PKPD 3&4

ADME General Rule

• Lipophilic, non-ionized, small molecules are easily absorbed and distributed
• Hydrophilic, ionized molecules are easily excreted

Distribution

• Distribution transports substances through the body to target tissues
• Volume of distribution (Vd) is calculated for relative comparison of distribution to tissues
• Vd is affected by blood flow to the tissue, tissue size, molecular characteristics, and PPB

Blood Brain Barrier Review

• Capillaries within the CNS (brain & spinal cord) are lined by specialized endothelial cells
• Selective transport of substances into the CNS is allowed in the blood brain barrier
• The P-glycoprotein pump removes harmful substances absorbed into the brain
• The hypothalamus does not have this

PPB

• PPB refers to the cohesion ('binding') with plasma protein molecules
• Drugs have varying 'affinity' for plasma carrier proteins
• Albumin binds acidic drugs and alpha-1-acid glycoprotein binds basic drugs
• Binding decreases distribution rates
• Binding can be competitive, reversible, and saturable
• Unbound drugs are effective, while bound drugs are not

Volume of Distribution

• Volume of Distribution (Vd) estimates how extensively a drug is distributed into tissues
• Relative comparison between drugs assumes all drugs distribute equally
• Vd is used in formulas for calculating a Loading Dose
• The Vd calculation is drug dose / measured drug plasma concentration
• Example: if the drug dose is 100 mg and the plasma concentration is 30 mg/L, Vd = 3.3 L
• Relative comparison: Furosemide = 8 L, Morphine = 230 L, Amiodarone = 5000 L

Metabolism

• Metabolism, also known as biotransformation, is an enzymatic chemical conversion to prepare a dug/substance for excretion
• The goal of drug metabolism is to prepare the drug for excretion, which results in the termination of the drug action
• The liver is the primary metabolizing organ, but other organs like the lungs, kidneys, and intestines also play a role
• Hepatic microsomal enzymes are involved

Drug metabolism

• Active drugs convert to inactive metabolites
• Active drugs convert to active metabolites
• Inactive drugs convert to active metabolites (prodrug)
• PO(oral consumption) drugs undergo "First pass" metabolism
• Some drugs are not metabolized and travel unchanged

Phase I metabolism

• Phase I includes HYDROLYSIS, REDUCTION, OXIDATION
• Cytochrome P450 enzyme group is main enzymes
• Ionized polar metabolites are excreted

Main CYP 450 enzyme groups

• CYP 3A4 + CYP 3A5 = 50% of drugs utilize these enzymes
• Dynamic drugs can induce or inhibit certain enzyme function, either increasing it to metabolize more of the substance, or decreasing it
• Drug interactions can occur, Inducers (like tobacco) or inhibitors like some antibiotics

Phase II metabolism

• Only some drugs require this phase
• CONJUGATION is the ionization of the substance involving 5 main enzymes
• Example: Acetaminophen converts to N-acetyl-p-benzoquinoneimine in Phase I, then conjugate with glutathione enzyme and excreted as inactive metabolites
• Acetaminophen overdose depletes stores of glutathione, resulting in build-up of the toxic intermediate metabolite and become saturable

Excretion

• Excretion eliminates the substances of the drug from the body
• Metabolites are eliminated based on their molecular characteristics; e.g. hydrophilic
• Kidneys are the primary organ of excretion, while other excretory pathways include the bile, saliva, lungs, etc

Renal Excretion

Factors affecting it:

• Molecular characteristics: ionization, hydrophilicity, and small size
• PPB
• Whether the substance has been metabolized
• Urinary pH
• Medically altered excretion of specific drugs

Renal Function

• Creatinine is used for bloodwork lab results
• GFR (normal = 125 ml/min) requires calculations

Clearance

• Clearance is the rate of elimination of a certain drug during a certain hour
• First-order elimination kinetics: Clearance of drugs depends on what durg
• Elimination proportionate to the drug serum concentration
• Example: Drug plasma concentration mg/dL or L
• Clearance is = elimination/peak plasma concentration and is in (total amount of urine voided in an hour:peak plasma concentration of drug
• Zero order elimination kinetics: Clearance will be the same
• The rate of it’s elimination or 'clearance' will be constant
• Example: ethanol (ETOH), aspirin (ASA), phenytoin (dilantin)

Half-life

• Half-life (t 1/2) is the time required for Cmax drug plasma concentration to decrease by one half (by 50%)
• The C-max is the highest [] of drug in blood in terms of bioavailibility
• Circulating drugs are continuously biotransformed for excretion
• If 'unchanged' => biotransformation not required
• Circulating drug is continuously excreted
• Calculation & knowledge is present in drugs
• Broad guideline to estimate frequency of administration 4x t1/2 = 90% of drug cleared

Pharmacodynamics

• Pharmacodynamics studies what the drug does to the body once it is distributed
• Describes the drugs therapeutic effect
• Some drugs (e.g. antiinfectives) bind directly to/in the body to/in bacteria/viruses
• Mostbind to protein structures: receptors that are 6 kinds
• Drug-receptor binding is: Saturable, dynamic and they only block the receptor and are therefore, reversible

Terminology

• Receptor Affinity is the 'strength' of binding or 'length' of binding
• It is specific, saturable, reversible. It may also be a magnetic attraction
• Drug Efficacy is its effectiveness
• Degree to which a drug induces maximal therapeutic effect
• Example: Motion sickness nausea = Gravol; chemo tx nausea – Ondansetron Note: antagonists have no efficacy and only block the receptor
• Potency = strength of the drug
• Tells how much of drug is required! Amount!
• Example: Drug A 20 mg & Drug B 10 mg = Drug B potency is higher!

Drug-receptor interactions: Agonists

• Agonists do what the body should do naturally
• Drug mimics the endogenous substance
• Receptors bind readily & produces very good effects
• Example: Morphine is good for pain because it mimics endorphins
• Primary (aka Full) agonists are extensively bind to existing receptors

Partial Agonist

• The body does little even if all receptors occupied
• The presence of a full agonist can act like an antagonist

Inverse Agonists

• Induces the OPPOSITE effect of the naturally binding substance
• e.g. Caffeine binds to adenosine receptors
• adenosine has a calming effect
• Caffeine does the opposite

Antagonists

• Blocks the receptor site to prevent endogenous or endogenous-like substances from binding
• Has no effect other than to block other substances from binding
• Example: Naloxone (Narcan) is (t'/2 = 1-2 hrs, so it is take 2 or 3 doses to fully help
• Have cell efficacy at certain cellular levels

Receptor Types

There are 6 major receptor types:

• G-protein (GPCR)
• Ion channels
• Nuclear receptors
• Enzyme types
• Non-enzyme 'JAK-STAT'

G Proteins

• Stimulates G-protein & second messenger systems = sympathomimetic stimulation
• Causes sympathomimetic stimulation

Ion Channels

• They most bind to voltage-gated channels and can be open/closed
• Example is Lidocaine-when its channels is open/closed, you can’t feel since there is no pain transduction

Nuclear Receptors

• Steroid molecule that is mostly bounded in cytoplasm
• Creates a change in a series of events in cytoplasm

Enzyme Binding

• has 2 types:

1. Intracellular enzymes
2. Transmembrane enzymes

Non-enzyme

• This requires a JAK-STAT, or the immunity supporting drug

Tolerance and Ressistance

• It is most common receptor to have people stop working
• When the receptor de-sensitization OR decreased number of viable receptors to a substance
• More drug is required to sustain result
• Addictive substances: Opiates, alcohol, benzodiazepines Drug Resistance
• When receptors stops functioning efficiently and weirdly