DDS Lecture 5 Content

Biopharmaceutics

Biopharmaceutics

study of effect of physical and chemical properties on ADME

ADME

• Absorption

• Distribution

• Metabolism

• Excretion

ADME for Oral administration

1. Gastrointestinal tract

2. Absorbed into circulatory, distributed

3. Absorbed into tissues

4. Can be metabolized

5. Excretion (from GI tract, circulatory systems, metabolic sites)

ADME for Intravenous injection

1. Circulatory systems

2. Absorbed by tissues

3. Metabolic sites

4. Excreted from GI tract, circulatory systems, tissues/metabolic sites

ADME for Intramuscular and Subcutaneous Injection

1. Tissues

2. Metabolic sites

3. absorbed into circulation

4. absorbed to GI tract

5. Excretion can happen at any point

Factors affecting drug absorption from GI

• pharmaceutical

• physicochemical

• physiological

• interactions

Pharmaceutical factors affecting drug absorption from GI

• tablet

  • dissolutions/disintegration

• excipients

Physiochemical factors affecting drug absorption from GI

• solubility

• hydrophilicity

• lipophilicity

• Ionization states

Physiological factors affecting drug absorption from GI

• GI pH

• metabolism

• mucosal thickness (most absorption = thinnest = small intestine)

• residence time (will spend most time in small intestine)

Interactions affecting drug absorption from GI

• food

  • some foods must be taken on empty stomach

• other drugs

  • antacids can decrease absorption

• micro flora

  • milk/calcium products can interact with

Passive Absorption

• energy independent

• follows concentration gradient

• dependent on ionization states

• dependent on lipophilicity

• dependent on duration and area of contact

• drug molecule should be neutral (no charge)

Fick’s law of diffusion

• need low thickness

• high concentration difference

• high area

• high permeability

Factors affecting Passive Absorption

• ionization states

• lipophilicity

• dissolution

• interactions

Calculating % ionization of Acid

Calculating % ionization of a base

Ionization in GI tract

• acidic drug: more ionized going down GI

• basic drug: less ionized going down GI

Lipophilicity

• affinity of a molecule or substance for lipid or aqueous environment

Dissolution

• Solid dosage forms must dissolve into solution before absorption into blood

• D= diffusion coefficient

• A= surface area (of drug)

• Cs= solubility of drug

• Cb=concentration of drug in bulk

• h=thickness of dissolution layer

Diffusion Coefficient (D)

• value of D depends on particle size of molecule and viscosity of dissolution medium

• presence of food in GI decreases D by increasing the viscosity of gastrointestinal fluids

Surface Area (A)

• smaller particle size = greater surface area = higher dissolution rate

Solubility in diffusion layer (Cs)

• directly proportional to intrinsic solubility

• can be increased by salt formation

Particle structure (in dissolution)

• polymorphism

  • different polymorphic forms have different solubility

• amorphism

  • amorphous form dissolves more rapidly than crystalline form

  • may convert to crystalline form upon storage

Interactions

• oral absorption of drugs may be affected by concurrent use of other substances/drugs that may

  • have large surface area upon which drug can be adsorbed (non-specific binding)

  • specifically bind/chelate drugs administered

  • alter gastric pH

    • antacids increase pH

  • alter gastrointestinal motility

    • higher motility = less absorption

    • lower motility = more absorption

Active Absorption

• requires energy

• movement against concentration gradient

• saturable kinetics

• selectively (in some cases)

• competitive inhibition

• drugs may act as substrates, inhibitors, or both

  • must have similar structure to natural substrates/inhibitors

Major transporters of active absorption

• peptide transports

  • used by penicillin-based drugs

• organic anion transporters

  • used by fexofenadine

• organic cation transporters

  • used by metformin

Inhibitors of active absorption

• grapefruit juice for organic anion transporter

Drug absorption in decreasing order

Solution > suspension > capsule > tablet > coated tablet

Drug role in dissolution/absorption

may be poorly soluble, hydrophobic

lubricant role in dissolution/absorption

usually hydrophobic

granulating agent role in dissolution/absorption

tends to hold ingredients together

filler role in dissolutoin/absorption

• may interact with drug

• should be water soluble

wetting agent role in dissolution/absorption

helps water penetration into tablet

disintegration agent role in dissolution/absorption

helps to break tablet apart

Volume of distribution (Vd)

• fluid volume that would be required to accommodate the total amount of absorbed drug in the body at the plasma at steady state of concentration

• amount of drug in body = drug absorbed (dose)

• C = amount of drug in blood

• not physical volume, extrapolated

• drugs with low Vd stay within vascular compartment (blood)

  • bc of strong plasma protein binding or inability to diffuse out of circulation

• drugs with high Vd are well-distributed throughout body or sequestered in tissue reservoirs (fatty tissues)

• helpful in dose calculation and frequency of dosing

Factors Affecting rate of distribution

• membrane permeability

• blood perfusion

  • vital organs have high perfusion: lungs, kidneys, heart, liver

Factors affecting extent of distribution

• lipid solubility

• pH -pKa

• Plasma protein binding

• tissue drug binding

  • drugs bind specifically to certain tissue

  • ex. bisphosphonate (osteoporosis med) binds selectively to osteoclasts, stay bound longer so need less frequent dose

Plasma Protein Binding

• drug must be free form to do biological action and be excreted

• always equilibrium between bound and free forms

• highly plasma protein bound drug = less free drug available to bind to site needed to perform action

Factors affecting Vd

• lipophilicity

  • general rule:

  • higher lipophilicity = higher Vd

  • higher hydrophilicity = lower Vd

• ionization

  • if drug is ionized at physiological pH, will not get distributed

• stereochemistry

• physiological

  • any disease that changes blood volume

• age and gender

  • skeletal muscles decrease with age

  • children have different Vd vs adults

  • hormonal diff between genders can affect

Drug metabolism

• the process by which the body chemically alters drugs to make them easier to excrete and reduce their toxicity

• increase water solubility

• 2 phases

• not all drugs can undergo

Factors affecting Metabolism

• inhibitors of metabolizing enzymes

• inducers of metabolizing enzymes

• age and gender

• stereochemistry

• genetic variation

• physiological factors

Excretion

• irreversible loss of drug from body

• primarily via hepatic and renal route

  • renal (urination) more common, preferred

    • must be water-soluble

  • also feces, sweat, saliva, tears, exhaled air (ex. alcohol), breast milk

Stages in renal excretion

1. Passive glomerular filtration

   1. depends on physiochemical properties

   2. molecules must be neutral

2. Active tubular secretion

3. Passive tubular re-absorption

Renal Clearance

rate of excretion/plasma conc

Factors Affecting Renal Excretion

• age

  • with age, renal function declines

• gender

  • hormonal differences

• renal dysfunction

• drugs inhibiting active secretion (probenecid)

Probenecid

• gout medicine

• in past, was given in combination with penicillin to inhibit active tubular secretion (so it stayed in body longer)

Enteral routes of administration

oral

parenteral routes of administration

• intravenous

• subcutaneous

• intramuscular

• intrathecal

• intraperitoneal

Mucosal routes of administration

• sublingual

• ocular

• nasal

• pulmonary

• rectal

• urinary

• reproductive tract

topical routes of administration

dermal

Oral dosage forms

• tablets

• capsules

• suspensions

• solutions

• syrups

• emulsions

Oral dosage form requirements

• stable in GI tract (chemical and metabolic stability)

  • stable at physiological pH of GI tract

  • stable against stomach enzymes

• absorbable (passive/active transport)

Oral dosage form advantages

• simple

• inexpensive

• convenient

• less invasive

oral dosage form disadvantages

• degradation of drug in GI tract

• first-pass metabolism

• slow onset of action

  • cannot use in emergency

First pass metabolism

• metabolism happens before drug gets into circulation (in liver, GI tract)

• drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the site of action or systemic circulation.

intramuscular route of admin

• parenteral

• absorption:

  • prompt absorption from aqueous solutions

  • slow absorption from repository depot preparations

  • 75-100% bioavailability

• can be used with moderate volumes, oily vehicles, some irritants, depot (sustained-release) injections

• Limitations

  • cannot be used concurrently with anti-coagulant therapy

    • vasular damage/bruising

  • may interfere with certain diagnostic tests

Intrathecal route of admin

• parenteral, injection into spine

• very fast absorption

• provides fast and effective spinal block of pain perception

• allows for maximizing drug concentration in CNS

• limited volume

• issues relating to dural puncture (infection, loss of pressure/fluid, headaches, dizziness)

• ex. Epidural pain relief, anticancer agents for brain cancer

Intravenous/Intraarterial route of drug admin

• parenteral

• Absorption:

  • circumvents need for cross-membrane absorption to get drug into circulation

  • effects may be immediate or almost immediate (good or bad)

  • 100% bioavailability

• Special utility

  • best route for emergency use

  • can be used with larger volumes/irritants

  • can be used for larger peptides and proteins

• Limitations

  • not suitable for poorly soluble or insoluble agents, oily vehicles

  • most cases require slow administration

  • increased risk of adverse events

Subcutaneous route of admin

• parenteral

• absorption:

  • prompt (aqueous)

  • slow (repository prep)

  • 75-100% bioavailability

• special utility

  • could be used for relatively insoluble suspensions

• limitations

  • limited volumes

  • irritation at injection site

  • pain

  • tissue necrosis

Buccal/Sublingual route of drug admin

• mucosal

  • not oral: remain in mouth, does not go to GI

• very prompt absorption

  • 60-80% bioavailability

• best route for treatment of periodontal disease

• allows for avoidance of first-pass effect (“facial triangle”)

• limitation: swallowing medication

  • if swallowed, will not work (dose is smaller than oral)

Intranasal route of admin

• mucosal

• prompt absorption

• best route for treatment of nasopharyngeal diseases (nasal congestion, sinus infection)

• limitations

  • limited volumes

  • irritation

  • probable systemic effects

Ocular route of admin

• mucosal

• prompt absorption

• best route for treatment of ophthalmic disease

• limitations

  • limited volumes

  • irritation

  • possible systemic effects

Pulmonary/Inhalation route of admin

• mucosal

• prompt absorption

• 5-100% bioavailability

• best route for treatment of pulmonary disease

• limitations

  • limited volumes

  • possible irritation

  • probable systemic effects

Rectal route of admin

• mucosal

• prompt absorption

• 30-100% bioavailability

• best route for treatment of anorectal diseases (hemorrhoids)

• optional route when oral delivery not feasible (vomiting, unconscious)

• avoids most of first-pass effect

• limitations:

  • limited volumtes

  • irritation

  • probable systemic effects

  • absorption can be irregular/incomplete

  • diarrhea

Epidermal/Transdermal route of admin

• topical

• variable absorption if skin abraded or inflamed

• best absorption with lipid-soluble drugs (steroids)

• 80-100% bioavailability

• best option for treatment of skin diseases

• convenient (transdermals)

• limitations

  • limited volumes

  • possible irritation

  • variable absorption

Bioavailability

• rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action

• graphically, conc vs time

• Peak: highest drug conc in blood serum

• Peak time: time it takes to reahc peak

• area under curve compared to compare bioavailabilities

Bioavailability utility

• determine amount/proportion of drug absorbed from dosage form

• determine rate of drug absorption

• determine duration of drug presence in biologic fluid/tissue

• determine relationship between drug blood levels and clinical effectiveness/toxicity

Factors affecting bioavailability

• ADME profile of drug

• enterohepatic circulation

  • drug absorbed, gets into liver, liver throws back to small intestine, which moves it back to liver

• presystemic metabolism

  • “first pass” metabolism

• oral drug can get paralyzed in GI, GI wall, liver before absorbed into circulation

Bioavailability formula

• max =100%

  • IV route

Minimum effective concentration

• conc of drug required to produce effect

• reaches conc at onset time

Duration of action

how long drug stays above/at minimum effective concentration

Relative bioavailability

• bioavailabilites of same drug in two different formulations

Bioequivalence

• pharmaceutical alternatives or equivalents which have exact same bioavailabilities when administered at same dose

• bioequivalence studies performed to compare extent of absorption of new product or generic products

• have same bioavailibility curve (same onset, peak, min effective concentration)

Methods to assess bioavailability

1. dissolution at administration or absorption site

   1. evaluates dissolution rate

2. Free drug in systemic circulations

   1. evaluates:

      1. blood level time profile

      2. peak blood level

      3. time to reach peak

      4. area under blood level time curve

3. Pharmacologic effect

   1. evaluates:

      1. onset of effect

      2. duration of effect

      3. intensity of effect

4. Clinical response

   1. controlled clinical blind or double-blind study, observed clinical success or failure

Factors affecting dosage regimen

• activity, toxicity

• pharmacokinetics

• clinical state

• management of therapy

• other factors

Activity/Toxicity and dosage considerations

• minimum therapeutic dose

• toxic dose

• therapeutic index

  • diff btwn conc of drug between minimum toxic conc (largest conc before toxic) and minimum effective conc

  • larger range = wide index

  • narrow index: calculate dose carefully

• side-effects

• dose-response relationships

Pharmacokinetics dosage considerations

ADME

clinical state dosage considerations

• age, weight, urine pH

  • urine pH crucial for excretion

• condition being treated

• existence of other disease

Management of therapy and dosage considerations

• multiple drugs

• convenience of regimen

• patient compliance

other factors in dosage considerations

• tolerance -dependence

• pharmacogenomics

• drug interactions

• lifestyle factors