Drug Distribution and Body Water Compartments

Body Water Compartments in a 70 Kg Person

• Plasma volume constitutes 6% of total body weight, equivalent to about 4.2 Liters
• Interstitial fluid is present between cells
• Plasma volume plus interstitial fluid totals 14 Liters, or 20% of total body weight (Extra Cellular Fluid)
• Total body water which is plasma + interstitial fluid + Intracellular amounts to 60% of total body weight, about 42 Liters

Apparent Volume of Distribution (Vd)

• Represents the volume that would accommodate the entire amount of drug in the body
• Assumes drug concentration throughout the body is the same as in plasma
• Vd is calculated as the amount of drug in the body divided by the plasma concentration
• Vd can also be determined by taking Dose/Conc

Factors Affecting Drug Distribution

• Perfusion is the blood flow to organs
• Diffusion across cell membranes determines distribution
• Capillary permeability is influential
• Binding of drug to plasma proteins affects drug distribution
• Binding of drug to cell and tissue constituents, also known as tissue affinity, impacts distribution

Perfusion and Drug Distribution

• Increased blood flow leads to increased drug distribution to that organ
• Brain, liver, and kidney tissues receive higher blood flow compared to skeletal muscles and adipose tissue
• Propofol, an anesthetic, exemplifies clinical value
• Blood flow variation explains short duration after IV injection
• High blood flow along with lipophilicity allows propofol to rapidly enter the CNS, inducing anesthesia
• Slower distribution to skeletal muscle and adipose tissue lowers plasma concentration, causing the drug to diffuse out of the CNS
• The reduced concentration gradient in the CNS leads to regaining consciousness

Propofol Anesthesia and Recovery

• Anesthesia is brain concentration is high
• Concentration declines due to diffusion down the concentration gradient
• Muscles and adipose tissue accumulate the drug
• Blood concentration of propofol decreases, leading to recovery

Diffusion and Drug Distribution

• Diffusion across cell membranes depends on lipophilicity
• Increased lipophilicity leads to increased distribution
• pH and pKa of the drug is a factor

Clinical Significance of Drug Distribution

• Lipid-soluble drugs penetrate the CNS readily
• Ionized or polar drugs generally fail to enter the CNS because of the blood-brain barrier
• Levodopa is hydrophilic and requires a specific transporter to enter the brain

Binding and Drug Distribution

• Binding of drug to plasma proteins decreases its diffusion to tissues and decreases Vd
• Binding of drug to cell and tissue constituents increases Vd
• Tetracyclines deposit in bone and teeth through chelation of Calcium ions
• Iodides concentrate in thyroid and salivary glands

Plasma Proteins and Drug Binding

• Albumin binds acidic drugs
• Lipoprotein and alpha 1 acid glycoprotein binds basic drugs
• Globulin binds thyroxin and sex hormones (steroid)

Drug Bound to Plasma Proteins

• Inactive
• Cannot pass through blood vessels
• Not highly distributed
• Not metabolized or excreted as readily (long duration)

Free Drug

• Diffusible
• Active
• Can be readily eliminated from the body

Importance of Volume of Distribution (Vd)

• An estimate of tissue uptake of drugs
• Small Vd, such as with frusemide, indicates limited tissue uptake
• Large Vd, such as with digoxin, indicates extensive tissue distribution
• In drug toxicity cases, dialysis is less effective for drugs with high Vd since most of the drug is in the tissues
• Dialysis is more useful for drugs with low Vd, as more of the drug remains in the blood and ECF
• Vd is used to calculate the loading dose (LD)
• LD equals VD multiplied by the steady-state plasma concentration Css

Drug Metabolism (Biotransformation)

• Occurs mainly in the liver but also in other organs like intestinal lumen or wall, lung, plasma, skin, and kidney
• Main aim is to convert the drug to a more polar (ionized) metabolite
• Increased polarity facilities easier excretion

Results of Drug Metabolism

• Abolishing of the activity by converting active form to inactive form
• Converting inactive prodrugs to active drugs
• Converting an active to more active one
• Converting drugs to a toxic metabolite that is then conjugated with glutathione, as is the case with Paracetamol

Types of Biotransformation Reactions

• Phase I reactions result in an Inactive Polar metabolites
• Still Active Non Polar metabolites can occur in Phase I
• Phase II reactions occur after Phase I reactions
• In Phase II, 99% of Drugs are Inactive and Polar
• Isoniazide (INH) are a reversed phase reactions

Phases of Biotransformation

• Phase I reactions are non-synthetic oxidation, reduction, or hydrolysis

• Phase I converts a drug to an ionized metabolite for excretion by unmasking a polar group

• Cytochrome P450 enzyme system are involved in Phase I

• Phase II reactions are synthetic and conjugates an endogenous substrate

• Substrates include glucuronic acid, glycine, glutathione, or sulfate

• This is conjugated with an ionized metabolite from Phase I to functional group of the drug or its metabolite

• Glucuronyl transferase enzymes are involved in Phase II

• Phase II forms non-toxic, highly polar, inactive, rapidly eliminated conjugates

Types of Metabolizing Enzyme Systems

• Microsomal enzymes include Cytochrome P450 (Phase I) and Glucuronyl transferase (Phase II)
• Microsomal enzymes are liable for induction and inhibition
• Non-microsomal enzymes include plasma Ach esterase and cytoplasmic xanthine oxidase
• The cytochrome P450 system has genetic variability

Factors Affecting Biotransformation

• Physiological changes in metabolizing activity due to age and sex
• Metabolism is generally higher in men than women, influenced by hormones
• Pathological factors affecting hepatic activity, such as liver cell failure
• Pharmacogenetic variations in metabolizing enzymes, affecting types and amounts
• Enzyme induction and enzyme inhibition are influencing factors

Enzyme Induction

• Certain drugs stimulate activity and amount of microsomal enzyme systems, increasing metabolism of themselves and other drugs
• Reversible and occurs over a few days, passing off over 2-3 weeks after withdrawal of the inducer
• Examples of Enzyme Inducers:
  • Phenobarbitone
  • Phenytoin
  • Carbamazepine
  • Rifampicin
  • Nicotine

Clinical Value of Enzyme Induction

• Increases its own metabolism causing tolerance to the drug, such as phenobarbitone
• Increases metabolism of other drugs causing failure of therapeutic effect
• Examples of drug interactions due to enzyme induction:
  • Rifampicin increasing metabolism of oral contraceptives, leading to pregnancy
  • Phenytoin increasing metabolism of vitamin D, leading to osteomalacia
  • Rifampicin increasing metabolism of warfarin, leading to decreased anticoagulation
• One way to overcome the effects of enzyme induction is to increase the dose

Enzyme Inhibition

• Certain drugs inhibit microsomal enzyme systems, decreasing enzyme activity
• This can lead to toxicity of other drugs
• Reversible, occurs over days and passes off over weeks after withdrawal of the inhibitor
• Examples of enzyme inhibitors:
  • Chloramphenicol
  • Erythromycin
  • Ciprofloxacin
  • Valproate

Clinical Value of Enzyme Inhibition

• Decreased metabolism of drugs given simultaneously increases their levels, causing risk of toxicity
• Examples of drug interactions:
  • Erythromycin inhibits metabolism of theophylline
  • Ciprofloxacin inhibits metabolism of warfarin, leading to bleeding
• One way to overcome the effects of enzyme induction is to decrease the dose

Drug Excretion

• The kidney is the most important route
• Other sites of excretion:
  • Lungs for volatile anesthetics
  • Saliva for iodides
  • Bile for rifampicin
  • Milk which has is importanace for lactating mothers

Renal Elimination of a Drug

• Consists of:
• Filtration
• Active Tubular Secretion
• Reabsorption

Drug Excretion: Interactions at Site of Excretion

• Alkalization of urine increases ionization of acidic drugs, decreasing tubular reabsorption and increasing excretion which is useful in treatment of toxicity
• Acidification of urine increases ionization of basic drugs, decreasing tubular reabsorption and increasing excretion which is useful in treatment of toxicity
• Probenecid competes inhibiting penicillin which prolongs its action
• Hyperuricemia is associated with diuretic (thiazide) administration

Effects of Drug Lipophilicity

• Increased drug absorption
• Increased Vd, (lipophilic drugs can penetrate into most tissues
• Lipophilic drugs can cross CNS
• Increased hepatic elimination due to being able to enter hepatocytes
• Decreased renal excretion due to increased tubular re-absorption
• Drug elimination does not always end the therapeutic effect
• Irreversible inhibitors like aspirin, have an affect after the drug is eliminated

Elimination Half-Life (t½2)

• The time to reduce drug plasma concentration to half its initial concentration
• t1/2 = 0.693 Vd / CLs (Clearance)

Elimination Half-Life (t½2): Factors

• The state of the eliminating organs such as the liver and kidney
• The delivery of the drug such as plasma protein binding limiting renal filtration
• Drugs with very high Vd escaping from elimination due to being in the tissue

Value of elimination t½

• It determines the dosage interval

Dosage and t½

• For drugs with smaller t½ resorts to IV infusion might be required
• Most drugs are given at t½
• When given less then more accumulation occurs
• If given greater than 50% reduction will occur at dosages
• It indicated Tss (time required to attain Css): about 4-5 t½

Steady State Concentration (Css)

• Represents drug plasma concentration where rate of intake equals the rate of elimination

Importance of Css

• To Maintain therapeutic drug level range
• Calculating the loading dose
• Calculating the maintenance dose

Types of Elimination Kinetics

• First Order Kinetics
• Zero Order Kinetics
• Saturation Kinetics

First Order Kinetics

• Metabolizing enzymes have unlimited capacity
• Rate of elimination is proportional to drug concentration
• Portion is eliminated e.g. 50%/ h.
• Remains constant
• Steady state concentration (Css) is reached repeated dosing
• Css is proportional to dose
• Changes are tolerated
• Not constant

Zero Order Kinetics

• Metabolizing enzymes have limited capacity.
• Rate of elimination is constant, even if drug concentration changes.
• Amount of drug eliminated per unit time, e.g. 50 mg/h, stays constant
• Not constant with higher doses
• No Css is reached; repeated dosing causes overshooting of of drug concentration
• Metabolites may vairy with dose
• Ex. Ethanol

Saturation Kinetics:

• In saturation first order is followed small and follows zero when dose is big, and elimination occurs
• Small changes lead to toxicity

Systemic Clearance (CLs)

• Represents fluid that is cleared from drug per unit time
• Calculated adding clearances
• CLs = renal clearance (Clr) + non-renal clearance (Clnr)

Systemic Clearance (CLs): Factors

• Blood flow to the clearing organ is directly proportional
• Binding of the drug inversely proportional
• The volume of distribution and activity of processes both directly proportional

Systemic Clearance (CLs): Significance

• Calculation of the maintenance dose (MD)
• Dosing regimen of drugs eliminated by glomerular filtration can be guided by is guided by creatinine clearance

Loading Dose

• Definition is dose to desired administration rapidly
• Two calculations oral and introvanous

Loading Dose Calculations

• IV LD = (Vd) × (desired Css)
• Oral Loading dose = (Vd) × (desired Css) /F

Loading Doses Administration and Use Case

• Loading doses can be given as a single dose or a series of doses
• Disadvantages of loading doses: include increased risk of drug toxicity
• Drugs useful when loading doses must have long 1/2 life

Optimization of the Dose: Maintenance Dose

• Definition: dose to maintain within therapeutic window
• IV infusion MD = Cl X Css
• IV injection MD = Cl X Css X time interval
• Oral MD = Cl X Css X time interval / F (bioavailability)

Elimination After Administration

• Risk interaction, as well as clinical significance

Dosing in Renal Impairment

• In renal it means the is manage administration properly

Drug Admin Summary

• Doses is accumulation to continuous administration
• The levels constants
• Steady state: 4-5 t1/2
• Washout: 4-5

Dosing High Risks

• Dosing Risks are present in narrow situations with specific agents

Types of Drug Interactions

• Pharmaceutical incompatibilities occur outside the body where mixed
• Pharmacokinetic include rate of absorption, of distribution, of metabolism, and elimination
• Pharmacodynamic means to effect near

Site Interactions

• At rate of absorption, chelate
• Drug interactions in the GI tract

Pharmacological Interactions

• Can involve protein and bleeding

Interactions involving Metabolism

• Enzyme and failure of therapy

Interactions at Excretion

• May involve renal excretions and other drug actions

Chemical Interactions

• Can involve Bp
• And Synergism
• Also has drug factors
• Includes antagonistic

Pharmacodynamics Terms

• Agonists are basic terms

Full Agonist

Definition: Interacts with the receptor and activating it and its affect Has Affinity and Efficacy

GRadual Curves

The curves are in relations of dose with the logs

Gradual Curve Parameters

• The main effect produced
• It is the dose then the effects produce

All Types

It the responses drugs

Parameters of Drug safety

• It involves different aspects and curves that affect the response

Chemical Antagonists

It relates to different chemicals and what the process can involve

Drug Interactioms

There can be drug interactions on what process is occuring

Tolerance

The dose affects the tolerance can affect And the tolerance happens from different cases in the body

Types of Tolerance:

The different types of tolerance can cause different reactions

Factors

Factors can modify the response can vary and can cause different responses to the drug Includes sex, weight, age etc..