Distribution

1
Distribution Fate

• Lecture 4

2
Distribution

• Drug disperses throughout system
• does not reach target
• silent receptors
• Distributes in
• Blood extracellular fluid
• organs tissues

3
Redistribution

• Drug releases re-enters circulatory system from
• Depot binding
• Protein binding
• Ion trapping
• Bound / unbound drug
• Ratio maintained
• Prolongs drug effects

4
Depot Binding

• Unable to cross membranes
• Slow drug effects
• or prevent
• Prolong drug effects
• not metabolized
• Termination of drug effects
• Redistribution

5
DepotBinding
Organs Tissues
Blood
Brain
CTZ
6
Protein Binding

• Large blood proteins
• albumin most abundant
• Nonselective binding
• Prevents drug from reaching target
• multiple drugs ? compete
• higher effective dose for 1
• Seldom clinical implications
• Valium 99 bound, 1 free
• Redistribution

7
Drug Fate

• Immediate long-term drug disposal
• Determines duration of drug effects
• drug in system ? drug effects
• Terminates drug effects

8
Half-life - t½

• After complete absorption
• Plasma half-life
• time blood levels drop by half
• distribution half-life
• elimination half-life
• metabolism excretion

9
Biotransformation

• Metabolism
• structure altered ? metabolite
• By enzymes
• site of action
• blood plasma
• liver
• Inactivation
• Some metabolites active
• e.g., valium, codeine

10
Liver

• Main site of metabolism
• nutrients
• detoxification
• 1st pass metabolism
• GI tract ? liver

11
Cytochrome P-450

• Main detoxification enzyme
• liver and intestine
• enzyme induction
• contributes to tolerance
• Inhibited by
• grapefruit juice
• 6',7'-dihydroxybergamottin?
• red wine to lesser extent

12
Excretion Kidneys

• Filtration of blood
• Excretion in urine
• Ionization required
• ion-trapping
• Active inactive form
• Koryak tribesmen (Siberia)
• Amanita muscaria

13
Excretion Kidneys

• Smoking cessation
• diet ? alkalinity of urine
• stress ? excretion
• Antidiuretic Hormone (ADH)
• regulation of water
• alcohol, caffeine inhibit
• dehydration

14
Excretion Other routes

• Lungs
• alcohol breath
• Breast milk
• acidic ? ion traps alkaloids
• alcohol same concentration as blood
• antibiotics
• Also bile, skin, saliva