GENERAL PHARMACOLOGY

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General pharmacology (Pharmacokinetics drug
and administration and absorption) Prof. Hanan
Hagar Dr.Ishfaq Bukhari Pharmacology Department
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What is Pharmacology?

• From the Greek pharmakon (drug),
• and legein (to speak or discuss)
• Broadly defined as the study of how chemical
  agents affect living processes.
• e.g Hormones, Neurotransmitters and drugs

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What is Pharmacology

• Pharmacology studies the effects of drugs and
  how they exert their effects.
• Acetylsalicylic acid (ASA) or Aspirin can reduce
• inflammation, , pain and fever
• It inhibit the action of a human cell membrane
  enzyme known as cyclooxygenase, which is
• responsible for the synthesis of a number of
• inflammatory mediators.
• Penicillin cures certain bacterial infections
• disrupt the synthesis of cell walls in
  susceptible
• bacterial strains by inhibiting a key enzyme.

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Some Pharmacology Definitions and Areas of Study

• Pharmacokinetics
• Study the fate of drugs once ingested. It covers
  , How the body absorbs, distributes,
• metabolizes, and excretes drugs (what the body
  does to a drug)
• Pharmacodynamics
• Study the mechanisms by which drugs work ,Also
  study endogenous agents (what the drug does to
  the body)

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Pharmacokinetics (Drug absorption)

• The student should be able to
• Discuss the different routes of drug
  administration
• Identify the advantages and disadvantages of
  various routes of drug administration
• Know the various mechanisms of drug absorption
• List different factors affecting drug absorption
• Define bioavailability

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Recommended books

• Lippincotts illustrated reviews (Pharmacology)
  by Howland and Mycek
• Basic and Clinical Pharmacology by by Katzung

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PHARMACOKINETICS

• PharmacokineticsIt is the study of what the body
  does to the drug i.e ADME
• ABSORPTION
• DISTRIBUTION
• METABOLISM
• EXCRETION
• of the drug
• Note Pharmacodynamic is what the drug does to
  our body

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Routes of drug administration
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Routes of drug administration
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Routes of drug administration

• Enteral
• via gastrointestinal tract (GIT)( Oral and
  Rectal )
• Sublingual
• Parenteral administration injections.
• Topical application
• Inhalation

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Oral administration
Disadvantages Advantages
- Slow effect No complete absorption - Destruction by pH and enzymes - GIT irritation - Food - Drug interactions Drug-Drug interactions First pass effect (low bioavailability). Not suitable for vomiting unconscious patient emergency bad taste drugs - Easy Self use Safe convenient - cheap - No need for sterilization
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Factors affecting absorption from GIT

• GIT motility changed by drug / diseases
• Presence of food
• Blood flow/surface area
• GIT juices
• pH of GIT fluids
• Chemical/drug interactions
• dosage form of a drug
• Most of the drug is absorbed with in 1-3
  hours,mostly it occurs in small intestine ,rate
  of absorption depends on lipid solubility
  ,ionization and pH.

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Factors affecting absorption from GIT

• Drugs administered in aqueous solution are
  absorbed faster completely than tablet or
  suspension forms.
• Drugs such as the tetracyclines, which are highly
  ionized, can complex with Ca ions in membranes,
  food, or milk, leading to a reduction in their
  rate of absorption.
• Factors that accelerate gastric emptying time,
  permitting drugs to reach the large absorptive
  surface of the small intestine sooner, will
  increase drug absorption unless the drug is slow
  to dissolve.

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First pass Metabolism

• Metabolism of drug in the gut wall or portal
  circulation before reaching systemic circulation
• So the amount reaching system circulation is less
  than the amount absorbed
• Where ?
• Liver
• Gut wall
• Gut Lumen
• Results ?
• Low bioavailability.
• Short duration of action of drugs (t ½).

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• First pass effect

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Stomach pH

• The low pH of the gastric contents (pH 12) may
  influence absorption of drugs because it can
  affect the degree of drug ionization. e.g, the
  weak base diazepam will be highly Ioninized in
  the gastric juice, and absorption will be slow.
• weak acid drug, acetaminophen will exist mainly
  in its unionized form and can more readily
  diffuse from the stomach into the systemic
  circulation.

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Small intestine

• The small intestine, with its large surface area
  and high blood perfusion rate, has a greater
  capacity for absorption than does the stomach.
• Conditions that shorten intestinal transit time
  (e.g., diarrhea) decrease intestinal drug
  absorption, while increases in transit time will
  enhance absorption by permitting drugs to remain
  in contact with the intestinal mucosa longer.

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• Oral Dosage Forms (oral formulations)
• Tablets (enteric coated tablets)
• Capsules (hard and soft gelatin capsules)
• Syrup
• Suspension
• Emulsion

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Spansule
Tablets
Soft- gelatin capsule
Hard- gelatin capsule
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Sublingual
Disadvantages Advantages
Not for - irritant drugs - Frequent use Rapid effect (Emergency) No first pass metabolism. High bioavailability No GIT destruction No food drug interaction Dosage form friable tablet
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Rectal administration
Disadvantages Advantages
Irregular absorption bioavailability. Irritation of rectal mucosa. Suitable for children Vomiting or unconscious patients Irritant Bad taste drugs. less first pass metabolism (50) Dosage form suppository or enema
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Parenteral administration

• Intradermal (I.D.) (into skin)
• Subcutaneous (S.C.) (under skin)
• Intramuscular (I.M.) (into muscles)
• Intravenous (I.V.) (into veins)
• Intra-arterial (I.A.) (into arteries)
• Intrathecal (I.T.) (cerebrospinal fluids )
• Intraperitoneal (I.P.) (peritoneal cavity)
• Intra - articular (Synovial fluids)

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Intravenous administration
Disadvantages Advantages
Infection Sterilization. Pain Needs skill Anaphylaxis Expensive. Not suitable for oily solutions or poorly soluble substance Rapid action (emergency) High bioavailability No food-drug interaction No first pass metabolism No gastric irritation Suitable for Vomiting unconsciousness Irritant Bad taste drugs. Dosage form Vial or ampoule
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• Ampoule Vial

Single use
Repeated use
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Injection Special Utility Limitations
I.D. Minute volume (0.1 ml) Suitable for vaccinations sensitivity test Not suitable for large volumes
S.C. 0.1 ml 1 ml Suitable for some poorly soluble suspensions and for instillation of slow-release implants e.g. insulin zinc preparation Not suitable for large volumes
I.M. larger volume 3-5 ml Suitable for moderate volumes, oily vehicles, and some irritating substances Not suitable for irritant drugs
I.V. Suitable for large volumes and for irritating substances Not suitable for oily solutions or poorly soluble substances Must inject solutions slowly as a rule
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• Drugs are mainly applied topically to produce
  local effects. They are applied to
• Skin (percutaneous) e.g. allergy test, topical
  antibacterial and steroids prep and local
  anesthesia
• Mucous membrane of respiratory tract (Inhalation)
  e.g. asthma
• Eye drops e.g. conjunctivitis
• Ear drops e.g. otitis externa
• Intranasal, e.g. decongestant nasal spray

Topical application
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Inhalation
Disadvantages Advantages
Only few drugs can be used Mucous membrane of respiratory system Rapid absorption (large surface area) Provide local action Minor systemic effect Less side effects. No first pass effect Dosage form volatile gases (anesthetics), aerosol, nebulizer for asthma
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Nebulizer Atomizer
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Transdermal patch

• a medicated adhesive patch applied to skin to
  provide systemic effect (prolonged drug action)
• e.g. the nicotine patches (quit smoking)
• Scopolamine
• (vestibular depressant)

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Drug absorption

• Is the passage of drug from its site of
  administration to its site of action through
  various cell membranes.
• Except for intravenous administration, all routes
  of drug administration require that the drug be
  transported from the site of administration into
  the systemic circulation.

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Drug absorption

• Is the passage of drug from its site of
  administration to its site of action through cell
  membranes.

Cell membrane
Sites of Administration
Sites of action
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Absorption distribution
Elimination
Sites of Administration
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Mechanisms of drug absorption

• The transport of drugs across membranes occurs
  through one or more of the following processes
• Simple diffusion passive diffusion.
• Active transport.
• Facilitated diffusion.
• Pinocytosis (Endocytosis).

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Cell membrane
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Simple or passive diffusion

• water soluble drug (ionized or polar) is readily
  absorbed via diffusion through aqueous channels
  or pores in cell membrane.
• Lipid soluble drug (nonionized or non polar) is
  readily absorbed via diffusion through lipid cell
  membrane itself.

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Simple diffusion
Low conc
High conc
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Simple diffusion

• Characters
• common.
• Occurs along concentration gradient.
• Non selective
• Not saturable
• Requires no energy
• No carrier is needed
• Depends on lipid solubility.
• Depends on pka of drug - pH of medium.

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Simple diffusion

• Drugs exist in two forms ionized (water soluble)
  nonionized forms (lipid soluble) in equilibrium.
  
• Drug ionized form
  nonionized form
• Only nonionized form is absorbable.
• Nonionized / ionized fraction is determined
• by pH and pKa
• As general basic drugs are more ionized and less
  diffusible in a relatively acidic medium, on the
  contrary basic are more lipid soluble and more
  diffusible in a relatively alkaline medium

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• PKa of the drug
• (Dissociation or ionization constant) pH at
  which half of the substance is ionized half is
  unionized.
• The lower the pKa value (pKa lt 6) of the acidic
  drug the stronger the acid e.g aspirin (Pka 3.0
  ),
• The higher the pKa value (pKa gt8) of a basic
  drug, the stronger the base e.g propranolol (
  pKa 9.4)

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• PKa of the drug
• (Dissociation or ionization constant)
• pH at which half of the substance is ionized
  half is unionized.
• pH of the medium
• Affects ionization of drugs.
• Weak acids ? best absorbed in stomach.
• Weak bases ? best absorbed in intestine.

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• Which one of the following drugs will be best
  absorbed in stomach (pH3)?
• Aspirin pka3.0
• warfarin pka5.0
• Arrange the following drugs in ascending order
  from least to greatest in rate of absorption in
  small intestine (pH7.8)?
• Propranolol pka 9.4
• Aspirin pka3.0

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Active Transport

• Relatively unusual.
• Occurs against concentration gradient.
• Requires carrier and energy.
• Specific
• Saturable.
• eg.
• Sugar, amino acids and Iron absorption.
• Uptake of levodopa by brain.

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Carrier-mediated Facilitated Diffusion

• Occurs along concentration gradient.
• Requires carriers
• Selective.
• Saturable.
• No energy is required.

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Active transport Passive transport
against concentration gradient (From low to high) along concentration gradient (From high to low)
Needs carriers No carriers
saturable Not saturable
Selective Not selective
energy is required No energy
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Carrier-mediated facilitated diffusion Active transport
along concentration gradient (From high to low) Against concentration gradient (From low to high)
Needs carriers Needs carriers
saturable saturable
Selective Selective
No energy is required Energy is required
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Phagocytosis (Endocytosis Exocytosis)

• Endocytosis uptake of membrane-bound particles.
• Exocytosis expulsion of membrane-bound
  particles.
• Phagocytosis occurs for high molecular weight
• Drugs or highly lipid insoluble drugs.

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(Exocytosis)
(Endocytosis)
OUT
IN
OUT
IN
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Mechanisms of drug absorption
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Factors modifying drug absorption

• GENERAL FACTORS
• lipid solubility
• Degree of ionization
• Drug solubility (aqueous sol better than
  oily,susp,sol)
• Dosage forms (depending on particle size and
  disintegration)
• Concentration of drugs
• Circulation at site of absorption
• Area of absorbing surface (small intestine has
  large surface area)
• Route of administration.

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Bioavailability

• Is the fraction of unchanged drug that enters
  systemic circulation after administration and
  becomes available to produce an action
• I.V. provides 100 bioavailability.
• Oral usually has less than I.V.