Lecture 1: Pharmacology Flashcards
Clinical aim of a drug
To achieve an effective drug concentration at the site of action long enough to produce a therapeutic action
Therapeutic window/index
The bigger the window, the safer the drug
What was the old method to measure therapeutic window/index?
LD50
- Put dosage in rats
- See what conc would kill 50% of the population
- Not used anymore [ethics]
Bioavailability
Proportion of dose of unchanged drug that reaches the site of action
Intravenous injection advantages
100% bioavailability
Rapid action
Oral route advantages
Safest, most convenient and economical route
Fick’s Law of Passive Diffusion
Rate = permeability x surface area x conc difference / thickness of membrane
How does a drug get into the blood stream from the gut lumen?
○ Passive diffusion
○ Factors
§ Membrane permeability
§ Surface area of membrane
§ Conc difference (more conc difference, more it will diffuse across)
Factors determining rate of passive diffusion
- Determined by biological variation
- Permeability depends on the drug itself
○ Lipophilic faster than hydrophilic
- Permeability depends on the drug itself
What are the four routes of administration?
Absorption
Distribution
Metabolism
Elimination
Site of action
Systemic circulation
Intravenous injection disadvantages
Sterile equipment needed
Trained personnel needed
Expensive
Potentially painful
Oral route disadvantages
Nearly always less than 100% bioavailability
Destruction by enzymes, pH and/or bacteria
Drug can complex with food
Absorption depends on rates of passage
How does the drug get into the blood stream from gut lumen?
- Passive diffusion
- Factors
- Permeability of membrane
- Surface area of membrane
- Conc difference (more conc difference, more it will diffuse across)
What are some other methods of absorption?
- Active transport
- L-DOPA
- Ion-pair absorption
- Pinocytosis
- Solvent drag
Pinocytosis
- Membrane that engulfs material and removes itself through cytosis
- Not much evidence for this
Solvent drag
- Purely experimental technique
- Drug dissolves in a[n organic] solvent
- Works theoretically
Small intestine as a main site of absorption
- Large surface area
- Alkaline pH
- Blood flow (1l/min) capillaries
Stomach
- Little drug absorption
- Small surface area
- Blood flow 150ml/min
- Quick to empty
- Acid pH (1-2)
- Ion trapping
Colon
- Little drug absorption
- Lumen filled w bacteria
Pen V
- Binds to food → reduces bioavailability
- Therefore, take on an empty stomach
Tetracyclines
Chelate muscles so absorption reduced by milk, antacids n iron preparations
Aspirins (NSAIDS)
- Irritates the stomach: dyspepsia, nausea, vomit, diarrhea
- 1/5 chronic users will hv gastric damage
First-pass metabolism
- Tend to be absorbed in the small intestine
- Drug pass through the liver before it gets to the systemic circulation
- Drug can be completely metabolized
- Drug broken down by acid
- Peptide drugs will be broken down completely before there are any effects
Inhalation
- Aerosols: absorption depends on particle size
- Lipid soluble anesthetics: rapid reabsorption
- Avoids first pass metabolism
Transdermal
- Outer layer (stratum corneum) rate limiting step
- Low input rates
- Patches (e.g. to give up smoking)
- HRT (menopause)
- Opioid analgesic for pain
- Ibuprofen gel: anti-inflammatory drug
Buccal n sublingual
- Passive absorption, pH 6/7, saliva may wash away
- Examples
- GTN (angina)
- Temgesic (buprenorphine, opioid painkiller)
Intranasal
- Epithelial metabolism
- Absorption: passive diffusion
- Examples
- GTN (angina)
- Desmopressin: diabetes insipidus, nocturnal enuresis)
Rectal
- Upper rectum: upper rectal vein, first pass metabolism
- Middle/lower rectum: avid first pass metabolism
- Absorption: passive diffusion (erratic)
- Examples
- Diazepam rectal tubes (status epilepticus)
- Diclofenac suppositories (pain n inflammation)
Plasma Protein Binding
The process by which drugs bind to proteins in the blood, affecting their distribution and elimination within the body
Tissue Distribution
The dispersion of a drug throughout various tissues in the body, influenced by factors such as tissue perfusion and drug lipophilicity
Blood Brain Barrier (BBB)
- Prevents drugs entering the brain
- Layer of tightly joined endothelial cells
- Lipid soluble drugs pass by passive diffusion
- Water soluble drugs only pass via carrier mechanisms
- Endothelial cells contain P-glycoprotein (Pgp) which is an active drug efflux pump
What happens to drugs during metabolism?
- Converted to inactive metabolites
- Converted to active metabolites (i.e. benzodiazepines)
- Excreted unchanged
Phase 1 Metabolism
- Transforms drug’s molecular structure
- E.g. oxidation, hydrolysis, reduction
- EFFECT
- Can introduce polar groups/ increase water solubility
- Abolish activity
- Produce toxic/non-toxic metabolites
- Often mediated by cytochrome P450 enzymes
Phase 2 Metabolism
- Attaches endogenous substance (e.g. sulphate/glucoronide) to parent drug/phase 1 metabolite
- Carried out by transferases (enzymes)
- Increases polarity/water solubility so can be eliminated in urine or bile
- Parent drug/metabolites can inhibit/induce the metabolism of other drugs: possible interaction
Renal excretion
- Unbound drug excreted
- Lipid soluble drugs can be reabsorbed in renal tubules; prolongs action
- Can change urinary pH to aid excretion (i.e. bicarbonate and aspirin)
- Some drugs (e.g. penicillin) are actively excreted
