Pharmacodynamics/Kinetics

Pharmacodynamics definition

How a drug interacts w/ the body (“drug does to body”)

Receptor interactions

Agonist or Antagonist

Agonist

Mimic endogenous ligand

Anatagonist

• Interferes w/ endogenous ligand

• Produces no pharmacologic effect

Types of receptors

• Enzyme linked

• Ligand gated ion channels

• G-protein coupled receptors

Enzyme linked receptors characteristics

• Ligand binds to receptor outside cell membrane

• Causes conformational change of receptor on the inside of the cell

Ligand gated ion channel

Open/close based on chemical messenger

G-protein coupled receptor characteristics

• G-proteins relay messages from receptors to enzymes

• Signal transduction inside cell to a 2nd messenger

2nd messengers inside the cell

• cAMP (3,5 cyclic adenosine monophosphate)

• Calcium

• IP3 (Inositol 1,4,5-trisphosphate)

• DAG (Diacylglycerol)

cAMP effect in heart

🡹 ca++ = 🡹 contractility

cAMP effect in lungs

🡻 ca++ = bronchodilation

Receptor regulation (down regulation)

• Receptor expression is usually dynamic

• Chronic stimulation of receptors often results in DEC’d receptors

Receptor regulation (Up regulation)

• Under-stimulation causes an INC in the number of receptors

• Up-regulation of acetylcholine receptors at motor end plate can lead to spinal injury

Pharmacokinetics definition

• Movement of drug thru biologic systems

• “Body does to drug”

Movement path of drugs

• Absorption

• Distrubtion

• Metabolism

• Elimination

Route of administration

• Oral

• Subcutaneous

• Sublingual

• Intramuscular

• Intravenous

• Inhaled

Oral route

• Most variable absorption

• 1st pass effect

1st pass effect

• Most drugs absorbed into GI tract enter the portal circulation prior to entering general circulation

• Reduces its bioavailability so may require higher doses

Sublingual route

Capillary bed allows drug to enter circulation immediately

Parenteral

any method of delivering substances, such as drugs or nutrients, directly into the body without using the digestive tract.

Parenteral routes

• IM (intramuscular)

• IV (intravenous)

• SQ (subcutaneous)

IV ADV

100% of drug available meaning no 1st pass effect

Inhalation route

• Large surface area for drugs to be absorbed

• rapid absorption into systemic circulation

Bioavailability definition

The fraction of administered drug that reaches systemic circulation

Factors influencing absorption

• Blood flow to site

• Route utilized

Distribution definition

Movement of drug to and from blood & various tissues of the body

Body compartments

• Central

• Muscle groups

• Fat groups

• Muscle poor groups

Central body compartments

• Vessel rich groups

• Heart, lungs, brain, kidneys, liver

T ½ alpha (alpha ½ life) – initial redistribution

• early distribution phase following drug administration

• rate at which the drug redistributes from the central compartment (plasma) to peripheral tissues

T ½ beta - elimination

• After alpha phase is complete the drug slowly redistributes back into the central compartment

• Once redistribution is complete, the drug is eliminated from the central compartment

• time it takes for the drug concentration in the central compartment to decrease by half after distribution equilibrium is reached

Distribution side effect

• Some drugs can accumulate in certain tissues (lungs or oxy of HLM)

• Can act as reservoirs of extra drug

Volume of distribution (Vd) definition

hypothetical volume of fluid into which the drug is being disseminated

Volume of distribution (Vd) formula

Amount of drug in body / concentration of drug in plasma

Example of drug w/ small Vd

• Neuromuscular blocking agents

• Rocuronium Vd = 0.25 L/kg

Example of drug w/ Large Vd

Digoxin is 500 L/kg

Extent of distribution of a drug w/ Vd/L = 5

• Plasma only (drug stays almost entirely in blood)

• 7% of body weight

Extent of distribution of a drug w/ Vd/L = 5-20

• Extracellular fluids (Plasma + interstitial fluid)

• 7-28% of body weight

Extent of distribution of a drug w/ Vd/L = 20-40

• Total body fluids (Plasma + interstitial fluids + Interstitial space)

• Basically everywhere water exists

• 28-56% of body weight

Extent of distribution of a drug w/ Vd/L = 20-40

• Deep tissues

• Leave bloodstream and accumulate in fat, muscle, organs

• >56% body weight (Vd is greater than the body’s actual water volume)

Protein binding of drugs

• Most drugs bind to proteins

• Albumin

• Alpha-1 acid glycoprotein (AAG)

Free drugs

Can travel in & out of tissues

More highly bound drugs

• Have a longer duration of action

• smaller volume of distribution

Protein binding characteristics

• Only free drugs are pharmacologically active

• Bound drugs are “trapped” = inactive

• Hypoalbuminemia may alter level of free drug

Highly protein bound drug characteristics

• Need to give high doses of it to get a therapeutic effect

• Majority is stuck to protein

Highly protein bound drugs

• Coumadin

• Diazepam

Examples of small Vd drugs that stay in bloodstream

• Heparin

• large proteins

Examples of large Vd drugs that accumulate in deep tissues outside of bloodstream

• Fentanyl

• Propofol