D5 - dose-response

Question 1

Dose response relationship - Dose response curve

Answer 1

○ X axis - level of drug (log)
§ Dose administered or level measured in the blood
○ Y axis - effect produced
§ By agonist or antagonist
- If the dose of the drug is too low - wont have a therapeutic effect
- If too high - large therapeutic effect but likelihood of adverse side effects
- Optimum dose - sufficient therapeutic effects with few adverse effects

Question 2

EC50

Answer 2

• EC50 - measure of agonist potency

○ concentration that produces 50% of the maximum effect

Question 3

IC50

Answer 3

• IC50 - inhibitory concentration 50
  ○ measure of antagonist potency
  ○ Concentration of antagonist required to inhibit 50% maximum effect

Question 4

EC50 and IC50 value is not used

Answer 4

EC50 and IC50 value is not used - not possible to generate a complete response curve
○ Not ethical to give high values of a drug known to give adverse effects
○ Instead , potency is expressed in the amount of dose given
§ Eg. Metoprolol given 100-200mg/day

Question 5

Potency

Answer 5

○ When one drug is more potent than other - the dose required to produce an effect will be relatively low
○ Eg. Atenolol is more potent than metoprolol - produces effects at lower doses
○ Differences in potency
§ Rarely a factor in choosing which drug to use
§ Dose is just altered to achieve the same level of effect
○

More potent drugs sometimes useful 
	○ Where there is limited capacity to administer large amount of the drug 
	○ Eg. Transdermal patches 
		§ Used to administer drugs across the skin 
		§ Extent to which a drug can move across the skin is limited 
		§ Best if potent drugs are used - effective at low doses 
	○ Eg. Anaesthetizing an elephant 
		§ Needs to fit in a dart
		§ Etorphine - 3000x more potent than morphine

Question 6

Drug effectiveness

Answer 6

• Not all drugs that produce the same therapeutic effect will produce the same maximum effect
  
  • Drugs producing a higher maximum effect is more effective
  • Difference in effectiveness is often a determining factor
  Eg. Morphine is a more effective pain reliever than ibuprofen
  - Because it produces greater levels of pain releif

Question 7

drugs that are more effective

Answer 7

• May act via a pathway that has a greater ability to produce a therapeutic effect
  § Eg. Activation of opioid receptors by morphine produces greater analgesia than the inhibition of cyclooxygenase by ibuprofen
  - May have a greater capacity to modulate the activity of a common drug target
  § Eg. Activation of opioid receptors by the full agonist morphine is greater than activation of by the partial agonist buprenorphine
  § Eg. Competitive antagonist can cause more extensive effect than an allosteric antagonist

Question 8

Dose response relationship

Answer 8

• Relative therapeutic potencies
  
  • Differences in potencies reflected by different positions along the x axis
  • Differences in maximum effect reflected on the y axis

Question 9

Optimum dose

Answer 9

• Using selective drugs

- Aid in therapeutic effect while reducing adverse effect

Question 10

Drug Selectivity

Answer 10

• Extent to which a drug preferentially acts on one drug target over other
  
  • Differences in affinity of drugs for targets
  • Selective drugs bind with higher affinity for target than to other macromolecules that may mediate adverse effects
  • A drug that activates 2 drug targets
    
    • A drug with similar affinity for the 2 targets will produce good and side effect equally
    • Drug with higher affinity for good effect will produce less side effect

Question 11

Eg. Adrenaline

Answer 11

• released from adrenal medulla during exercise
  - Stimulates B1 receptors
  § Increases heart rate and force of contraction by stimulating B1 receptors
  - Can also cause relaxation of smooth muscle by stimulating B2
  § Present on airway smooth muscle cells
  - Metoprolol
  § Binds to and blocks both B1 and B2
  § Much lower affinity for B2 - indicated by higher Ka value
  At low concentrations
  □ Significant binding to B1
  □ Vary little binding to B2 in airways
  □ Binds selectively to B1

Question 12

Higher concentrations of metoprolol

Answer 12

○ Binds to lower affinity targets
○ Increasing dose causes more B2 receptors being bound
○ People with asthma - worsen symptoms by inhibiting relaxation of airway smooth muscles by activation of B2 receptors
○ Reduce potency of B2 agonist salbutamol
○ Loss of selectivity at high doses is typical for all drugs

Question 13

Target selectivity

Answer 13

○ Governed by pharmacodynamic factors - affinity

○ Eg. Metoprolol has higher affinity for B1 than B2, so at low doses it will target the heart and not the airways

Question 14

Tissue selectivity

Answer 14

○ Governed by pharmacokinetic factors
○ How it is administered
○ Eg. In asthma, airway selectivity is achieved by
1. Delivering drugs directly to airways eg. Inhalers
2. Using drugs activated within airways eg. Inhaled Ciclesonide is a prodrug only activated by lung esterases only found within the lung
3. Using drugs rapidly inactivated when outside of the lungs eg. Inhaled fluticasone is extensively inactivated by the liver
Using drugs that cannot gain access to other organs/tissues eg. Ipratropium bromide doesn’t cross the blood brain barrier, so there are less CNS side effects

Question 15

Delivering drugs directly

Answer 15

Delivering drugs directly to airways eg. Inhalers

Question 16

Using drugs activated within

Answer 16

2. Using drugs activated within airways eg. Inhaled Ciclesonide is a prodrug only activated by lung esterases only found within the lung

Question 17

Using drugs rapidly inactivated when outside

Answer 17

3. Using drugs rapidly inactivated when outside of the lungs eg. Inhaled fluticasone is extensively inactivated by the liver

Question 18

Using drugs that cannot gain access to other organs/tissues

Answer 18

4. Using drugs that cannot gain access to other organs/tissues eg. Ipratropium bromide doesn’t cross the blood brain barrier, so there are less CNS side effects

Question 19

Magic Bullets

Answer 19

○ Preferred if the drug targets a distinct molecular disease entity known to drive the disease process
○ Called ‘Magic bullets’
○ Eg. Chronic myeloid leukaemia
driven by the enzyme BCR-Abl which can be selectively inhibited by imatinib

Question 20

Magic Shotguns

Answer 20

○ Some drugs target multiple entities in the disease process
○ Called ‘Selective, non selective drugs’
○ Magic shotguns
○ Eg. High blood pressure
§ Hypertension is due to
□ increased cardiac output
□ increased totally peripheral resistance
§ Influenced by B1 receptors in the heart and other receptors in blood vessels
§ Nebivolol
□ Blocks targets that cause an increase in cardiac output - and activate other targets that will reduce peripheral resistance
□ Produces a common outcome - drop in blood pressure
○ Could also administer multiple selective drugs
Useful in multifactorial diseases - cancer, CNS and cardiovascular disorders

Question 21

Selectivity - relative term

Answer 21

○ Labetolol
§ Binds with high affinity for both alpha and beta adrenoceptors - low affinity for other receptors
§ ‘adrenoceptors’ selective antagonist
○ Phentolamine
§ Blocks alpha adrenoceptors
§ ‘Alpha adrenoceptor’ selective antagonist
○ Prazocin
§ Selectively blocks alpha 1
§ Low affinity for alpha 2
§ ‘Alpha 1 adrenoceptor’ selective antagonist
○ Tamsulosin
§ ‘Alpha 1A’ selective antagonist

Question 22

Warfarin

Answer 22

• Therapeutic and adverse effects are produced through a single target, but high doses produce adverse effects
  
  • Used to treat deep vain thrombosis
  • Anticoagulant activity
  • High levels associated with bleeding or haemorrhage
  • Inhibits enzyme vit k epoxide reductase - blood thinning activity
  • At high doses
    ○ Causes haemorrhage
    ○ Therapeutic and adverse effects are produced along the same drug dose continuum

Question 23

Metoprolol

Answer 23

• Some drugs bind single targets, but may produce adverse effects because the targets are widely distributed and multifunctional
  
  • Metoprolol used to treat angina associated with cold fingers and toes and a lack of energy
  • Adverse effect are due to it blocking B1 receptors at sites other than the heart - liver and blood vessels
  • Dose - effect curve for therapeutic effect are super-imposed
  • All doses effective therapeutically are likely to produce adverse effects which will increase with increasing dose of the drug
  Adverse effects can be reduced by administering drugs locally
  ○ Eg. Timolol is a B blocker used for glaucoma
  § Can be administered directly to the eye
  § smaller adverse affects with local administration of the drug

Question 24

Diphenhydramine

Answer 24

• Some drugs are more likely to produce adverse effects if they are non-selective
  
  • Eg. Anti-histamines
  • Diphenhydramine
    ○ First generation antihistamines relieves nasal congestion and hey fever by blocking histamine receptors
    ○ Cause sedation and dry mouth by blocking muscarinic acetyl choline receptors in exocrine glands and CNS
  • Diphenhydramine
    ○ Higher affinity for H1 receptors than muscarinic acetyl choline receptors
    ○ Some dose separation of good and bad dose response curves
    § Exists overlap of therapeutic and adverse effects
    § Citirazine associated with fewer adverse effects

Question 25

Paracetamol

Answer 25

• Bind to single targets and produce few adverse effects through that target but can be metabolised to confer toxicity
  
  • Can cause hepatotoxicity when administered as an overdose
  • At high doses, converted into chemically reactive metabolite which accumulate and cause liver necrosis
  • Well separated curves - possible to achieve analgesia without adverse effects