Drug receptor interactions-pharmacokenitics Flashcards
Pharmacokinetic
Body’s effect on a drug
Pharmacodynamic
Drugs effect on body
Bioavailability
AUC oral availability/AUC injected availability
AUC injected = 100 % available
Covalent therapeutics
Uncommon: irreversible, recovery usually reqs synthesis of new receptors. Typically longer lasting, less specific
Ex: aspirin, alkylators, organophosphates
Hydrophobic therapeutics
Most common: weak acids or bases work well as drugs because they can be lipid soluble as neutral elements, or ionized and become water soluble
Racemic mixture
Mix of chiral and non-chiral isomers. Extends patent
4 things that make a drug therapeutically useful
Able to reach site of action
Can interact with receptor
Acceptably selective for therapeutic and adverse effects
Excreted at reasonable rate
G protein couple receptors
7 transmembrane regions
Receptor act-> G protein act -> effector act -> 2nd messenger act
- Effectors: Adenylate cyclase, guanylate cyclase, phoslip C
- examples: glucagon, beta receptors, muscarinic ACh
Competitive/non- competitive antagonist
Competitive: reversible, doesn’t change Emax, alters EC50
Non-competetive: irreversible, alters Emax
Both bind active site* note not all antagonist bind receptors
EC50/ED50
EC50: concentration reqd to achieve 50% max effect
ED50: dose required to achieve EC50 in 1/2 the population
* Kd is dissoc. Constant. When Kd > EC50, system has spare receptors. Kd is generally a good approximation of EC50
Therapeutic window/ index
Index ED50->LD50 (not clinically useful)
Window ED50 -> bottoms of index before lethality curve really begins.
Tolerance
PD: drug alters body (receptors) such that drug is less effective i.e. insulin resistance.
PK: body alters drug (increased metabolism/clearance) such that drug is less effective
Factors influencing drug absorption
Rate: dissolution, gastric emptying, blood flow, membrane barriers
Extent: dissolution, membrane permeability, efflux transporter substrates
Passive diffusion of drugs
Most important/common; lipid soluble via PM, water soluble via aqueous pore channels. [ ] dependent
Endocytotic drug absorption
B12 colobamin
pH trapping
Lipid Soluble form (electroneutral) passes though PM and is the ionized and trapped as water soluble. Weak acids/bases do this, hence they tend to be ideal drug choices.
Routes of administration
Greatest to least bioavailability: IV > IM > enteral
- IV has 100% bioavailability
- transdermal present other issues: formulation and physiological condition of patient make a big difference in administration
- rectal can have first pass or not depending on how high up you go. The vena cava is systemic.
Factors affecting absorption
pH of drug, bloodflow, surface area (intestine more efficient that stomach), contact time, food, P-glycoproteins
P- glycoprotein
Multi drug resistant transportation pore: kicks drugs out of cell
Selective, saturateable, inhabitable (grapefruit)
Bioavailability formula
AUC Oral/AUC IV
Amount of viable drug available after first pass phenomena
Cmax/Tmax
Cmax = [max] Tmax = how long it takes to get to Cmax
Vd
Volume of distribution
Vd = total amount of drug(dose given if IV)/plasma [drug]
Or
Vd = dose/Clearance
Drug half life
(0.693xVd)/Clearance
1st/0th order kinetics
Most drugs are first order
- first order elimination is proportional to concentration of drug perfusing organs. Elimination is only proportional to plasma [ ] at steady state.
Steady state
When admin = clearance.
- typically this takes 4-5 half lives
Factors effecting distribution
Blood flow to organ, surface area, concentration gradient of plasma protein bound drug, to tissue unbound drug.
Peaks and troughs
Peak is dose dependent
Trough is time dependent
Orphan receptors
Receptors above the threshold of EC50/Kd ratio
i.e. Kd > EC50
Drug half lives N2Ks
1 H/L = 50%
2 H/L = 75%
3 H/L = 87.5%
Loading dose
Ldose = (Vd * [desired])/bioavailability
Maintenance dose
M dose = (CL * [desired])/bioavailability
Endocytosis
Entry method of large molecules like proteins
hsp90
Heat shock protein: steroid binding protein that unfolds DNA to initiate TXN. 30 mins -hours
Ligand receptors
Growth factors (EGF, IGF, TGF) Insulin (Trk)
G protein types (3 primary)
Gs - increase cAMP
Gi - decrease cAMP
Gq - increase IP3/DAG via Phospholipase C
Potency vs. efficacy
Potency - lower EC50
Efficacy - higher Cmax
* note: make sure you know parameters (pop/pt)
PGE function (in general)
Stimulator/activator
- smooth muscle contraction (Airways/uterus)?
- vascular smooth muscle contraction/parturition (+oxy)
- wakefullness
- fever
- immunosuppressive
- oncogenic
PGD function (in general)
Opposite PGE
Leukotrienes
- Mostly inflammatory (IBD)
- lipoxin a/b coronary vasoconstriction
hGR - a
Classic glucocorticoid receptor
- inhibited by HGR - B
hGR-B
Inhibits the function of bound hGR-a
Cushings disease vs. syndrome
Diseases is in the brain (lots of ACTH and cortisol)
Syndrome is in the adrenals (lots of cortisol with NO ACTH)
