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Topic :
Basic Pharmacology

Presented by
Swapnil Singh
GPAT (AIR 04) NIPER (AIR 03)

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Flow of Content
Introduction

Absorption

Distribution

Metabolism

Excretion

References

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Definition
 Pharmacology (P’cology) is the science of drugs
 Oswald Schmiedeberg regarded as the “father of pharmacology”
 Divided in several branches like
 Pharmacokinetics
 Pharmacodynamics
 Pharmacotherapeutics
 Chemotherapy and toxicology etc.
 The two main division for our study are Pharmacodynamics and
Pharmacokinetics
 Drug

Administered
in body

Drug Exert Body exerts

some effect some effect
on body on drug

P’CODYNAMICS P’KINETICS
Routes of drug administration (R.O.A.)

R.O.A.

Local Systemic

Enteral(Through
Topical Parenteral
GIT)

Intra-articular Oral IV, IM, SC, SL,

TD, Nasal,
Intrathecal Rectal
Inhalational

IV:Intravenous, IM:Intramuscular, SC:Subcutaneous, SL:Sublingual, TD:Transdermal

R.O.A., Some IMP. Points
Contd…
 Local Routes:
 Very low or no systemic absorption
 Systemic Routes:
 Oral: Safer and Economical, some drugs are ineffective because of High first Pass Metabolism
(eg. nitrates, lignocaine, propranolol, ), Degradation (Insulin, penicillin G)
 Sublingual: Avoids First Pass Metabolism , Used in Emergencies, Only lipid soluble and non
irritating drugs
(eg. of drugs administered by this route Nitroglycerine, isosorbidedinitrate etc.)
 Transdermal: Only for drugs Highly lipid soluble
 Nasal: eg. Nafarelin (GnRH agonist), calcitonin and desmopressin
 Inhalational: Rate of drug delivery can be controlled like I.V. Infusion, antiasthmatic and
inhalational anaesthetic agents
 Rectal: Avoids first pass metabolism upto 50% (Diazepam in febrile seizures)
 Intravenous: Bolus(Dose injected at once) or Infusion(Continuous delivery over a period of
time)
 Intradermal: Through Bleb, Vaccines
PHARMACOKINETICS
 ADME study: Absorption, Distribution, Metabolism, Excretion
 ABSORPTION:
Drug

Un-ionised
Ionised form
form

Water soluble Lipid soluble

Cant cross Cross

biological biological
membrane membrane
1. Absorption contd…
 So, for absorption of drug from biological membrane it should be
present in unionised lipid soluble form
 Ionisation depends on pH of surrounding medium and pKa of drug
 Lets make it simple, ABSORPTION WILL OCCUR WHEN MEDIUM IS
SAME,
Means acidic drugs will remain unionised in acidic environment and
get absorbed while basic drugs will remain unionised in basic
environment and get absorbed
 Ionisation of a drug is neither 100% nor 0% (Weak acids or bases),
therefore a drug should never be 100% lipid or water soluble
Absorption (contd…)
 pH-pka relationship
pka is the pH at which drug is 50% ionised and 50% unionised
 Acidic drug will remain unionised in acidic medium but will ionise in basic medium and basic
drug will remain unionised in basic medium and ionise in acidic medium
 Suppose an acidic drug having pKa of 4 was placed in pH 4, it will be 50 % ionised and 50%
unionised, NOW same drug is kept in medium of pH 3 (acidic), it remains lipid soluble. But, if
it is kept in pH 2 what will happen, obviously it becomes more lipid soluble because more of
the drug is un-ionised, But Numerically HOW MUCH???
 Concepts:
 If the pH of the medium is less than pKa (Medium becomes acidic)
 For Acidic drugs, unionised form increases and ionised form decreases
 For Basic drugs, ionised form increases and unionised form decreases

 If the pH of the medium is more than pKa (Medium becomes basic), opposite happens
 Absorption (contd…)

 Ionised or Unionised fraction depends upon difference (d, only magnitude)

between pH and pKa
 When pH=pKa, d=0, 50% ionised 50% unionised
 When pH-pKa=1, d=1, one form is 90% and other is 10%
 When pH-pKa=2, d=2, one form is 99% and other is 1%
 When pH-pKa=3, d=3, one form is 99.9% and other form is 0.1%

 Example: (Acidic drug, pKa=3)

pH of medium (pH-pKa) Ionised from % Unionised form %
3.0 0 50 50
4.0 1 90 10
5.0 2 99 1
6.0 3 99.9 0.1
Bioavailability
 Fraction of administered drug that reaches into the systemic circulation in the
unchanged form

Presystemic or first pass metabolism

 By IV route it is 100%
Bioavail. (contd…)
• It can be calculated by
comparing AUC (Area under
the curve) for I.V. route and
for the desired route or can
also be calculated by
comparing excretion in urine
• AUC tells about extent of
absorption
• Tmax tells about rate of
absorption
• Cmax is max conc. obtained
Fig. Plot between plasma conc. and time to
in plasma
calculate bioavailability
• Bioequivalence = ±20%
bioavailability

𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = 𝐴𝑈𝐶𝑡𝑒𝑠𝑡 ∗ 𝐷𝑜𝑠𝑒 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 ∗ 100 ÷ (𝐴𝑈𝐶 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 ∗ 𝐷𝑜𝑠𝑒 𝑡𝑒𝑠𝑡)

MEC: Min. effective conc.,
MTC: Max therapeutic conc.
2. Distribution
 After drug reaches to the blood it is distributed to many tissues, which is
determined by a hypothetical parameter Volume of Distribution (Vd)
 It is the volume that would be required to contain the administered dose if
that dose was evenly distributed at the at the conc. measured in plasma
 Higher Vd means more amount of drug was entering in tissue
 Depends on lipid solubility and protein binding
 Lipid soluble drug crosses blood vessel easily and thus have high Vd
 If a drug is highly bound to plasma protein it behaves like a large molecule and unable to
cross the blood vessel, thus goes less into the circulation and have low Vd

 Only free form (not bound to plasma protein) of drug is responsible for action
as well as metabolism of a drug. Thus, Plasma protein binding makes drug long
acting by reducing its metabolism
Distribution (contd…)
 Volume of distribution (Vd):
𝐷𝑜𝑠𝑒 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 𝐼.𝑉.
 𝑉𝑑 =
𝑃𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐.(𝐶𝑜)

 Measure of the distribution of the drug, more Vd means more

amount of drug is in tissue and less is in plasma
 Vd is the main determinant of Loading Dose
 Chloroquine is the drug with highest Vd (1300l/kg)
 Total Body
Water (42 L)

Extracellular Intracellular
Fluid (14 L) fluid (28 L)

Plasma (3 L)

Interstitial
Fluid (11 L)
Distribution (Contd…)
 After a drug reaches plasma there are four possibilities:

Molecular
Ionisation Description Vd
Weight
Highly ionised Not able to cross blood
High Low (around 3 L, Vol. of plasma)
(Water soluble) vessel
Some of it can reach Around 14 L (Vol. of plasma + Vol.
Highly ionised Low
interstitial fluid of Interstitial fluid)
Un-ionised (lipid
Low Enter in cell also High 42 (plasma+ISF+ICF)
soluble)
Vd even greater than total body
Un-ionised Low High affinity for tissues
water (>42 L)
3. Metabolism (Biotransformation)
 Chemical alteration of the drug in the body
 Needed to render the nonpolar (lipid soluble) compounds into polar
(lipid-insoluble) to excrete them outside the body
 Primary site is liver, others are kidney, intestine lungs and plasma
 Biotransformation of drug may lead to following three events:

 1. Inactivation
Most drugs render inactive or less active metabolites

 2. Active metabolite from an active drug

Many drugs are partially converted to one or more active metabolites;
Active Drug Active Metabolite
Chloral hydrate Trichloroethanol
Morphine Morphine-6-Glucoronide
Cefotaxime Desacetyl cefotaxime
Allopurinol Alloxanthine
Procainamide N-acetyl procainamide
Primidone Phenobarbitone
Diazepam Oxazepam
Digitoxin Digoxin
Imipramine Desipramine
Amitriptyline Nortriptyline
Codeine Morphine
Spironolactone Canrenone
Metabolism (Contd…)
 3. Activation of inactive drug
Prodrug concept
Prodrug Active form
Levodopa Dopamine
Enalapril Enalaprilat
Dipivefrine Epinephrine
Proguanil Cycloguanil
Prednisone Prednisolone
Bacampicillin Amoxicillin
Sulfasalazine 5-Aminosalicylic acid
Metabolism (Contd…)
 Biotransformation reactions are of two types:
 1. Nonsynthetic/Phase I/Functionalisation reactions:
Functional group is generated or exposed
Metabolite may be active or inactive
Major reactions involved are:
 Oxidation (Major), Reduction, Hydrolysis, Cyclisation, De-cyclisation

 2. Synthetic reaction/Phase II
Conjugation by endogenous substrate to form a highly polar water soluble compound which
is easily excreted
Major reactions involved are:
 Glucuronide conjugation (Major), Acetylation, Methylation, sulphate, glycine, or glutathione
conjugation
Metabolism (Contd…)
 Metabolism may occur with the help of:

 Microsomal enzyme: present in smooth endoplasmic reticulum

 Ex; monooxygenases, cytochrome P450, and glucoronyl transferases
May be induced or inhibited by other drug

 Non microsomal enzyme: present in cytoplasm and mitochondria

 Ex; flavoprotein oxidases, esterases, amidases and conjugases
Not inducible by other drugs but shows genetic polymorphism
Metabolism (Contd…)
 Drug metabolising by microsomal enzyme is called as substrate and
chemical increasing or decreasing that enzyme is called as inducer
or inhibitor respectively

Enzyme Increase Decrease

inducer metabolism effect

Dose should
Tolerance
be increased
 Enzyme Inducers
Enzyme inducer

G Griseofulvin

P Phenytoin

R Rifampicin

S Smoking

Cell Carbamazepine

Phone Phenobarbitone
 Enzyme Decrease
Inhibitors Metabolism

Predisposes
toxicity
Enzyme inhibitors
Enzyme inhibitors
Vitamin Valproate
K Ketoconazole
Cannot Cimetidine
Cause Ciprofloxacin
Enzyme Erythromycin
Inhibition Isoniazid
Cytochrome P-450
 450 denotes their strong absorbance at 450 nm
 Superfamily of microsomes
 CYP3A4 is involved in metabolism of 50% drugs
CYP3A4

Root word Gene number

Family Sub-family

Nomenclature
Hoffman elimination
 Inactivation of the drug in the body fluids by spontaneous
molecular rearrangement without the agency of any enyme,
eg; Atracurium
4. Excretion
 Passage out of systemically absorbed drug
 Major route is kidney; involves glomerular filtration, tubular
reabsorption and tubular secretion
 1. Glomerular filtration: Depends on plasma protein binding and renal
blood flow. Does not depends upon lipid solubility because all substances
crosses the fenestrated glomerular membrane
 2. Tubular reabsorption: Depends on lipid solubility
More lipid More Less
soluble reabsorbed excretion

 Lipid solubility depends on ionisation, ionised drug will be excreted

 Acidic drug Urine Drug ionizes;
poisoning alkalinised excreted

Barbiturates, salicylate Sodiumbicarbonate Acidic drug in basic medium

Basic drug Urine Drug ionizes;

poisoning acidified excreted

Morphine, amphetamine Ammonium chloride

Excretion (contd…)
 3. Tubular secretion: Does not depend on lipid solubility or plasma protein
binding.
Separate pump for acidic and basic drugs are present in nephron; drug
utilising same pump may show drug interaction; eg. Probenecid decreases
excretion of penicillin
Kinetics of elimination

Metabolism Excretion Elimination

 Pharmacokinetics model may be one or two compartment

One compartment Model:
Drug having less or no distribution in tissues, elimination is
continuous and the log plasma conc. vs time curve is linear (frst
order kinetics)
One compartment model
Co Slope of this curve is –k (rate constant)

Clearance = k * Vd
Log scale

k = 0.693/t1/2

Extrapolation of this curve on y-axis is Co used to

calculate Vd

Vd= Dose/Co
Some imp formula
 Renal clearance: u = urine conc. of drug
v = rate of urine flow
p = plasma drug conc.
Renal cl.= uv/p

 Total body clearance = rate of elimination/p

Order of kinetics
 Drug may follow zero or first order kinetics
Rate of elimination α (plasma conc.)order
 For zero order kinetics, (plasma conc.)0 is equal to one, it means
rate of elimination is independent of plasma conc. or it is constant
 For first order kinetics rate of elimination is proportional to plasma
conc.
 First order kinetics (linear) Zero order kinetics (Non linear)

Constant fraction of drug is eliminated per Constant amount of drug is eliminated per
unit time unit time

ROE proportional to Co ROE independent of Co

Clearance (Cl) remains const. Cl is more at low conc. and less at high conc.

Half life (T1/2)remains const. T1/2 less at low conc. and more at high conc.

Most drugs follow first order kinetics Very few drugs eg; Alcohol
Half life (t1/2)
 Time required to reduce the plasma conc. half to its original value
 It is a secondary P’kinetic parameter derived from two primary
P’kinetic parameter Vd and clearance (Cl)
 Determines dosing interval and time required to reach steady state
conc.
 Does not affect dose of the drug
t1/2 = (0.693 * Vd)/Cl
References
 Garg GR, Gupta S. Review of Pharmacology, sixth edition, 2012,
Jaypee publishers, New Delhi
 Tripathi KD. Essentials of medical pharmacology, sixth edition,
2008, Jaypee publishers, New Delhi
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