Objectives:
1) Common routes of drug administration, metabolism and excretion!
*2) - using your knowledge of Pka and the pH, predict the relative case of permeation!
3) Name proteins in the blood that have important inert drug binding sites!
4) By graphically depicting the blood level vs. the elimination for drugs, compare and contrast
drugs subject to zero-order and first order elimination!
Pharmacokinetics (PK) : what your body does to the drug. Study of the time course of
absorption, distribution, metabolism and excretion (ADME) !
Absorption- Amt of drug that reaches systemic circulation expressed as bioavailability (F)= F
stands for the fraction of dose that reaches systemic circulation from absorption and avoids
first pass effect. IV admin F=1 = 100% bioavailability!
Routes: mouth (sub-lingal bypasses first pass effect) , GI tract (subject to first-pass effect) ,
rectum, IV, IM, Subcutaneous, topical/transdermal, inhalation administration. !
**When converting IV to PO (oral) dose, bioavailability and duration of action must be taken into
account!!! (ex. With Lasix- 40mg IV dose would be 80 mg po bc only 50% of drug absorbed)!
Oral Absorption: Increased first-pass effect=drug metab in liver and excreted before GI
absorption= decreased bioavailability!
• Lipophilic drugs= greater absorption!
• High hepatic extraction ratio drugs= most affected by first pass effect= weaker absorption!
• Weak base drug (high pKa) best absorbed in basic environment (small intestine)!
• Weak acid drugs (low pKa) best absorbed in acidic environment (stomach) !
• Small intestine is primary site of drug absorption !
• When drug pKa=solution : The ph ratio of charged : uncharged drug molecules is 50:50 !
• Fastest absorbing to slowest absorbing: solution> suspension>solid dosage form !
• Faster gastric emptying rate= shorter time to max concentration or Tmax. !
• Decreasers of Gastic emptying rate: supine posture, high fat foods, drugs: anticholinergics,
narcotic, analgesics, tricyclic anti-depressants!
• Increasers of Gastric emptying rate: smoking tobacco, drug metoclopramide !
• P-Glycoprotein- non-specific pump that can help excrete drugs. Efflux pump located in
esophagus, stomach, small/large intestine that pumps drug back into the GI tract.!
• P-glycoprotein inducer or inhibitor is given with a P-glycoprotein substrate for interacting
drugs where P Glycoprotein affects the absorption. Ex. Rifampin is an inducer given with
dabigatran (Pradaxa) !
,IV Administration: !
• Pros: 100% bioavailable (F + 100%) no first-pass effect, higher peak concentrations more
quickly- shorter time to Tmax, rapid dose titration!
• Cons: increased risk of toxicity and infections, invasive, must be admin by health provider,
diluent related complications ( side effect related to the vehicle in IV compound) ex.
Voriconazole and phenytoin. !
SC and IM administration:
• Pros: fast absorption from aqueous water soluble solutions, easier to administer than IV,
can be used for suspensions to extend duration and release of drug, can be used for drugs
in oil-based vehicles ( ex. Long acting injectable anti-psychotics given IM) !
• Cons: IM more painful than SC, tissue damage, volume limited to 5mL SC, 2.5mL buttocks
SC and 1mL IM in other areas. Absorption varied based on lipid solubility, site of
administration, exercise. IM Contraindicated in patients with sig. thrombocytopenia, SC
contraindicated in sig. edema!
Pulmonary Administration
• Pros: rapid onset, local effect, minimizes systemic adverse effects, gaseous and volatile
drugs can be administered for systemic effects- large surface area of absorption in resp.
tract. !
• Cons: requires coordination (ex. Inhaler hard for kids to use), delivery can be variable,
inhalers must be primed and may empty without prior notice!
Topical Admin:
• Epidermis= lipid barrier whereas Dermis is freely permeable to many drugs.!
• In-tact Mucous Membranes: conjuntiva, nasopharynx, oropharynx, urinary bladder. Used
for local effects, minimize systemic exposure, or can have significant systemic effects
( desmopressin intranasal spray), rapid onset of action. Intranasal: max 1ml/nostril
(concentrated formulas needed bc volume limited) !
• Skin: absorption dependent on surface area where drug is applied, blood flow (increased
with inflammation, exercise, thin skin, higher lipid solubility) !
Alternate Routes of Administration
• Infliltrate injection: inject directly into tissue- local anesthesia without sign systemic
absorption (ex local anesthetic, lidocaine injection) Duration increased when administered
with vasoconstrictor (epinephrine)!
• Rectal- not as common in US but used in infants more. 50% drug absorbed bypasses first-
pass effect. But absorption may be irregular, incomplete, and irritation in rectal mucosa
possible!
, Distribution of drug to various tissues. !
Depends on several factors: !
• Perfusion- rate of delivery to tissues, depends on: cardiac output, regional blood flow,
capillary perm, tissue volume !
• Diffusion- ability to pass from circulation to tissue- most common mechanism of drug
transport through a biological membrane, depends on lipid solubility of drug and may vary
some based on transmembrane pH gradient of weak acid/bases!
• Volumes- blood volume, lymph volume etc. !
• BInding- affinity of drug to tissue or circulating proteins ( such as albumin protein in blood)
unbound drugs give you pharmacological effect. !
Protein Binding
*Unbound drug= free “active drug” that is circulating and can bind with receptors to induce a
response. Low albumin states (severe hepatic disease, malnutrition) may result in lower total
drug levels and higher fraction of free drug. !
*Bound drug- drug is bound to receptors of proteins and therefore is not free to bind to
receptors of target tissue. Drug/protein complex may be too large to leave capillaries or
proteins may release the bound drug gradually. !
Plasma proteins: !
• Albumin is major binding protein that acts as an inert plasma binding site!
• AAG (alpha-1-glycoprotein)!
• Lipoproteins and globulins !
Tissue Binding
• Fat: high lipid soluble drugs can accumulate in fatty tissues, less blood flow, most common
area where tissue can bind ( think things like to stick to fat) !
• Muscle: well perfused!
• Bone: less well perfused- potential for absorption on bone- crystal surface, drugs can
accumulate at higher concentrations than extracellular fluids. Depends on intracellular
concentration and if binding is reversible. Can result in prolonged release of drug from
tissue. Ex of this is with biphosphonates used to treat Osteopenia and Osteporesis can be
found 10 yrs later on bone- only annual dosing regimen is used. !
Central Nervous System!
Tight junctions in brain capillary endothelial cells and pericapillary glial cells ( blood brain
barrier). Meningeal and encephalic inflammation can increase permeability. Higher lipid
solubility and smaller molecules greater likelihood to cross blood brain barrier.
1) Common routes of drug administration, metabolism and excretion!
*2) - using your knowledge of Pka and the pH, predict the relative case of permeation!
3) Name proteins in the blood that have important inert drug binding sites!
4) By graphically depicting the blood level vs. the elimination for drugs, compare and contrast
drugs subject to zero-order and first order elimination!
Pharmacokinetics (PK) : what your body does to the drug. Study of the time course of
absorption, distribution, metabolism and excretion (ADME) !
Absorption- Amt of drug that reaches systemic circulation expressed as bioavailability (F)= F
stands for the fraction of dose that reaches systemic circulation from absorption and avoids
first pass effect. IV admin F=1 = 100% bioavailability!
Routes: mouth (sub-lingal bypasses first pass effect) , GI tract (subject to first-pass effect) ,
rectum, IV, IM, Subcutaneous, topical/transdermal, inhalation administration. !
**When converting IV to PO (oral) dose, bioavailability and duration of action must be taken into
account!!! (ex. With Lasix- 40mg IV dose would be 80 mg po bc only 50% of drug absorbed)!
Oral Absorption: Increased first-pass effect=drug metab in liver and excreted before GI
absorption= decreased bioavailability!
• Lipophilic drugs= greater absorption!
• High hepatic extraction ratio drugs= most affected by first pass effect= weaker absorption!
• Weak base drug (high pKa) best absorbed in basic environment (small intestine)!
• Weak acid drugs (low pKa) best absorbed in acidic environment (stomach) !
• Small intestine is primary site of drug absorption !
• When drug pKa=solution : The ph ratio of charged : uncharged drug molecules is 50:50 !
• Fastest absorbing to slowest absorbing: solution> suspension>solid dosage form !
• Faster gastric emptying rate= shorter time to max concentration or Tmax. !
• Decreasers of Gastic emptying rate: supine posture, high fat foods, drugs: anticholinergics,
narcotic, analgesics, tricyclic anti-depressants!
• Increasers of Gastric emptying rate: smoking tobacco, drug metoclopramide !
• P-Glycoprotein- non-specific pump that can help excrete drugs. Efflux pump located in
esophagus, stomach, small/large intestine that pumps drug back into the GI tract.!
• P-glycoprotein inducer or inhibitor is given with a P-glycoprotein substrate for interacting
drugs where P Glycoprotein affects the absorption. Ex. Rifampin is an inducer given with
dabigatran (Pradaxa) !
,IV Administration: !
• Pros: 100% bioavailable (F + 100%) no first-pass effect, higher peak concentrations more
quickly- shorter time to Tmax, rapid dose titration!
• Cons: increased risk of toxicity and infections, invasive, must be admin by health provider,
diluent related complications ( side effect related to the vehicle in IV compound) ex.
Voriconazole and phenytoin. !
SC and IM administration:
• Pros: fast absorption from aqueous water soluble solutions, easier to administer than IV,
can be used for suspensions to extend duration and release of drug, can be used for drugs
in oil-based vehicles ( ex. Long acting injectable anti-psychotics given IM) !
• Cons: IM more painful than SC, tissue damage, volume limited to 5mL SC, 2.5mL buttocks
SC and 1mL IM in other areas. Absorption varied based on lipid solubility, site of
administration, exercise. IM Contraindicated in patients with sig. thrombocytopenia, SC
contraindicated in sig. edema!
Pulmonary Administration
• Pros: rapid onset, local effect, minimizes systemic adverse effects, gaseous and volatile
drugs can be administered for systemic effects- large surface area of absorption in resp.
tract. !
• Cons: requires coordination (ex. Inhaler hard for kids to use), delivery can be variable,
inhalers must be primed and may empty without prior notice!
Topical Admin:
• Epidermis= lipid barrier whereas Dermis is freely permeable to many drugs.!
• In-tact Mucous Membranes: conjuntiva, nasopharynx, oropharynx, urinary bladder. Used
for local effects, minimize systemic exposure, or can have significant systemic effects
( desmopressin intranasal spray), rapid onset of action. Intranasal: max 1ml/nostril
(concentrated formulas needed bc volume limited) !
• Skin: absorption dependent on surface area where drug is applied, blood flow (increased
with inflammation, exercise, thin skin, higher lipid solubility) !
Alternate Routes of Administration
• Infliltrate injection: inject directly into tissue- local anesthesia without sign systemic
absorption (ex local anesthetic, lidocaine injection) Duration increased when administered
with vasoconstrictor (epinephrine)!
• Rectal- not as common in US but used in infants more. 50% drug absorbed bypasses first-
pass effect. But absorption may be irregular, incomplete, and irritation in rectal mucosa
possible!
, Distribution of drug to various tissues. !
Depends on several factors: !
• Perfusion- rate of delivery to tissues, depends on: cardiac output, regional blood flow,
capillary perm, tissue volume !
• Diffusion- ability to pass from circulation to tissue- most common mechanism of drug
transport through a biological membrane, depends on lipid solubility of drug and may vary
some based on transmembrane pH gradient of weak acid/bases!
• Volumes- blood volume, lymph volume etc. !
• BInding- affinity of drug to tissue or circulating proteins ( such as albumin protein in blood)
unbound drugs give you pharmacological effect. !
Protein Binding
*Unbound drug= free “active drug” that is circulating and can bind with receptors to induce a
response. Low albumin states (severe hepatic disease, malnutrition) may result in lower total
drug levels and higher fraction of free drug. !
*Bound drug- drug is bound to receptors of proteins and therefore is not free to bind to
receptors of target tissue. Drug/protein complex may be too large to leave capillaries or
proteins may release the bound drug gradually. !
Plasma proteins: !
• Albumin is major binding protein that acts as an inert plasma binding site!
• AAG (alpha-1-glycoprotein)!
• Lipoproteins and globulins !
Tissue Binding
• Fat: high lipid soluble drugs can accumulate in fatty tissues, less blood flow, most common
area where tissue can bind ( think things like to stick to fat) !
• Muscle: well perfused!
• Bone: less well perfused- potential for absorption on bone- crystal surface, drugs can
accumulate at higher concentrations than extracellular fluids. Depends on intracellular
concentration and if binding is reversible. Can result in prolonged release of drug from
tissue. Ex of this is with biphosphonates used to treat Osteopenia and Osteporesis can be
found 10 yrs later on bone- only annual dosing regimen is used. !
Central Nervous System!
Tight junctions in brain capillary endothelial cells and pericapillary glial cells ( blood brain
barrier). Meningeal and encephalic inflammation can increase permeability. Higher lipid
solubility and smaller molecules greater likelihood to cross blood brain barrier.
