L290 Exercise-Drug Interactions Flashcards
Physiological changes with exercise that can influence drug pharmacokinetics - list 7 changes
- Redistribution of BF (↑ muscle mass)
- Altered skin temperature and/or altered hydration
- ↑RR and tidal volume
- ↓ gastric emptying
- ↓ intestinal transit time
- Loss of water from plasma into tissues
- Altered metabolic enzyme activity
How does sweat affect PK? Which drugs in particular might this affect?
- Sweat increases absorption
- Transdermal drugs
↓ gastric emptying - how does this affect PK?
↓ delivery of oral drug to the SI → ↓ abs
↓ intestinal transit time - how does this affect PK?
→ speeding up of oral drug movement → ↓ abs
Loss of water from plasma into tissues - how might this affect PK?
- Potentially affects binding proteins, crucial for some drug distribution
Altered metabolic enzyme activity - how might this affect PK? In whom in particular might this occur?
- E.g. in trained individuals - possible consequence for e.g. half-life
↑RR and tidal volume - which drugs might this affect in particular?
Inhaled drugs
Re-distribution of blood flow during physical activity: how it might have implications on ADME
- Absorption: depending on route of administration
- Distribution: increased muscle and skin blood flow
- Metabolism: decreased hepatic blood flow
- Excretion: decreased renal blood flow
Clinical use of insulin
Type 1 diabetes, advanced Type 2 diabetes
Route of admin: insulin
- injection (also inhalation, pump)
Plasma [insulin] with ex vs rest
exercise > rest
Mechanisms for increased plasma [insulin] with ex (2)
a. ↑BF to skin, muscle → ↑absorption
b. ↑ tissue sensitivity to insulin
Factors determining effect of ex on insulin (5)
- Type of insulin
- variable onset and duration
- dosing schedule and route
- Proximity of exercising limbs
- Close to limb → ↑ abs
- Type, duration and intensity of exercise
- Prolonged ex might need glucose supplements
- Amount of muscle mass
- Level of fitness
Determinants of blood glucose during ex with insulin (3)
- Pre-exercise glucose levels
- Patency of counter-regulatory mechanisms
- Carbohydrate supplementation
a. simple or complex
b. rate of absorption
c. timing of administration
Exercise-induced hypoglycaemia - possible mechanisms (3)
- Accelerated insulin absorption from sites near exercising muscles
- Exercise-mediated enhancement of insulin action
Lack of decline in insulin secretion during exercise
- Exercise-mediated enhancement of insulin action
Exercise-induced hyperglycaemia - mechanisms (3)
- Excessive carbohydrate supplementation
2. Too large a reduction in insulin dose
GTN: clinical use
Angina
Route of admin: GTN
- transdermal for prophylaxis
- (sublingual for acute angina)
Plasma [GTN] with ex vs rest
- sauna > exercise > rest
Mechanisms for increased plasma [GTN] during ex (3)
- ↑ skin BF
- ↑ kinetic energy of drugs with ↑ skin temp
- ↑ hydration may improve absorption of drugs
Implications for increased transdermal absorption of GTN (2)
- May provide benefit for exercising patient to minimise exercise-induced angina
- Decline in preload ∴ ↓O2 demand of heart- Potential for vasodilation in skin and exercising muscle to cause
A. Excessive hypotension B. Diversion of coronary BF
- Potential for vasodilation in skin and exercising muscle to cause
Clinical use: salbutamol
Asthma
Route of admin: salbutamol
Inhalation
Plasma [salbutamol] with ex vs rest
exercise > rest
Mechanisms for ↑ plasma [salbutamol] during ex (3)
- ↑ RR
- ↑ pulmonary blood flow
- ↑ epithelial permeability
Implications of ↑ plasma [salbutamol] (2)
- may provide benefit for exercising patient to minimise exercise-induced asthma
- *despite higher BA, because of ↑BF and RR, bronchodilator effects are less prolonged - need more frequent dosing!
Effects of exercise in the gut are…
variable
List to possible effects of exercise on gut
A. Inhibits gastric emptying
B. ↑ intestinal motility
Which cohort is not affected by decreased gastric emptying with ex?
Trained athletes - adaptation occurs
Clinical use: warfarin
Anticoagulant
Route of admin: warfarin
Oral
INR (no PK data) with warfarin in ex vs rest
exercise
Mechanisms of decreased INR (unconfirmed) with ex (using warfarin) (2)
- ↑ binding of warfarin to albumin
2. ↑ metabolism with training
Implications of decreased [warfarin] with ex
↓ free warfarin, ↓ INR (i.e. shorter clotting time) → ↑ risk of thrombosis with ex
Clinical use: digoxin
heart failure, atrial arrhythmia
Route of admin: digoxin
Oral
plasma/muscle [digoxin] with ex vs rest
- Plasma [digoxin]: exercise less than rest
- Muscle [digoxin]: ex > rest
Mechanisms of ↓ plasma [digoxin] with ex
redistribution due to increased binding to skeletal muscle
Implications for ↓ plasma [digoxin] with ex
• reduced efficacy to increase contractility and control rate
TI and Vd of digoxin
- narrow TI
- high Vd - high binding affinity to skeletal muscle normally
Clinical use of b-blockers
hypertension, angina
Route of admin of b-blockers
oral
[b-blocker] with ex vs rest
Effect of short duration exercise will vary with drug:
• Plasma [propranolol]: exercise > rest
- Propranolol NS β blocker
• Plasma [atenolol]: exercise > rest
- Atenolol S β blocker
• Plasma [carvedilol]: exercise = rest
- Carvedilol NS β and α blocker
Mechanisms of ↑ plasma [beta-blockers] with ex (2)
- ↓ hepatic clearance for propranolol (→ ↓ metabolism)
↓ renal clearance for atenolol (→ ↓ excretion)
Implications of ↑ plasma [beta-blockers] with ex
- ↑ risk of exercise-limiting adverse effects e.g. bronchoconstriction, fatigue (from NS block of b2-mediated skeletal muscle VD)
- → patient’s ability to exercise is more difficult → poor exercise compliance: important to encourage compliance because this effect tapers off
Why use drugs in sport? (2 reasons)
- Hide the use of other drugs
- Diuretics (→ ↓ [banned substance] in urine)
- Improve performance
For a substance to be prohibited in sport, what conditions must it meet?
Must meet two of the following three conditions:
1. Potential to enhance, or does enhance performance in sport 2. Potential risk to the athlete’s health 3. World Anti-Doping Agency has determined that the substance or method violates the spirit of sport
Therapeutic Use Exemptions (TUE): what are they?
- Available if an athlete suffers an acute or chronic medical condition that a doctor can only treat with a prohibited substance
- Athletes must receive approval before using substance
Clinical use: b2-agonists
Asthma
Route of admin: b2-agonists
Inhalation
Potential advantages in sport with b2-agonists (3)
With systemic administration:
• ↑skeletal muscle BF → ↑ O2 supply and lactic acid removal reduces fatigue
• Anabolic effect: ↑ muscle mass ( → strength)
• Catabolic effect: ↓ body fat
Potential adverse effects with b2-agonists (2)
- Tachycardia: NS activation of cardiac b1-adrenoceptors
2. Muscle tremor: activation of skeletal muscle b2-adrenoceptors
Status in Sport: b2-agonists
- Prohibited for any route other than inhalation
* No TUE required for salbutamol (maximum dose 1600 mg/day, urine concentration
Potential advantage in sport: GCS (1)
• Anti-inflammatory action can mask pain so athlete can compete despite injury
Potential disadvantage in sport and adverse effects: GCS (5)
- Damage to tissue before full recovery (bc can’t heed body’s warning signs)
- Chronic use can cause:
A. Osteoporosis
B. Growth suppression (children)
C. Skin fragility
Increased infections
- Chronic use can cause:
Status in Sport: GCS
• Approved without a TUE
- Topical use with skin creams, eye drops, topical mouth applications, nasal sprays and ear drops
- Inhalation for asthma (certain preparations only)
• Require abbreviated TUE if administered via intra-articular route
• Prohibited TUE required for systemic administration (oral, intravenous, rectal)
