Lecture 11: Time Course of Delayed and Accumulative Drug effects

Question 1

What are the Time courses of Drug effects?

Answer 1

1. Immediate (drug effects are immediately related to observed drug concentration e.g. in plasma)
2. Delayed (drug effects are delayed in relation to observed drug concentration)
3. Cumulative (drug affects are determined by the cumulative action f the drug)

Question 2

Are there sites of drug action in the plasma?

Answer 2

There are no sites of action in the plasma –> therefore drug effect will be delayed
- Exception: Heparin + Anticoagulants (bind to RBC and platelets located in blood) –> but binding still isnt immediate as still has to bind to receptors

Question 3

What are 3x reasons for delayed drug effects?

Answer 3

1. Distribution to the Effect site (e.g. in brain have to diffuse into blood and cross blood-brain barrier etc): Pharmacokinetics
2. Binding to the receptor: receptor-kinetics
3. Physiological Intermediate: physio-kinetics (time for drug action to change physiological intermediate substances before drug response if observed)

Question 4

What are the typical reasons for short and long delays?

Answer 4

1. Short delays (mins): due to distribution (to effect binding site)
2. Long delays (hours+): due to physiological (intermediates)
   - delays can be due to individual reasons or multiple factors

Question 5

Distribution to effect site

Answer 5

Understood in terms of anatomy
Blood is in a “Central compartment” but the effect site isnt
Driving force compartment for the deliver of drug to tissues: Rapidly mixing central blood volume
Often due to delays in:
1. Perfusion of tissues
2. Diffusion across Blood vessel walls
3. Diffusion through Extracellular spaces

Question 6

What is an example of Delayed drug effects to distribution to effect site

Answer 6

Thiopentone (rapidly inducing anaesthetic) distributing to Brain
Peak concentration: occurs at the end of infusion (because afterwards it distributes to tissues (esp. fatty)) –> ** Termination of action of Thiopentone is mainly due to Redistribution**
Anaesthetic agents Slows brain waves: 1. Initially there is an increase in frequency due to patient arousal/awareness of injection. –> 2. Slowing of electoncathogram –> 3. Delay in relation to peak plasma concentration
Reason: delay is due to molecules taking time to get from blood to brain (e.g. cross blood brain barrier)
** graph

Question 7

Effect compartment model

Answer 7

It is difficult to measure drug concentrations at the site of action, therefore an empirical “effect” compartment is proposed
1. Time to reach a steady state/constant rate of input into = determined by elimination 1/2 life of Plasma/central compartment
2. Constant plasma drug concentrations = constant input into effect compartment = determined by equilibration half-life
Overall: equilibration process is determined by 1/2 life of loss from effect compartment
** graph

Question 8

What is the time course of accumulation of a drug determined by?

Answer 8

1/2 life of elimination

NOTE the rate of infusion (rate of infusion determines concentration levels reached)

Question 9

Determinants of Equilibration 1/2 life

Answer 9

Equilibration 1/2 life = Effect compartment 1/2 life

1. Volume of effect compartment: organ size + tissue binding (apparent volume distribution)
2. Clearance of effect compartment: blood flow + diffusion

Question 10

Thiopentone limiting determiants re Equilibration 1/2 Life

Answer 10

1. Volume: binds to GABA receptors in brain which has a relatively small volume distribution throughout the brain
2. Clearance: Rapid perfusion of brain –> high blood flow to the brain –> thiopentone is washed out rapidly
   Overall: Thiopentone has a Short equilibration half life = 1min
   (therefore takes 4min/4 half lives to reach a steady state in the brain + 90% equilibration)

Question 11

Binding to a receptor

Answer 11

Drugs reach effector compartment –> Bind to receptor
- usually is a rapid process
- however some drugs do dissociate slowly –> receptor binding is the major factor causing delayed drug effect for these drugs
Very potent drugs tend to dissociate slowly:
1. Digoxin (effects heart)
2. Ergotamine (effects on uterus and blood vessels)

Question 12

Digoxin when Binding to receptor

Answer 12

Overall: slow AV conduction and increases cardiac contractility

1. Volume: extensive binding to heart to NaKATPase –> large apparent volume distribution as is locate everywhere/lots in heart muscle
2. Clearance: Rapid perfusion of heart (well diffused vs others tissues e.g. fat)
3. Slow unbinding from NaKATPase (most likely cause of delayed onset of digoxin effects)

Question 13

Time Course of Digoxin

Answer 13

**graph
Cp= plasma concentration –> can be used to predict average tissue conc.
Ct = tissue concentration = non specific therefore wont reflect distribution/equilibration at heart (site of action)
1. Plasma concentration is falling over first 3 hours as drug effect is increasing –>distribution to tissues –> time for drug to reach site of action
2. Peak effect occurs 3 hours after initial dose
3. ** Effect compartment (Ce effect) reaches peak before average tissue concentration. Partially sue to more Rapid perfusion of heart vs. other bodily tissues e.g. Fat

Question 14

Digoxin Equilibration half life

Answer 14

Slow

1. Long dissociation half life = long time to reach binding equilibrium = delayed onset of digoxin effects
2. Long dissociation half life = also makes digoxin such a Potent drug

Question 15

Ratio re. Equilibrium Receptor Binding

Answer 15

Association half life : dissociation half life

Therefore Digoxin: Long dissociation half life = small concentration producing 50% binding at equilibrium = high potency

Question 16

Two part Mechanistic model

Answer 16

1. Distribution delay from the blood –> heart interstitial tissues (based on PBPK model)
2. Subsequent slow Receptor Binding (E.g. NaKATPase for digoxin)
   - receptor occupancy was used to predict the inotropic effect
   * *model

Question 17

Physiological Intermediate

Answer 17

1. Drug Action: inhibiting Vit K recycling back into active for
2. Rapid effect: decreased synthesis of clotting factors
3. Delayed response: prolonged coagulation time (INR)

Question 18

INR

Answer 18

International Normalised Ratio

Question 19

Warfarin in relation to Physiological intermediate

Answer 19

Anticoagulation, treats:
1. deep vein thrombosis
2. prevents blood clots + emboli associated with atrial fibrillation
3. Inhibits Vit K recycling in liver –> decreasing synthesis rate of clotting factors
Observable response: increased time for blood to clot (have slowed the synthesis of clotting factors, but they still need to leave the body –> elimination half life of clotting factors) (measured via INR)

Question 20

The Vitamin K cycle and associated drug action

Answer 20

Vitamin K = essential co-factor for synthesis of clotting factors

1. Prothombin complex precursors –> activated by gamma-dlutamul decarboxylase –> Prothrombin complex proteins/Protein clotting factors (have a slow turnover in blood)
2. Simultaneously Vitamin K is inactivated –> forms Vitamin K epoxide
3. Warfarin in quickly absorbed form drug (Fast acting - mins) –> reaches liver and enters cells –> inhibits Vitamin K reductase from becoming Vit K epoxide reductase
4. This stops the recycling of VitK epoxide back to active form –> Prothrombin/clotting factor synthesis is reduced
   * *diagram

Question 21

Warfarin Time Course

Answer 21

time course of change = half life of proteins (e.g. factor VII)
slow elimination = new warfarin steady state = assoc. INR change
Average dose of warfarin = close to C50 of warfarin inhibition
Steady state INR: - higher INR at low C50 - lower INR at high C50
Time to reach a new steady state INR = only determined by the half life of clotting factors
** graph

Question 22

Warfarin Delayed response

Answer 22

1. C50 for synthesis is 1.5 mg/L
   - synthesis is reduced 50% at C50
   - [prothrombin complex] is reduced 50%
2. Critical parameter: prothrombin complex 1/2 life = about 14 hours
   - Therefore takes 4 half lives to reach Steady state (of elimination) (2-3 days)
   Note: wait a week before measurement: allows warfarin to reach a steady state (re. dose and INR) due to delayed effects

Question 23

Delayed response of ACE inhibitors

Answer 23

e.g. Enalapril, has a slow effect on blood pressure, due to:
1. Loss of Na
2. Decrease in Plasma volume
Sodium turnover takes about a week to reach a new steady state (delayed effects due to physiological turn over)

Question 24

What are often an outcome of cumulative drug action?

Answer 24

1. clinical outcome benefits

2. adverse effects

Question 25

Diuretics and heart failure

Answer 25

1. Heart failure medication: Digoxin, ACE inhibitors and Betablockers are all used to improve survival
2. Diuretics (e.g. frusemide): provide relief of symptoms via:
   a) relieve Congestive HF symptoms due to excess fluid : e.g. breathlessness. ankle swelling, dropsy
   b) Net reduction in fluid causes benefit (Na loss causes H2O loss)
   - kidneys retain less fluid –> encourage fluid loss

Question 26

Frusemide Diuretic effect Emax model

Answer 26

rapidly reversible action on the Na+ transporter in the PT

• sigmoidal Emax model: frusemide conc vs Na excretion rate
• Max Na+ excretion ate is 180mmol/Hr –> naturally 1L of plasma contains 140mmol of Na
• heart failure can tolerate large doses of frusemide as kidneys aren’t working

Question 27

Frusemide Diuretic effect time course

Answer 27

1. Illustrated by large Oral dose (120mg). Quick initial effect –> plateaus for 2x hours –> drops rapidly
   - loss of effect is faster than plasma concentration –> due to steep concentration-effect relationship with Hill=3
   (too high concentraiton = lead to less of an effect)
2. 40 mg dose. 1/3 of concentration of larger dose. but the maximum effect 40mg dose = nearly as big at 120mg maximum effect
   - due to peak concentration achieving nearly 80% of Emax
   - no long plateau = concentraiton isnt wasted

Question 28

Schedule Dependance with Frusemide diuretic 120mg and 40mg doses over 12 hours

Answer 28

Cumulative Na excretion = area underneath the effect curve = schedule dependance
Note: curve is time vs sodium excretion
AUEc predicts cumulative response
1. Smaller dose more frequently = 50% increase in overall response
Note: exposure/total concentration was 120mg for both
Therefore Schedule dependance illustrates:
Effect depends on 1. Dosing schedule 2. Total dose
- schedule dependance is predictable as it is quickly reversible
- commonly seen in drugs whose outcome is dependant on cumulative response, effect approaches maximum after each dose

Question 29

Maths behind Schedule Dependance with Frusemide diuretic 120mg and 40mg doses over 12 hours

Answer 29

40mg x 3 = AUCe of 600mmol (Na per 12 hours)
120mg x 1 = AUCe of 400mmol (Na per 12 hours)
–> Response is increased by 50% using 40mg doses three times per day
- even through total dose over 12 hours is identical

Question 30

Irreversible Anti-cancer agents

Answer 30

1. Action: Irreversibly binds to cell structure (DNA/regulatory proteins) and remains until cell dies –> therefore doesnt show schedule dependance as is an irreversibly binding drug
2. Delayed effect: Block of cell division/cell death
3. Cumulative response: slowing/reversal of tumour growth
   Note: many anti-cancer agents are in this category (cisplatin, cyclophosphamide, busulfan)

Question 31

Dose Individualisation r.e. Busulfan

Answer 31

Busulfan ablates bone marrow prior to bone marrow transplant
- poisons bone marrow within a few days via irreversibly binding to DNA and not dissociating
Response is due Cumulative exposure (AUC) (Amount of cells killed depends on the total amount of Busulfan given)
Plasma concentration are used to guide individual treatment (predicts size of subsequent doses)