713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY

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Pharmacokinetics Drug Absorption
Topic 2

• 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY
• Dr. Korawuth Punareewattana

Faculty of Veterinary Medicine, Khon Kaen
University
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Topic Contents

• Foundation of Pharmacokinetics
• Definition and Processes
• Passage of drug across biological membranes
• Mechanisms of drug transport
• Pharmacokinetics Drug absorption (1st step of
  PK)
• Definition
• Bioavailability and first pass effect
• Route of drug administration and Drug absoption

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Pharmacokinetics concepts

• Pharmacology consists of 2 process
• Pharmacokinetics (PK) - ??????????????
• PK describes how the body affects a specific drug
  after administration
• Or What body does to a drug
• Pharmacodynamics (PD) ?????????????
• PD describes how a drug affects the body system
  after administration
• Or What drug does to the body
• Or drug action

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Pharmacokinetics or Drug disposition

• Processes of Pharmacokinetics
• The ADME scheme
• A - Absorption
• D - Distribution
• M - Metabolism
• or Biotransformation
• E - Excretion

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Pharmacokinetics
Distribution
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Passage of Drugs across Biological membrane

• Drug transport is a foundation to all ADME
  processes
• Physicochemical determinants
• Membrane characteristics
• Drug properties
• Mechanism of drug transport
• Passive diffusion
• Carrier-mediated transport
• Bulk flow
• Filtration
• etc

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Membrane characteristics

• Bilayer of amphipathic lipids ? barriers
• Embedded proteins

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Drug properties

• Molecular weight, shape and size
• Water solubility (basic property)
• Lipid solubility
• Ionization

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Molecular weight, shape and size

• Small molecules more chance of crossing membrane

Selective permeability
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Lipid Solubility
Movement directly through the lipid bilayer
requires that the substance dissolve into the
lipid bilayer
Partition coefficient (Kp) solubility in
lipid / solubility in water
Permeability
Kp
Increase lipid solubility causes increased
partition coefficient Increase in partition
coefficient causes increased permeability.
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Ionization

• General rules
• A drug usually exists in 2 forms unionized and
  ionized forms
• Unionized drug can passively diffuse across
  membrane
• The ratio of unionized drug will indicate
  direction of passive diffusion
• Factors affecting ionization are
• pH of the medium
• pKa (acid dissociation constant) of the drug
• Acidic drug tend to ionize in more basic medium
• pH pKa log (ionized / nonionzized)
• Basic drug tend to ionize in more acidic medium
• pH pKa log (nonionized / ionized)

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Ionization

• Henderson-Hasselbach Equations for calculations

Equation for Acids Equation for Bases
                                               
CH3COO- H CH3COOH
NH3 H NH4
K
K
H acceptor H donor
pH pK log
CH3COO- CH3COOH
NH3 NH4
pH pK log
pH pK log

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Example Acidic drug pKa 6
pH pKa log (ionized / non-ionized)
Stomach fluid pH 2
More non-ionized Ionized
Plasma pH 7
Less non-ionized Ionized
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Some data for practice calculation
Plasma pH 7.4 CSF 7.4 Stomach 1.4 Small
Intestine 8.0 Rumen 6.7
Acidic drug pKa Basic drug pKa Ampicillin 2.5
Strychnine 8.0 Sulfadiazine 6.5 Aminopyrine 5.
0 Aspirin 3.4 Procaine 9.0
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Mechanisms of Drug Transport

• Transcellular transport
• Passive diffusion
• Carrier-mediated transport
• Facilitated diffusion
• Active transport
• Ion-pair transport
• Endocytosis or
• Pinocytosis
• Paracellular transport
• Bulk flow
• Filtration

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Passive diffusion

• Drugs that can passively diffuse through cell
  membrane
• must be
• Lipid soluble
• Unionized form
• Move according to concentration gradient

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Carrier-mediated transport

• Facilitated diffusion
• Carrier needed
• Can be saturated
• No energy required
• Move along conc. gradient
• Active transport
• Carrier needed
• Can be saturated
• Energy required
• Move against conc. gradient

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Ion-pair transport and endocytosis
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Bulk flow and Filtration

• Bulk flow is an important way of a drug to move
  out of blood vessel
• Filtration is an important way to excrete drug

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Pharmacokinetics Drug Absorption

• Absorption
• describes the rate and extent at which a drug
  leaves its site of administration.Bioavailability
  
• is the extent to which a drug reaches its site
  of action, or to a biological fluid (such as
  plasma) from which the drug has access to its
  site of action.
• Note
• Absorption first pass effect
  bioavailability
• So bioavailability is not the same as absorption

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Factors Affecting Drug Absorption

• Dose, Concentration, and Rate of administration
• Dosage forms
• Physical and chemical properties of drugs
• Physiological Factors
• Routes of drug administration

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Factors Affecting Drug Absorption Dosage forms

• Dosage forms with different formulations
• Clearly affect drug absorption
• Depend on how well they can be dissolved
  Liberation process

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Factors Affecting Drug Absorption
Physicochemical Properties of Drug

• Acid or Base
• Degree of ionization
• Polarity
• Molecular weight
• Lipid solubility or...
• Partition coefficient (Kp)

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Factors Affecting Drug Absorption
Physicochemical Properties of Drug

• Lipid solubility and Absorption

Barbiturate Kp Absorbed from rat colon
0.7 4.8 28 51
12 20 30 40
barbital phenobarbital pentobarbital secobarbital
Data from Schanker LS. J Pharmacol Exp Ther
12381, 1958.
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Factors Affecting Drug Absorption Physiological
Factors

• Gastric motility
• Gastric emptying time
• pH at the absorption site
• Area of absorbing surface
• Blood flow
• Presystemic elimination
• Ingestion with or without food

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Factors Affecting Drug Absorption Physiological
Factors

• pH at the absorption site

absorbed at
pKa 2.3 3.0 3.5 4.2
pH 4 40 64 41 62
pH 5 27 35 27 36
pH 7 0 30 --- 35
pH 8 0 10 --- 5
Acids 5-nitrosalicylic salicylic
acetylsalicylic benzoic
Bases aniline 4.6 40
48 58 61
aminopyrine 5.0 21
35 48 52 quinine
8.4 9 11
41 54
Data from Schanker LS, J Pharmacol Exp Ther
12381, 1958.
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Factors Affecting Drug Absorption Physiological
Factors

• Area of absorbing surface

absorbed in 1 hr
absorbed in 10 min Drug from stomach
from small intestine phenobarbital
17 52 pentobarbital 24 55 promethazine
0 38 ehtanol 38 64 Data
from Magnussen MP. Acta Pharmacol Toxicol
26130, 1968.
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Factors Affecting Drug Absorption Routes Oral
Ingestion (PO)

• Several factors affect absorption by this route
• - So absorption may change drastically based on
  these factors
• Dosage forms (physical state of drug)
• Drug concentration
• Surface area of absorption
• Blood flow to GI
• GI activity
• Food
• Bacteria in GI
• First past effect (hepatic metabolism)
• Entero-hepatic cycle

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Factors Affecting Drug Absorption Routes Oral
Ingestion (PO)

• Enterohepetic cycle First pass effect

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Factors Affecting Drug Absorption Routes
Parenteral administration

• Subcutaneous
• Slow absorption
• Intramuscular
• Fast absorption
• Intra-peritoneal
• Rapid absorption
• Large absorbing area
• Intravenous, Intra-arterial
• No absorption

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Factors Affecting Drug Absorption Routes
Pulmonary absorption

• Gaseous and volatile drugs may be inhaled and
  absorbed by the pulmonary epithelium and mucous
  membranes of respiratory tract.-almost
  instantaneous absorption-avoids first-pass
  metabolism-local application

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Factors Affecting Drug Absorption Routes
Topical (Transdermal route)

• Few drugs readily penetrate the skin- Absorption
  is proportional to surface area- More rapid
  through abraded, burned skin- Inflammation
  increases cutaneous blood flow and, therefore,
  absorption- Enhanced by suspension in oily
  vehicle and rubbing into skin

Transdermal systemic effect Epicutaneous
local effect absorption no absorption
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????????????????????Bioavailability (F)

• The fraction of a dose that reaches the systemic
  circulation in a chemically unaltered form
• Fractional availability F
• Quote as percentage or decimal e.g. 25 or
  0.25
• Has no units

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Bioavailability (F)
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Incomplete oral bioavailability
2. Chemical, enzymatic or bacterial attack
4. First pass metabolism in gut wall or liver
3. Failure of absorption pGP efflux
Liver
1. Failure of disintegration or dissolution
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Group activity

• Split into 8 groups
• Practice conversation using Questions and Answers
  on Lecture contents to get a thorough
  understanding
• Choose a topic to write a short essay
• Topic sentence
• Supporting sentences
• Examples
• Concluding sentence
• Presenting your essay
• By telling or reading