PHARMACOKINETICS AND PHARMACODYNAMICS

DR O E MAJEKODUNMI Consultant Psychiatrist Neuropsychiatric Hospital Aro Abeokuta

Introduction

Modern drug treatment in psychiatry began with introduction of effective psychotropic medication in the early 1950. Specifically, antipsychotic properties of Chlorpromazine were discovered in 1952 by the French Psychiatrist, Jean Delay and Pierre Deniker. immipramine in 1957-58 by Kuhn. The last fourty fifty years had witnessed the development of other psychotropics including those belonging to the new generation

Pharmacokinetics

While pharmacodynamics is concerned about the effects of drugs on the biological activities of the body, pharmacokinectics is the study of the effect of the body on drugs. It mainly involves absorption distribution and elimination.

Route of administration and absorption

1. Enteral Oral Sublingual Rectal 2. Parenteral intramuscular intravenous Subcutaneous Inhalational Topical Intranasal Intrathecal Transdermal etc

IV Route.

Intravenous injection is the most rapid method of drug administration Advantages. Rapid & useful in emergencies. Dose can be titrated against response. Large volume can be given slowly. Avoids first pass metabolism. Disadvantages. Carries the highest risk of sudden and life threatening side effect, air embolism, sepsis, thrombosis, accidental injection to arteries & tissues, not for insoluble drugs.

IM route

Intramuscular usually result in absorption over 10 30 minutes depending on blood flow to the muscle and aqueous solubility. Lipid soluble rapidly absorbed. Depot antipsychotic preparations are formulation of drugs in inert oil which is absorbed very slowly IM paraldehyde may give sterile abscess. Creatine phosphokinase released after IM-interfere with cardiac enzyme assay. Route contraindicated in patients on anticoagulants. IM Diazepam poorly absorbed-crystallizes at site.

Oral Route

Oral route is the most common but absorption is subject to metabolism by the liver (first pass effect) leading to variable plasma concentrations for many drugs The first pass effect is the fraction of absorbed drug reaching the systemic circulation unmetabolized
Other methods of administration are not generally important for psychotropic drugs.

Absorption

Factors that affect absorption of orally administration drugs include: Gastro intestinal tract fluid, Lipid solubility G I T local PH Motility and Surface area

Absorption contd

Absorption occurs by passive diffusion across membranes. This rate depends on the drugs molecular shape and weight, its lipid solubility and degree of ionization. Weak acids are readily absorbed as they are unionized in the acid gastric juice PH (2-3). The reverse is the case with weak alkaline. An antacid reduces gastric absorption of weak acids such as aspirin. Much of the absorption takes place in the small intestine due to its large surface area and long transit times.

Distribution and bioavailability

Once absorbed into the plasma, drugs are distributed to various body tissues which depend on tissue perfusion plasma protein binding and permeability to tissue membranes Only unbound (free) drug in the plasma is available to cross the blood brain barrier. Highly plasma protein bound drugs (e.g. many anti depressants and anticonvulsants) may displace each other from binding sites leading to increased free plasma concentrations and potential for greater therapeutic effect or toxic effects.

Distribution and bioavailability contd

The distribution of a drug to the brain is governed by the brains regional blood flow Blood brain barrier Drugs affinity for its receptors in the brain High cerebral blood flow, high lipid solubility and high receptor affinity increases therapeutic effect of psychotropic drugs Most psychotropic drugs are lipid soluble and passively diffuse in and out of the brain. However, L Tryptophan and L dopa are actively transported into the brain.

Distribution and bioavailability contd

VOLUME OF DISTRIBUTION

A drug volume of distribution is a measure of the apparent space available to contain the drug in the body which is determined by the following: Age Sex Adipose tissue content and Disease state
BIOAVAILABILITY

This is the fraction of the total amount of drug administered which can be recovered from the blood stream.

Metabolism
The liver is the most important site of metabolism of most psychotropic drugs. The major metabolic routes are: (i) Non synthetic reactions Oxidation Reduction and Hydrolysis which may produce inactive or active compounds and (ii) Synthetic reactions or conjugation (mostly with glucuronic acid) which Produce inactive water-soluble compounds. The cytochrome P450 (CYP) families of enzyme are responsible for non synthetic oxidative metabolism of the majority of psychotropic drugs.

Metabolism contd

The CYP enzymes act primarily in the endoplasmic reticulumm of the hepatocytes and the cells of the intestine. Disease state such as viral hepatitis or cirrhosis may affect efficiency of drug metabolism in the CYP enzymes. Drugs may induce or inhibit the activity of microsomal enzymes leading to increased or decreased metabolism.

Drug influence on CYP system

Occur in three ways (i) Induction (alcohol, barbiturates anticonvulsants nicotine). Cimetidine an inducer of CYP3A4 may increase metabolism of alprazolam which is a substrate of CYP3A4 (ii) Non competitive inhibition Some drugs that are not a substrate for a particular CYP enzyme may indirectly inhibit and slow metabolism of substance for that enzyme. e.g. fluoxetine (inhibitor of CYP2D6 may inhibit metabolism of amitriptyline which is a substrate for the CYP2D6).

Drug influence on CYP system

(iii) Competitive inhibition concerned administration of two or more substrates for a particular enzyme which may produce competitive inhibition for the same enzyme.

Elimination

While excretion can occur in the lungs, in bile sweet milk and saliva, the kidney is the most important route. Metabolism of the parent drug to ionized and nonlipid-soluble compounds enhances renal excretion. Lithium is excreted primarily by the kidneys. Increase Plasma lithium concentration can result from reduction from renal blood flow, concurrent use with non-steroidal anti inflammation drugs, angiotesin converting enzyme inhibitors, dehydration and renal impairment.

Time of peak plasma concentration is determined by route of administration and rate of absorption. With repeated doses of a drug, equilibrium is achieved between absorption and elimination. This is termed steady state concentration. It is dependent on the dose administered interval between doses and half life of the drug (the amount of time it takes to reduce the drug plasma concentration by half).

Pharmacodynamics
Pharmacodynamics involves receptor binding (including receptor sensitivity), postreceptor effects, and chemical interactions. Receptor - is a cellular component, usually protein to which a drug binds with a high degree of selectivity producing changes in the cell which leads to its response.

Receptor
They are found in two main sites: On the surface of cells - These receptors bind neurotransmitters and bring about cellular responses by affecting ion channels or second messenger systems. Within the cytoplasm or nucleus - These receptors usually bind hormones (e.g. thyroxine, glucocorticoids).

Agonists are drugs which mimic endogenous neurotransmitters whereas antagonists block their effects. Some drugs are classified as partial agonists because they can not bring about maximum response even at full receptor occupancy. Partial agonists are said to have lower efficiency than full agonists.

Dose Response curve

Most drugs bind reversibility to receptors and as the concentration increases the response increases until all the receptors are occupied. This is illustrated as dose response curve which plots the drug concentration against the effects of the drug.

Dose Response curve

Dose Response curve

Potency of a drug refers to the relative dose required to achieve certain effects. Haloperidol is more potent than Chlorpromazine because about 5 mg of haloperidol is equivalent to 100 mg of Chlorpromazine. However, their clinical efficiency is equal. Clinical efficacy is the maximum clinical response achievable by administration of drug.

Therapeutic index is a ratio of the median toxic dose to the median effective dose. It is a measure of toxicity and safety of a drug. The median toxic dose is the dose at which 50 percent of patients experience a specific toxic effect, and the median effective dose is the dose at which 50 percent of patients have a specified therapeutic effect. Lithium and phenytoin have low therapeutic index and as such they require close serum monitoring.

Clearance of a drug is the volume of plasma from which the drug is completely removed per unit time. The amount eliminated is proportioned to the concentration of the drug in the blood. Tolerance results when a person becomes less responsive to a particular drug dosage when administered over time. This may result from alteration in the sensitivity or numbers (up or down regulation) of receptors. This mechanism also explains delay in the therapeutic effect of days to weeks of most psychotropic drugs. Development of tolerance may sometimes be associated with appearance of physical dependence on the drug.

Benzodiazepines.

Actions mediated by benzodiazepine receptors in the CNS which increases GABA Activity Good oral absorption. IM route less rapid. IV route very rapid. High protein binding. Metabolism to desmethyldiazepam-long t half-problem in elderly.

Tricyclics.

Absorption orally good,high protein binding. Metabolism involves demethylation and hydroxylation. Amitriptyline goes to nortriptyline,imipramine to desipramine. Excretion-high first pass,long t-half,allowing once daily oral administration nocte.

MAOIS.

Mostly lipid soluble,oral absorption good. Biotransformation-hydrazine compounds partly via acetylation. Excretion-inhibition of MAO continues after cessation of drug. Continue dietary/drug restriction for 2 weeks after stoppage.

Neuroleptics.

Absorption for CPZ good orally. High protein binding for CPZ Biotransformation of CPZ give active metabolites,e.g.7 hydroxychlorpromazine with high dopaminergic activity. Excretion-t half of CPZ about 12-24 hours,for haloperidol it is longer.

Lithium.

Absorption good orally. Controlled-release (C-R).preparations available. No protein binding/Biotransformation. Excretion-70-80% proximal tubular reabsorption. Lithium & sodium compete for proximal tubular reabsorption. Lithium retention follows Sodium diuresis.

Carbamazepine.

Anticonvulsant, absorption is slow and unpredictable. CR preparation available. Biotransformation includes auto induction of enzymes.Carbamazepine10,11-epoxide formed-also antiepileptic. The half-life at initiation of treatment ranges from 18 to 54 hours. After about a month it decreases to about 12 hr. resulting from autoinduction of the CYP enzymes

Phenobarbitone.

Oral absorption good,Peak C after 6 hours. IM route good. Biotransformation in liver to inert products. Excretion:10-40% unchanged in urine. Adult T1/2 about 100 hours,give once daily.

Prescribing in Special situations

Pregnancy -Medication best avoided especially in first trimester -Decision to prescribe psychotropics in pregnancy should be taken in the light of the potential risk to the foetus and the risk of untreated maternal disorder. -Preferences should be given to older medications -Depot medication should be avoided - mood stabilizers are generally teratogenic hence should be avoided or should require special monitoring

Breast feeding

Lactating mothers secrete lipophilic drugs into milk (diazepam notorious). Lipophilic drugs cross placental barriers (psychotropics). Breast feeding should be avoided when mother is taking MAOIs, Lithium and Clozapine Consider non pharmacological treatment

Children

Body Composition

total body water & extracellular fluid adipose tissue & skeletal muscle

Microsomal metabolizing enzymes in Children are not active until about 8 weeks post natal. Renal excretion mechanisms poor in first few weeks of life - decreased renal blood flow, glomerular filtration, & tubular function yields prolonged elimination of medications Smaller doses should be used

Elderly

Increase risk of adverse effect due to -altered pharmacokinetics -increased sensitivity to drugs -drug interactions with other drugs -coexisting physical illness Use lower doses of medication and avoid drugs with long half-lives