Pharmacology

Learning objective

• To introduce basics of pharmacology

• To understand pharmacokinetic concepts

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 Outline

• Introduction

• Pharmacokinetics

– drug absorption and distribution

– drug metabolism and excretion

– dosage regimen and dose adjustment

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 Introduction

• Pharmacology
– deals with drugs and their interaction with the biological
system (through regulatory molecules) to produce responses
– A drug is any sub. that modify the biological function
through its actions at molecular level
• useful to prevent, diagnose, and treat diseases
– Branches: pharmacokinetics, pharmacodynamics,
pharmacotherapeutics, toxicology

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 Nature of drugs

• Sources: plants, animals, microorganisms, minerals,

synthetic, genetic engineering
Digoxin
• Nomenclature Heparin
Penicillin
– Chemical name Ferrous sulphate
Aspirin
– Non-proprietary/generic name Growth hormone
– Proprietary/brand/trade name®

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 Nature of drugs…

• Routes of admn
– Enteral: oral, rectal, sublingual/buccal
– Parenteral: intravenous, intramuscular, subcutaneous,…;
topical, transdermal, inhalational
NB. - Advantages & limitations
– drug design in appropriate dosage form for admn
(tablet, capsule, suppository, solution, suspension,
aerosol, ointment, cream, lotion,…)

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Some of the dosage forms

tablets capsules suppositories

oral solution injectables transdermal patch

inhaler ointment
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 Route Advantages
Oral (po) easy, convenient, relatively safe
Sublingual fast, bypass portal circulation
Rectal partly avoid FPE, pediatric use
Intravenous (IV) max. BA (avoid FPE, dose accuracy),
fast, large volume admn, for drugs
with poor oral absorption
Intramuscular (IM)/ for drugs with low oral BA,
subcutaneous (SC) rapid, depot formulation
Inhalational rapid absorption, local use
Topical easy, non-invasive, lack FPE, patient
acceptance, topical (for local)/
transdermal (for systemic effect)
Limitations
slow absorption, if vomiting,
subject to first pass effect
(FPE) [limit bioavailability (BA])
may not be applicable to all
inconsistent absorption,
some patients dislike
require technical person,
challenge to reverse,
hypersensitivity reactions
pain at inj site, hypersensitivity
inhaler technique affect BA
slow absorption
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 Pharmacokinetics (PK)

• PK processes (ADME)

– Absorption

– Distribution

– Metabolism

– Excretion

• PK knowledge is essential to optimize drug admn

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 Pharmacokinetics…

Plasma concentration-time curve after a single oral drug admn

MEC (Minimum Effective Conc.), MTC (Minimum Toxic Conc.)

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 Drug absorption

• From site of admn to systemic circulation

• Transport mechanisms (across the membrane)

– Aqueous diffusion

– Lipid diffusion

– Carrier mediated transport

• Facilitated diffusion

• Active transport

– Vesicular transport
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 Passive diffusion

• Molecules spontaneously diffuse

along the conc. gradient

– net transfer to the low conc. area

• Driving force is the drug conc. gradient across the memb.

• Best explained by Fick’s law of diffusion

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 Passive diffusion…

Fick's law of diffusion

• Where,

– dQ/dt: rate of diffusion; A: surface area; h: thickness

– D: diffusion coefficient, amount that diffuses across a given

unit area per unit time when the conc. gradient is a unit

– K: lipid-to-water partition coefficient of the drug

– CGI - Cp: drug conc. difference b/n the GIT & the plasma

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 Passive diffusion…

• Since D, A, K, & h are constant under usual absorption

conditions, permeability coefficient (P), a combined constant,
can be defined

• As Cp << CGI

• The relationship is an expression for a first-order process

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 Carrier-mediated transport

• carrier proteins at intestinal brush border & basolateral memb.

– Facilitated diffusion:- along conc. gradient

– Active transport:- against conc. gradient, energy-consuming

• selective, saturable, and can be inhibited

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Carrier-mediated transport…

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 Factors influencing GI absorption

• Physicochemical properties of the drug

 lipophilicity, degree of ionization, particle size, solubility, concn, Mwt

• Anatomy & physiology of absorption site

 pH at absorption site, gastric emptying time, blood flow,
surface area of absorption, transit time (gut motility)

• Nature of the drug product (formulation factors)

 dosage form, route of admn, manufacturing procedures

• Presence of food/other drugs (interaction, pH change, gastric emptying)

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 Effect of pH and PKa

• For drugs that are either weak acids or weak bases,

the extent of ionization influences rate of drug transport.
This in turn depends on dissociation constant (Ka) of the drug,
and the pH of absorption medium

• Absorption is determined by the extent to which the drug

exists in its unionized (lipid soluble) form at absorption site

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 Bioavailability

• Bioavailability is defined as

– rate & extent to which the drug reaches systemic circulation

• Factors affecting bioavailability

– Extent of absorption, and first pass elimination

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 Drug distribution

• From the site of admn into the tissues

• Factors affecting drug distribution

– Plasma protein binding

– Presence of barriers

– Tissue uptake

– Rate of blood flow

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 Drug distribution…

• Volume of distribution (Vd)

– apparent volume of fluid to which the drug distributes

– relates amount of drug in the body to plasma conc.

– relationship between Vd and plasma protein binding

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 Drug metabolism

• Main site: liver; intestine, plasma

• Phase I [Functionalization]

– cytochrome (CYP) P450 enzymes mediate most reactions:

oxidation, reduction, hydrolysis

– generate reactive functional groups [hydroxyl, thiol, amine…]

• Phase II [Conjugation]

– glucuronidation, sulfation, acetylation, methylation,

amino acid or glutathione conjugation
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Drug metabolism…

UGT: uridine diphosphate–glucuronosyltransferase 24

 Drug metabolism…

The fraction of clinically used drugs metabolized by phase 1 & phase 2 enzymes
CYP: cytochrome P450; DPYD: dihydropyrimidine dehydrogenase; GST: glutathione-S-transferase;
NAT: N-acetyltransferase; SULT: sulfotransferase; TPMT: thiopurine methyltransferase; UGT: uridine
diphosphate–glucuronosyltransferase

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 Drug metabolism…

• Consequence on biol. activity: inactivation/ activation (pro-drugs)

• Enzyme induction/inhibition: impact on biol. activity

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 Drug metabolism…
Genetic polymorphism (Examples)

• CYP2C9: hydroxylation, poor metabolizers (PM) –

Warfarin (anticoagulants) -  bleeding risk

• CYP2C19: oxidation, PM - Clopidogrel [prodrug)] ( biol. effect);

extensive metabolizers ( therapeutic efficacy)

• NAT2: N-acetylation, PM - Isoniazid (peripheral neuropathy)

• Butyrylcholinesterase (BuCE): ester hydrolysis, PM -

Succinylcholine (muscle relaxant) - prolonged apnea

 Pharmacogenomic testing for clinically safe & effective therapy

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 Drug excretion

• Major route: kidneys

Other routes: lungs, hepatobiliary, secretions (milk, sweat,..)

• Net excretion depends on

– glomerular filtration rate (GFR)

– tubular reabsorption

– tubular secretion

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 Drug excretion…

Trapping of a weak base in urine when the urine is more acidic than the blood
Henderson-Hasselbalch principle applied to drug excretion in the urine
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 Drug excretion…

• Weak acids, eg. aspirin/salicylates. Trapped in basic environment.

- Treat overdose with sodium bicarbonate to alkalinize urine

• Weak bases, eg amphetamines, Trapped in acidic environment.

- Treat overdose with ammonium chloride to acidify urine

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 Order of elimination

First-order Zero-order
− rate of elimination  drug conc. − rate of elimination is constant

− constant fraction eliminated − constant amount eliminated

− plasma conc. exponentially − plasma conc. linearly

− applies for most drugs − eg. phenytoin, aspirin, ethanol

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 Drug clearance and half-life

• Clearance (CL),

• Half-life (t1/2) is the time required for the amount

or conc. of the drug in the body to fall by 50%.

– CL & t1/2 are constant (1st order elimination)

– help to determine percentage of drug remain in system,

and the time to reach the steady state

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 Exercise

• A patient was given 200 mg a) 25 mg

dose of a drug, and 100 mg b) 50 mg

was eliminated during the first c) 75 mg
2 hrs. If the drug follows first-
d) 100 mg
order elimination kinetics,
e) Cannot be predicted
how much of the drug will

remain 6 hrs after admn?

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 Dosage regimen

• Dosage regimen is a plan for drug admn over a period of time.

– To maintain prolonged therapeutic activity, many drugs

are given in multiple-dosage regimen (maintenance doses)

– To achieve target blood level rapidly, loading dose may be used

• Optimal dosage regimen results in achievement of therapeutic

levels of the drug without exceeding the minimum toxic conc.

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 Dosage regimen…

• When repeated equal doses given at constant freq.,

Steady-State (SS) drug conc (Cp = Css) will be reached

At Steady-State, rate of drug entering (input = infusion rate) will be equal to

rate of drug leaving the body (output = elimination rate) 37
Dosage regimen…

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Dosage regimen…

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 Summary

• Understanding pharmacokinetic (PK) concepts enable us

to choose the appropriate route of drug administration,
to accurately determine a dosage regimen, and to avoid or
minimize possible drug interactions at ADME level

• Thus, knowledge of PK principles help to optimize drug

administration for achieving the desired clinical outcomes

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