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The Disposition of Drugs. Olaf H. Drummer Monash University, Melbourne AUSTRALIA [email protected] Definitions. Disposition refers to total process of absorption, distribution, metabolism and excretion of drugs

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The disposition of drugs

The Disposition of Drugs

Olaf H. Drummer

Monash University, Melbourne

AUSTRALIA

[email protected]


Definitions
Definitions

  • Disposition refers to total process of absorption, distribution, metabolism and excretion of drugs

  • Pharmacokinetics refers to the science which studies the relations between blood concentration and time


Absorption
Absorption

  • All substances must be absorbed to be biologically active.

  • The extent and rate a drug is absorbed is dependent on the substance, the formulation, and the route of administration.

  • The biological activity will therefore be dependent on the absorption and its physiochemical properties


Drug administration
Drug Administration

  • Parenteral routes

    • dose delivered by injection and not through alimentary canal

    • includes all forms of injections and routes of administration which bypass mesenteric circulation

  • Enteral routes

    • drugs that are delivered through alimentary canal

    • includes oral, sublingual, buccal and rectal administration


Routes of administration

Oral

Intravenous

Intramuscular

Intraperitoneal

Subcutaneous

Rectal

Intrathecal

Inhalation

Buccal

Sublingual

Percutaneous

Ocular

Intranasal

Intraarterial

Routes of Administration

There are many routes by which drugs can be administered


Profiles of absorption
Profiles of Absorption

  • Each route of administration has a different pharmacokinetic profile

  • The parenteral routes have the quickest onset of action, particularly IV, although inhalation and intranasal dosing can give very rapid absorption

  • Orally administered drugs have a much slower onset with Cmax occurring typically at 1-2 h post dose,



Mechanisms of drug absorption
Mechanisms of Drug Absorption

The gastrointestinal barrier is best considered a semipermeable membrane, with two primary mechanisms to allow transport of drugs

  • Passive Diffusion

    • proportional to concentration gradient

    • highest for lipid soluble drugs

    • highest for unionised drugs

  • Facilitated Diffusion

    • endogenous substances eg glucose, amino acids

    • few drugs eg penicillamine, 5-fluorouracil


Factors affecting gastrointestinal absorption
Factors Affecting Gastrointestinal Absorption

  • Gastrointestinal motility

  • Splanchnic blood flow

  • Particle size and formulation

  • Physiochemical factors


Gastrointestinal motility
Gastrointestinal Motility

  • Most drugs are not absorbed in the stomach but rather the small intestine

  • Gastric emptying will therefore affect rate of delivery to the jejumen

  • Motility has a big effect on drug absorption

    • food affects motility and rate of gastric emptying

    • slowed by migraine, diabetic neuropathy etc

    • metoclopramide increases gut motility

    • morphine and other opioids reduces motility


Splanchnic blood flow
Splanchnic Blood Flow

  • This refers to the flow of blood through the mesenteric system

  • Blood flow is reduced in hypovolaemic states such as those caused by disease or injury

    • following overdose to drugs causing coma

    • following serious injury including abdominal area

    • propranolol absorption increased dramatically following food


Gastric emptying and detection in stomach contents
Gastric Emptying and Detection in Stomach Contents

  • It may take several hours for drugs to be removed from stomach

  • This time may extend to days in coma!

  • Drugs may appear in stomach contents from biliary excretion or vomiting!

  • Consider these factors when interpreting gastric data


Particle size and formulation
Particle Size and Formulation

  • The formulation of orally administered drugs can greatly affect the extent and rate of absorption

    • tablets are more likely to be affected than capsules, suspensions and solutions in that order

  • This applies particularly to drugs with sparing solubility in acid medium

  • Certain excipients can retard absorption

    • eg dicalcium phosphate with tetracycline

  • Particle size of drug can be very important


Controlled released drugs
Controlled Released Drugs

  • Formulation of some drugs are controlled to delay release or sustain release over a longer period of time

    • coated tablets (sugar and film-coated)

    • slow release formulations (verapamil etc)

    • enteric coated (to prevent release in stomach)

      • Aspirin, KCl, NSAIDs

  • Membrane-controlled delivery include patches for steroids, nicotine, nitroglycerine, fentanyl


Physiochemical factors
Physiochemical Factors

  • These factors alter the chemical state of the drug for absorption by

    • binding drug to another molecule affecting absorption, or

    • alteration of pH of stomach and small intestine by other drugs, by food or disease state

    • the degree of ionization of the drug in the gut

    • the use of food which can increase, decrease or not alter the rate and extent of absorption


Gastric vs intestinal absorption
Gastric vs Intestinal Absorption

  • Acidic drugs tend to be at least partially absorbed in stomach since at the pH of the stomach the molecule is unionised,

    • eg acetylsalicyclic acid, NSAIDS, captopril

  • Basic drugs are only poorly absorbed in stomach

  • Most absorption occurs in small bowel, duodenum, jejumen and ileum

  • Large intestine inefficient in absorbing drugs


Effect of food on drug absorption
Effect of Food on Drug Absorption

  • Food may increase, decrease or not affect drug absorption

  • In most cases food alters the rate of absorption but doesn’t affect the extent

  • In some cases food may substantially alter the extent of absorption and rate of absorption


Examples of food effects
Examples of Food Effects

  • Food reduces ethanol absorption (5-10%)

  • Food effects many antibiotics - some increase others decrease (penicillins, erythromycin)

  • Food delays absorption of digoxin

  • Food increases absorption of thiazide diuretics

  • Food increases absorption of phenytoin


Blood alcohol concentration variation with time and food
Blood Alcohol ConcentrationVariation with Time and Food

CHO>protein>fat

Fasting

Food


Pharmacokinetic constants
Pharmacokinetic Constants

  • Half-life

    Time taken to halve level

  • Volume of distribution

    Artificial apparent volume to which drug equilibates

  • Clearance

    body’s ability to remove drug


Pharmacokinetic terms
Pharmacokinetic Terms

10

0

C

Vd = Dose / C0

k

k = 0.693/t1/2

mg/L

Cl = Dose/AUC

4

2

t1/2

1

24

0

Time (hours)


Volumes of distribution l kg
Volumes of Distribution(L/kg)

Frusemide 0.1

Diazepam 1

Morphine 2

Digoxin 6

Tetrahydrocannabinol 20

Chlorpromazine 20


Blood burden v vd
Blood Burden v Vd

Vd (L/kg)% Drug in blood

0.10 40

0.15 27

0.60 6.7

1.0 4.0

10 0.40


Estimation of drug consumption
Estimation of Drug Consumption

  • Suspected overdose of diazepam.

  • Blood level 2.0 mg/L

  • What dose was consumed?

  • Vd = 2 L/kg

  • Dose = 2 x 2 = 4 mg/kg body weight

  • Amount of drug in body = 4x70=280 mg


Body burden of diazepam
Body Burden of Diazepam

  • Blood concentration suggests therapeutic use, ie 0.9 mg/L

  • No diazepam in gastric contents, ie no recent use of diazepam

  • Body burden 323 mg or 65 5-mg tablets!

  • Vd calculation gave an estimate of 42 mg!


Estimation of drug usage
Estimation of Drug Usage

  • The previous result is likely to be quite inaccurate and even misleading.

  • Vd assumes state of equilibration - usually not likely in overdoses.

  • Vd assumes linear kinetics - usually not likely in overdose when saturation kinetics apply.

  • 280 mg implies overdose, but could be accumulation with chronic use.


Estimation of drug usage1
Estimation of Drug Usage

  • To estimate likely amounts of drugs consumed it is advisable to rely on case reports in which amount of drug consumed is known and have given a quantified result.

  • Alternatively, several key tissues reflecting substantial body burden is required.


Conclusions
Conclusions

There are many factors affecting the disposition of drugs.

Knowledge of the disposition of drugs is essential in order to properly assess toxicological results



Definitions1
Definitions

  • Metabolism Refers to the process of biotransformation of the administered substance to another chemical substance.

  • Excretion

    Refers to the elimination or process of removal of foreign substances.


Schema Showing Drug Movement

Receptors/Site of Action

Tissue reservoirs

free bound

bound free

Systematic

Circulation

Absorption

Excretion

free drug

bound drug

metabolites

Biotransformation


Metabolism
Metabolism

  • There are two main types:

    • Phase 1 - introduce or expose a functional group, eg hydroxylation.

    • Phase II - are conjugation processes which lead to rapid excretion, eg glucuronidation reactions


Metabolic pathways
Metabolic Pathways

  • Phase I Processes

  • N-dealkylation

  • O-dealkylation

  • Hydroxylation (aliphatic and aromatic)

  • Oxidation (nitrogen and oxygen)

  • Deamination

  • Hydrolytic


Metabolism1
Metabolism

  • Dealkylation

RNH

RNHCH

2

3

  • Hydroxylation

R

OH

H

R


Methamphetamine
Methamphetamine

hydroxylation

CH

3

{

HO

CH

CHNHCH

2

3

N-dealkylation

CH

3

CH

CHNH

2

2


Alprazolam
Alprazolam

  • doses 0.5-4 mg daily

  • blood levels 20-60 ng/ml

  • half-life 6-22 hours

  • metabolized by hydroxylation to -hydroxy alprazolam (also active)


Diazepam
Diazepam

  • doses 5-40 mg daily

  • blood levels <1000 ng/ml

  • half-life 40-100 hours

  • metabolized

    • by N-dealkylation to nordiazepam (also active),

    • hydroxylation to oxazepam (active)

  • Temazepam is N-methyl analog of oxazepam (active)

Metabolites

Nordiazepam

Temazepam

Oxazepam


Flunitrazepam
Flunitrazepam

  • 1 or 2 mg tablets

  • peak blood concentrations 0.02 mg/L [2 mg]

  • half-life 17 hours

  • Metabolized to

    • 7-amino-flunintrazepam

    • 7-acetamido-flu…

reduction

7-amino metabolite


Temazepam
Temazepam

Hypnotic

  • 10-20 mg doses (night)

  • blood levels < 1000 ng/ml

  • half-life 4-15 hours

  • metabolized by N-demethylation (oxazepam) and conjugation

  • common benzodiazepine

  • impairs driving skills


Phase ii processes
Phase II Processes

  • Glucuronidation

    eg paracetamol, morphine, diazepam

  • Sulfation

    eg paracetamol, steroids, salbutamol

  • Acetylation

    eg clonazepam, sulfonamides


Oxazepam
Oxazepam

  • 15-60 mg doses (night)

  • blood levels < 1000 ng/ml

  • half-life 4-15 hours

  • metabolized by conjugation

  • Other hydroxylated benzodiazepines also conjugated

    • Temazepam

    • Lorazepam



Paracetamol acetaminophen
Paracetamol (Acetaminophen)

NHCOCH

NHCOCH

3

3

SCH

CHCOOH

2

OH

NH

OH

2

N-acetylation = mercapturic acid conjugate

Sulfate and glucuronide conjugates


Paracetamol acetaminophen excretion data
Paracetamol (Acetaminophen)Excretion Data

  • Paracetamol 2%

  • Paracetamol glucuronide 45-55%

  • Paracetamol sulfate 20-30%

  • Cysteine & mercapturates 15-55%

  • Parent drug excretion increases in overdosage to 10-20%


Hydrolysis and esterification
Hydrolysis and Esterification

Cocaine metabolized to BZE and EME

Also

Transesterification to cocaethylene


Sites of metabolism
Sites of Metabolism

  • Most drugs are metabolized by the liver since the liver is the major metabolic organ in terms of source of enzymes and size of organ.

  • Kidneys, lungs, skin and the gastrointestinal tract are also significant sources of metabolism.

  • Heroin for example is metabolized by esterases in blood.


Microsomal metabolism
Microsomal metabolism

  • Phase I processes are mainly mediated by enzymes found in the endoplasmic reticulum or microsomes.

  • Microsomal enzymes are largely the cytochrome P-450 group.

  • Twelve cytochrome P-450 gene families are known, these are called CYP1, CYP2 etc with several sub-groups.


Mechanisms of excretion
Mechanisms of Excretion

  • Biliary and Fecal Excretion

    - Some drugs are excreted into bile eg morphine, when this occurs drugs are then excreted via feces or are reabsorbed in the GIT ie - entero-hepatic recirculation.

    - Some drugs are incompletely absorbed and are therefore excreted via feces.

    - High molecular weight drugs or conjugates are particularly good substrates.


Mechanisms of excretion1
Mechanisms of Excretion

  • Other routes of elimination.

    - respiration eg ethanol

    - saliva eg most “non-bound” drugs

    - sweat eg cocaine

    - hair eg most substances

    - breast milk eg lipophilic drugs



Types of drug interactions
Types of Drug Interactions

  • Metabolic

  • Effect on protein binding

  • Pharmacodynamic

    • CNS depression

    • Cardiac dysrhythmias

    • Other drug interactions

      • Eg serotonin syndrome, NMS


Metabolic drug interactions
Metabolic Drug Interactions

  • Inhibition of enzymes

    • disulfiram on ethanol metabolism

    • ethanol on methanol metabolism

    • inhibitors of tubular secretion

    • cimetidine on P-450 enzymes

    • ketoconazole

    • corticosteroids


Inhibitors of tubular secretion
Inhibitors of Tubular Secretion

  • Many acidic drugs inhibit or compete with tubular secretion

    • probenecid

    • penicillins

    • salicyclic acid

    • frusemide

    • allopurinol


Cimetidine inhibition of p 450
Cimetidine Inhibition of P-450

  • Cimetidine, but not other H-2 antagonists inhibit microsomal p-450 metabolism

  • Drugs affected include:

    • ACE inhibitors

    • Anticoagulants

    • beta-blockers

    • benzodiazepines

    • phenytoin

    • theophylline

    • verapamil


Other inhibitors
Other inhibitors

  • SSRIs – many

  • MAOIs - some

  • Anti-fungals

    • Ketoconazole

  • Anti-retrovirals

    • Acyclovir etc

  • Propoxyphene

  • Alcohol


Examples of drug interactions

Alcohol

Liver microsomal enzymes

MAOI inhibitors

Inhibition of P450, serotonin

Propoxyphene

Inhibits CYP3A4

Serotonin reuptake

Fluoxetine, paroxetine

Barbiturates

induction of P450

Barbiturates, benzodiazepines,

Cocaine

Alcohol, amphetamines

Opioids

Benzodiazepines

Antidepressants

Benzodiazepines

O-alkylated opioids

Methamphetamine, MDMA

Non-conjugated benzodiazepines

Examples of Drug Interactions


Protein binding
Protein Binding

  • Drugs are often bound to blood proteins such as albumin, alpha-1 glycoprotein, lipoproteins, hemoglobin etc

  • The component of as drug that is not bound is only active

  • Biological activity is proportional to free drug concentration

  • At least 2 bindings sites for acidic are known on human serum albumin (I & II)

  • Basic drugs bind to other sites


Protein binding cont
Protein Binding cont.

  • Warfarin-like binding occurs for warfarin, phenytoin, valproate, frusemide, salicylate, sulfonylureas etc

  • Diazepam-like binding occurs for diazepam, NSAIDs, probenecid, tryptophan, sulfonylureas etc

  • Drugs in each group displace bound drugs

  • Toxicity possible by co-admininstration of two or more drugs.


Drug binding to plasma albumin
Drug Binding to Plasma Albumin

Diclofenac 99.5%

Diazepam 95-99%

Warfarin 95-99%

Amitriptyline 90-95%

Chlorpromazine 90-95%

Valproic acid 90-95%

Phenytoin 90%

Quinine 70-90%

Aspirin 50%


Renal disease and protein binding
Renal Disease and Protein Binding

  • Renal disease impairs protein binding, particularly with acidic drugs - doubling in free concentration expected

    (8.4% to 20% for valproate)

  • Diazepam binding impaired in renal disease (1.2% to 4.7% in uraemics)

  • Basic drugs not generally affected by renal disease


Relationship between valproic acid binding in plasma and renal function
Relationship between valproic acid binding in plasma and renal function

% Unbound VPA

Creatinine clearance


Liver disease and protein binding
Liver Disease and Protein Binding renal function

  • Liver disease often affects protein binding, larggely by the change in serum albumin concentration but also by increased bilirubin concentrations

  • Diazepam binding decreased 0.5 -1.5 fold in alcoholic cirrhosis

  • Tolbutamide was affected similarly during acute phase of viral hepatitis

  • Salicylate, phenylbutazone binding also reduced in alcoholic cirrhotics


Pharmacodynamic interactions
Pharmacodynamic Interactions renal function

  • This is caused by an “adverse interaction” by two or more chemicals on each others effects

  • Most commonly seen with the use of Central Nervous System (CNS) Depressants

    • alcohol plus benzodiazepines

    • mixture of tranquilizers/hypnotics

    • alcohol plus morphine/heroin


Cns depression
CNS Depression renal function

  • Persons with a high BAC are more likely to suffer adverse consequences from other CNS depressant drugs

    ie BAC 0.25% and heroin users

    ie BAC 0.25% and benzodiazepines

    ie morphine 0.4 plus chlorpromazine 0.5

  • Death therefore more likely at lower concentrations than when one drug alone is used


Case examples
Case Examples renal function

Person found deceased with no significant pathology at autopsy

Case 1

Ethanol 0.42%

No other drugs detected

Case 2

Ethanol 0.26%

Temazepam 1.2 mg/L

In the presence of 2 CNS depressant drugs toxicity

of ethanol is increased


Cardiac dysrhythmias
Cardiac Dysrhythmias renal function

  • Disturbances in heart rhythm can occur in certain cases such as:

    - use of cocaine and amphetamines

    - overuse of propoxyphene

    - overuse of tricyclic antidepressants

    - overuse of tranquilizers

    - overuse of digoxin

    - overuse of antiarrhythmics (verapamil, amiodarone, lignocaine, quinidine)

    - use of a combination of two or more drugs


Other drug interactions
Other Drug Interactions renal function

  • There are numerous reported adverse drug interactions. Those of interest to the toxicologist are:

    - moclobemide and tri-cyclics

    - monoamine oxidase inhibitors such as tranylcypromine and tricyclics

    - digoxin and quinidine/verapamil

    - recreational use of lignocaine


Serotonin toxicology

Serotonin Toxicology renal function


Serotonin
Serotonin renal function

  • Major monoamine involved in regulating mood, temperature regulation, endocrine activity, sexual behaviour, sleep and motor systems, smooth muscle tone peripherally in git and blood pressure regulation

    • depression, anxiety, obsessive compulsive disorder, psychosis, eating disorders

  • Produced from l-tryptophan (amino acid)

  • Some 15 receptor subtypes known, each linked to a different physiological role!


Serotonin syndrome
Serotonin Syndrome renal function

  • Characterised by:

    • altered mental status

    • restlessness

    • myoclonus

    • hyperreflexia

    • diaphoresis

    • hyperrthermia

    • tremor

    • incoordination

Not all subjects exhibit all symptoms!


Drugs capable of causing ss
Drugs capable of causing SS renal function

  • SSRI used to excess - individually or combined

    • sertraline, fluoxetine, citalopram, paroxetine, fluvoxamine etc

  • Combination with moclobemide (MAOI-A)

  • Combination with MAOI-B

    • seligiline etc

  • Some tricyclic antidepressants

    • clomipramine, desipramine

  • Trazodone, nefazodone antidepressants

  • Tramadol (non-opiate narcotic)

  • Buspirone (anti-anxiety)

  • Most benzodiazepines


Ss cont
SS cont. renal function

  • Anti-psychotics

    • clozapine, olanzapine, risperidone

  • Sumatriptan (migraine treatment)

  • Odansetron (for nausea)

  • Antiviral drugs

    • acyclovir etc

  • Antifungals

    • fluconazole etc

  • Amphetamines incl. Ecstasy


References
References renal function

  • Drug Treatment by Avery

  • Pharmacology by Rang and Dale

  • Biopharmaceutics and Clinical Pharmacokinetics by Gibaldi

  • Ellenhorn’s Medical Toxicology

  • The pharmacological basis of therapeutics by Goodman and Gilman

  • The Forensic Pharmacology of Drugs of Abuse by Drummer


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