examples of intramuscular drugs
- vaccines - antipsychotics - contraceptives
Which route of administration has the shortest duration
Oral
Which route of administration has the longest duration?
Intravenous
What type of proteins do drugs bind to?
Plasma proteins
What are the three plasma proteins that drugs bind to?
- plasma albumin - beta globulin - acid glycoprotein
Which protein binds to weak acids?
Albumin
Which proteins bind to weak bases?
Acid glycoprotein
What is the relationship between dose and free (active) concentration?
Non-linear
How does a small increase in drug concentration create a large increase in free drug concentration?
- majority of the drug has already been bound - increases in concentration= more free drug in the plasma - few proteins to bind to
What is a concern of taking drugs like aspirin/sulphonylureas?
Drug interactions
How do drug interactions increase the likelihood of overdose?
- two drugs can be bound to plasma proteins - binding of one drug can prevent the binding of the other - large concentration of free drug=overdose
What factors affect tissue distribution?
- lipid solubility - plasma protein binding - molecular weight ETC
Which drug will end up leaving the plasma- heparin or ethanol?
Ethanol
Which drug will end up diffusing from the extracellular space into the total body water- theophylline or paracetamol
Paracetamol
How do lipid soluble drugs pass the blood brain barrier?
Passive diffusion
How do water soluble drugs pass pass the blood brain barrier?
Carrier mechanisms
Which cells in the liver metabolise drugs?
Hepatocytes
What happens to drugs after metabolism?
- converted to inactive metabolites - converted to active metabolites e.g. benzodiazepines - excreted unchanged
Where does drug metabolism occur?
Liver
Which enzyme carries out phase 1 metabolism?
Cytochrome P450 enzymes
Describe phase 1 of drug metabolism
- transforms molecular structure of the drug e.g. oxidation, hydrolysis, reduction - introduce a polar group and increase water solubility - abolishes activity - produces toxic or non-toxic metabolites
Which enzyme carries out phase 2 metabolism?
Transferases
Describe phase 2 (conjugation) metabolism
- attaches endogenous substance (e.g. sulphate) to parent drug/phase 1 metabolite - increases polarity/water solubility so can be exerted in urine or bile
What type of metabolites does phase 1 metabolism produce?
Primary
What type of metabolites does phase 2 metabolism produce?
Secondary
Why is there a concern of a drug interaction from parent drug/metabolites?
Parent drug/metabolites can inhibit/induce metabolism of other drugs
What is the major route of excretion?
Renal
Is the bound or unbound drug excreted?
Unbound
What is the consequence of lipid soluble drugs being reabsorbed in renal tubules?
Action is prolonged
How does changing urinary pH aid excretion?
Polarises and ionises the drug which aids excretion e.g. bicarbonate and aspirin
Consequence of kidney damage for excretion
Drug accumulation
Which form of drug is the most dangerous when kidney damage occurs- changed or unchanged drugs
Unchanged e.g. lithium, penicillins, atenolol
Possible consequences of biliary excretion into intestine
- conjugation - reabsorption from bile (enterohepatic circulation) back into the bloodstream e.g. imipramine, morphine
Alternative routes of excretion
- saliva - sweat - tears - expired air - breast milk
