General Pharmacology 11 to 20
Describe the difference between a Competitive and an Irreversible antagonist?
- In fixed concentration of agonist, increasing conc. of antagonist will lead to progressively inhibited response, but an increasing agonist conc. can overcome to still evoke maximal response (agonist conc / effect curve shift to right)
- High comp. antagonist conc. prevent response completely if agonist conc. fixed
- Irreversible (Noncompetitive)
- Bind so tightly or covalently as to make receptor unavailable to agonist.
- Number of remaining receptors may then be too low to allow maximal response to occur regardless of agonist conc. (unless spare receptors)
- Length of effect of irrev. antagonist will reflect turnover of receptors involved rather than rate of elimination of antagonist
Give an example of an antagonist.
- Competitive: naloxone, flumazenil, Propranolol, isoprenaline, naltrexone, nalmefene
- Irreversible: phenoxyenzamine, MAOI
What is meant by 'Total Body Clearance' of a drug?
- Describes the ability of the body to eliminate a drug.
- It refers to the theoretical volume of plasma emptied of drug per unit time (usually L/h).
- Total body clearance reflects the sum of all clearance process including renal, hepatic and other
Name 2 drugs that have a high hepatic clearance and explain why this is important.
- Lignocaine, Morphine, Propranolol, Pethidine.
- Drugs with high hepatic elimination may only be suitable for parenteral administration or have significant dosing variations depending on the route of administration
What factors determine drug half-life?
- Volume of Distribution and Clearance (t1/2 = 0.693 x Vd/ Cl )
- Vd and clearance change with disease states – cardiac, hepatic and renal failure
What routes of drug administration are there?
- Enteral: Sublingual, buccal, oral, rectal
- Parenteral: SC, IM, IV, intrathecal, epidural
Pass Criteria: Enteral/oral + 3 non-enteral
What factors affect the rate of drug absorption from the small intestine?
- Ionisation status of drug:
- Intestinal motility; increased motility lead to reduced transit time and drug absorption
- Gut Factors
- Gut surface area, blood flow, solubility of drug, formulation of drug
Pass Criteria: Must mention drug factors and gut factors
What are potential disadvantages of rectal drug administration?
- Erratic absorption because of rectal contents
- Local drug irritation
- Uncertainty of drug retention
Pass Criteria: 1 out of 3 required
With regard to drugs, what is 'potency'?
- Potency refers to the affinity or attraction between an agonist and its receptor.
- A good measure of drug potency is the EC50 – the concentration that produces 50% of the maximal response.
How is this different to Efficacy?
- Efficacy is the maximal response that a drug (agonist) can produce (Emax) when all receptors are occupied, irrespective of the concentration required to produce that response.
How does this differ from a competitive antagonist?
- Potency is the measure of how much drug is required for effect. It is measured in EC50, the concertrtion or dose required to produce 50% of the maximal effect.
- Efficacy is the measure of maximum effect that a particular drug may have.
Graph drugs with different potencies and efficacies.
List the factors affecting placental drug transfer?
- Lipid solubility
- Molecular size
- Placental transporters
- Protein binding
- Placental and foetal drug metabolism
Pass: 2 of 5
What is meant by foetal therapeutics?
Drug administration to the pregnant woman with the foetus as the target
Give examples of drugs administered for this purpose?
Corticosteroids (for lung maturation)
Phenobarbitone (induce enzymes for glucuronidation of bilirubin)
Antiretrovirals (decrease HIV transmission) Antiarrhythrnics
In children, what factors change with age and alter pharmacokinetics?
- Body Size and Composition —
- Growth of child — most doses calculated in mg/kg
- Adult is 50% water 20% extracellular
- Term neonate 70-75% water 40% extracellular
- Pre term neonate 85% water
- Influences drugs distributed in extra cellular space
- Fat 15% in adults
- 1% in pre term infants
- Plasma proteins
- Albumin — Decreased levels in neonate
- Potential for increased toxicity in neonates if drugs are highly protein bound
- Jaundiced neonates — if drug highly protein bound, will displace bilirubin and cause kernicterus
- Drug Metabolism
- Most drugs metabolised in liver
- Only 50-70% of adult values
- Slow clearance and prolonged elimination half lives
- Drug excretion
- GFR lower in newborns than older infants
- Neonate 30-40% adult values
- 3 weeks 50-60 % adult values
- 6-12 months Adult values
Pass: body size and composition, and drug metabolism and excretion.
Define drug elimination half life.
Time required to change the amount of drug in the body by 1/2 during elimination
Is there a formula you can use?
Prompt: What factors affect half-life? Prompt: Can you explain what that means?
T1/2 = 0.7 x Vd/clearance (0.7 approx log 2)
How does knowledge of a drug’s half life help us clinically?
Indicates time to steady state after dose change. 50% after 1, >90% after 4
NOTES: Concept required. Both bold to pass
In the context of drug-receptor interactions, what is the difference between a full agonist and a partial agonist?
High concentrations of full agonists can evoke a maximal response, but partial agonists cannot evoke maximal response at any concentration
Under what circumstances can a partial agonist act as an antagonist?
Prompt: Can you use opioids as an example?
In the presence of a full agonist