Pharmacodynamics=what drug does to body

·         Drug-receptor binding

·         D+R ↔ DR

·         ED₅₀   =dose which 50% of patients experience therapeutic effect

·         TD₅₀    =dose which 50% of patients experience toxicity (side effects)

·         LD₅₀    =dose at which 50% will have lethal effect

·         Therapeutic window - efficacy without unacceptable toxicity

·         TI = TD₅₀ / ED₅₀

o    High TI = wide therapeutic window=BETTER

o    Low TI = small therapeutic window

DR* What happens when drug binds

 Full: drug bind and max responses on all DR*-Activating and inactive (ex: MSO4)

Patial:Stabilized DR+DR* (Buspirone)

Inverse: Stabilizes DR in case of R* natural state (inactivate the active)

Stabilization of DR and preventing DR*

Competitive-reversible binding :( competes with agonist knocking them out. 

Noncompetitive-cant bump outh antagonist. Binds and prevents agonist form comming in. 

Nonreceptor-agonist inactivations (protamine sulfate), mediates opposite response of agonist (betablockers). Sits by and overpowers agonist. 

·         Distribution

·         Metabolism

·         Excretion

Systemic circulation is considered “free” drug=free to go to any sites and free to be metabolized.  Free active metabolite can go  back into circulation and metabolize further.

·         Molecular size and shape

·         Solubility at site of absorption

·         Degree of ionization

·         Relative lipid solubility of its ionized and non-ionized forms

o    Passive diffusion=passively cross membrane.  Need to be small and hydrophobic so they can pass through lipid core

o   Facilitated diffusion - energy independent (does not require ATP).  Some type of transporter carrying drug across membrane.

o    Active transport - energy dependent (depends on ATP)

o    Endocytosis-when drugs attach to outside of membrane and membrane engulfs drug

pKa=pH=log(HA/A)

pKa=pH at which 50% of drug is ionized 

pH Trapping: nonionized: crosses membrane easily, ionized: stuck and cant cross as easy  Weakly acidic drugs (ASA)- when it crosses the membrane it will get ionized (get a charge) so it can't go back. 

o    Protonated in stomach (nonionized)

o    Deprotonated in plasma (ionized) and cannot penetrate back to GI tract

If pH is less than pKa, the protonated, electrically neutral form of the drug will predominate.
-If pH is greater than pKa, the deprotonated, electrically charged form of the drug will predominate.

Ionized drugs are charged and cannot penetrate through membrane.    It is the unionized form that can penetrate through the membrane.  Drug with a pka of 4.  Put in environment where pH is 4.  ASA put in environment where pH is one which pushes the ASA from pH of one to 7.  pka of ASA is still 4 and then will push make the drug into the ionized form.  It will then not make the ionized ASA go back to stomach. –This is known as pH trapping.  

Small

Hydrophobic

Active Transport

Facilitated Transport

(intrathecal)-bypass. 

rate and extent drug leaves admin and goes systemic

Bioavailability: fraction absorbed. IV 100%

Factors:

Increase Concentration=Increase Absorption

Circulation at site of absorption

Drug Solubility

Surface area

Enteral (Aspirin): first pass metabolism, slow delivery

Parenteral (Morphine): irreversible, pain, fear. Mucouse Membrane (beclomethasone): Great, no first pass metabolism, painless.

Transdermal (nicotine): lipophilic drug, slow delivery, irritatiing, no first pass.  

Parenteral Routes:

SubQ (Xylocaine): slow ondet, small volumes, can be oil

IM (Haloperidol): Intermediate onset, effects lab tests, painfull, bleeding, oil based drugs

IV (Morphine): Rapid onset, controlled drug delivery, peak related toxicity. 

Intrathecal (methotrexate): Bypass BBB, Infection, Highly skilled personnell required. 

Intital Phase: regional blood flow (muscle, vicera, skin, fat)=slow

Second Phase: Distribution to tissues. Rapid to interstitial compatments. Restricted in lipid-insoluble drugs. drug binding plasma proteins. 

Volume of Distribution: Vd=dose/(drug)plasma

 Low Vd=retained within vascular compatment         High Vd=distributed into non=vascular compatments. Depends on drug which is better.                               "First in First out/ Last in Last out" 

Active drug - inactive drug (most common)

Active drug-Active metabolie=either more active, just as active or less active. 

Active drug-toxic metabolie

Prodrug-active drug (GI drug-Liver-more active) 

Unexcretable drug-Exretable metabolite

must be unbound 

Phases

1: oxidation/reduction

2: cojugation/hydrolysis

Phase 1: CYP450 (enzyme)=rapid excretion into urine. If not excreted, undergoes Phase 2. 

Hydroxyl group add to drug and result drug will be water-soluble. Watch with Alcohol, MAO. 

CYP450

Inhibition: Amioderon increases cooumadin and dig it prvents it from being metabolized so need less coumadin/ or dig. 

Phase 2: some drugs can go stright to phase 2. Large Polar conjugate. In this phase we add glucuronate, sulfate, glutathione, acetate= polar compound. 

Excreted rapidly in the urine and feces

Ex: active conjugate of morphine (morphine glucuonide) is more potent analgesic.

CYP450: Tegretol can decrease coumadin so need moer coumadin. Antibodies decrease birth control 

 Ex:  

Acetaminophen-phase 2 directly

 >90% metablolism Glucoronidation & Sulfation-Excreted Metabolites. 

10% CYP450-nacetly benzo-conjugation by glutithione-excretion

• increased transcription or translation
• decrease degradation-so build up
• Induction by another drug or autoinduction (carbamezapine-2 wks later requires much lower plasma concentration so will hae to increase dose)

Genetics

  45%C & B -Slow Acetylator: Watch Isoniazide (TB) it will increase toxicity

90% Asians-Fast Acetylator 

8% C-CYP450 is non-functioning so increase psych drugs, codein - morphine. 

Diets: Grapefruit juice=can really significantly affect metabolism. Particularly taking durgs with narrow therapeutic index. 

Lungs: anesthesia drugs

Renal: GFR Most common

Feces: used to tx GI problems (C-dif: PO VANCO) 

CL=(M+E)/(Drug)plasma

Clearance Kinetics:

First Order: increase in plasma conentration = Increase in Clearance (1:1) Not saturated

Zero Order: Increase in plasma concentration w/no increase in clearance (saturated) 

Half-Life

Takes about 5 half lifes to reach steady state. 

T1/2=time it takes for plasma concentration to be reduced by 50%

T1/2= 0.693/k K=elimination rate constant. 

Factors that Affects Half-Life: Changes in Vd (elderly decrease muscle mass)

Changes in clearance (organ failure) 

 Type 1 Hypersensitivity

Onset: 15-30 min

Sx: Hives, Uticaria, Anaphylaxis

PK: Antigen-Binding IgE on mast cells, Histamine, and serotonin

PCN causes 

Onset: min-hrs

Sx: Hemolysis (Toxic Epidermal Necrolysis)

PK: IgG Mediated and compliment binding cell bound antigen Neutrophils, macrophages, natural killer cells

Cefotephin causes

Onset: 3-8 hrs

Sx: Cutanieous Vasculitis And Toxic Epidermal Necrolysis

PK: IgG and complement binding soluble antigen. Neutrophils macrophages, natural killer cells, reactive oxygen species and chemokines  

Mitomycin C causes

Onset: 48-72 hrs

Sx: Macular Rashes & Organ Failure

PK: IgE and cell mediated, MHC, cytotoxic t lymphocytes, macrophages, and cytokines.

TB Test

Sulfa causes

Autoimmune (Lupus)