Glucuronyl transferase
the only phase II enzyme that is microsomal and inducible
CYP450
microsymal enzymes in the liver, perform oxidation of multiple drugs and foreign molecules. form OH
subtypes of CYP450
3A4- metabolize >50% drugs
2D6- impairs codeine metabolism
2E1- metabolizes & is induced by alcohol (increases drug toxicity!!)
Why is CYP2E1 dangerous?
it increases the metabolism of acetaminophen and increases potential hepatotoxicity caused by the metabolites
Smoking/chargrilled foods are inducers of
CYP 1A2
Barbiturates/phenobarbital, St Johns Wort are inducers of
CYP 2A6, 2B6, 2C8, 2C9, 2C18, 3A4
Ethanol is an inducer of
2E1
Grapefruit juice is an inhibitor of
CYP 3A4
Fluoxetine (Prozac) is an inhibitor of
2D6
most common types of phase II rxns
functional groups (OH, SH, NH2) conjugated with glucuronic acid
Genetic polymorphisms
mutations lead to enzyme deficiency and altered response to drugs
How do you “free” the drug to make it re-absorbable?
remove the conjugate! undoes the phase II step basically. done by digestive enzymes in the GI tract
Excretion of drug is enhanced by:
- agents that bind drugs in the intestine (Charcoal) thus increasing peristalsis
- antibiotics that eliminate GI bacteria
Estrogen (birth control) is re-absorbed into the enterohepatic circulation. This is normal!
Problem: when abx are taken, this reduces the amount of GI bacteria and therefore the drug is not unconjugated or re-absorbed
Result: drug is excreted from body! you get pregnant.
Antibiotics effect on estrogen
they decrease birth control reabsorption consequently eliminating it from body
larger Vd
means harder to purify the blood through hemodialysis bc it does not bind to the plasma
At high and toxic concentrations, what happens to elimination orders
Drugs normally eliminated by first order kinetics are now eliminated by zero order kinetics
gastric lavage
not recommended after 4 hours
activated charcoal is a form of tx for acute poisoning
will absorb many toxins
Smaller the Vd
more effective dialysis
Activated charcoal used to treat poisoning
by absorbing chemicals
Ammonium Chloride used to treat poisoning
acidify urine (bases)
Sodium bicarbonate used to treat poisoning
alkalinizing the urine (acid)
Drugs that treat poisoning by chelating metals:
Dimercaprol, Penicillamine, Deferoxamine, Calcium disodium edetate
Dimercaprol
used to treat poisoning from: arsenic, gold, mercury, acute lead
Penicallamine
used to treat poisoning from: copper (wilson disease, resistant case of rheumatoid arthritis)
Deferoxamine
iron poisoning
Calcium disodium edetate
lead poisoning
Acetylcysteine (inactivates toxins)
acetaminophen poisoning
Atropine is an antidote for
Cholinesterase inhibitor poison
Cyanide poisoning
tx: sodium nitrite, Na thiosulfate, and amyl nitrite
Ethanol is an antidote for
methanol or ethylene glycol poisoning
Fomepizole is an antidote for
ethylene glycol poisoning
Antibodies are antidotes for
various toxins
Dimercaprol
Arsenic poisoning
Penicillamine
Copper poisoning
Deferoxamine
Iron poisoning
Calcium disodium edetale
Lead poisoning
G6PD deficieny
Pamaquine- induced Hemolytic Anemia d/t genetic variation of G6PD gene
G6PD supplies NADPH & glutathione in RBC
Sex linked mutation; X chromo
NAT2
I.e. of Change in Protein Function mutation
txr of Acetyl group results in formation of an Amide on the drug
R allele= rapid acetylation –> Hepatotoxicity
r allele= slow acetylation –> Lupus
Test: Give Isoniazid and determined plasma conc @ specific time after administered
CYP-2D6 Mutation
A deletion, duplication, or SNP
Can be Poor, Intermediate, Normal, or Ultrarapid Metabolizer
Ex: Nortriptyline, Codeine, Debrisoquin
OATP1B1
Drug Transporter Polymorphism
Sinusoidal membrane of hepatocytes, affects uptake of statin drugs
Mutations= reduced response to HMG Coenzyme A Reductase Inhibitors AKA Statins
HLA Human Leukocyte Antigen
Immune Gene Polymorphism
Response mediated by cytotoxic CD8 T cells
Involved in hypersensitivity rxns- SJS/TEN
Ex: Abacavir sensitivity, screen for HLA B*5701 variant
Probe Drugs
used to evaluate ratio of metabolite to drug- measure the plasma concentration of metabolites
Enantiomer
mirror image
Example of a Lipid soluble, Hyrdophobically bonded drug
Anticonvulsant,
Local Anesthetic
Covalent bond; often irreversible; very strong
Aspirin,
DNA-alkylating agent,
Cholinesterase inhibitors
Potency
Dose required to produce a given effect
Are potency and efficacy related?
NO
Efficacy
Ability of a drug to initiate a response
The lower the EC50
The more potent the drug
Physiological antagonism
(functional) acts through a totally different mechanism to counteract the effects of agonist
generally not as specific or easy to control
I.e. reversing fall in BP produced by Histamine with Epinephrine
Chemical antagonism
directly interact w/agonist to inactivate it
I.e. inactivating Heparin w/Protamine Sulfate, Neutralizing stomach acid w/antacids
TKR Tyrosine Kinase Receptors
Insulin Epidermal & Nerve Growth Factor Platelet Derived Growth Factor CA relation to this Imatinib/Gleevec- cancer drug, works by signal transduction inhibiton
Cytokine Receptors
Growth hormone
Erythropoietin
Interferons
Interleukins
Desensitization
Acute. Receptor keeps getting hit with something it doesn’t respond to it like normal. i.e. gun violence. Will not change number, just less sensitive to effects!
Down-regulation
Chronic.Takes weeks-months. Receptors CHANGE IN NUMBER. Pharmacodynamic change.
Ras/Raf pathway
associated with Receptor Tyrosine Kinase pathways
RTKs activate the Ras/Raf pathway
Major targets for cAMP
Protein Kinases
PKA;PKC
Tachyphylaxis
very rapid development of tolerance following repeated dose over a short period of time
i.e. smoking meth
Physiologic tolerance
when two agents w/opposing effects are given together
Histamine (vasodilation) & Norepinephrine (vasoconstriction)
Pharmacodynamic tolerance
classic “drug tolerance”
response decreases d/t change in receptor # or fx
Pharmacokinetic tolerance
response decreases bc the enzyme that metabolizes the drug are induced
Barbiturates & alcohol; warfarin
Overextension type of adverse effects
Drug does TOO much of what it’s supposed to do:
Sedative hypnotics: excessive CNS depression
Antiarrhythmic: Arrhythmia
Insulin & other anti-DM: Hypoglycemia
ASA, Warfarin, Heparin: Hemorrage
Organ Directed Toxicity
Some drugs are toxic to organs/tissues with no connection to therapeutic effect
Aminoglycoside abx: Renal & Ototoxicity
Acetaminophen: Hepatotoxicity
Tetracycline (acne): Teeth discoloration, Bone growth retardation
Thalidomide, Methotrexate, Phenytoin, Warfarin: Teratogenic effects (birth defects)
Metabolite toxicity: Acetaminophen & Isoniazid toxicity
To cross a membrane, a drug must be
LIPID SOLUBLE &
NON IONIZED
What is the point of ion trapping?
to increase elimination of that drug
If you make urine basic:
acidic drugs will be trapped and excreted from the body
i.e. Sodium Bicarb
If you make urine acidic:
basic drugs will be trapped and excreted from the body
i.e. Ammonium Chloride
Basic drugs that can accumulate in the BREAST MILK and become trapped (bc breast milk is acidic)
Tetracyclines
Phenobarbitol
Rate limiting for First Order Elimination
plasma concentration
Rate limiting for Zero Order Elimination
the biological system
if given repeatedly in high doses, will NOT develop a steady state bc it’s not dependent on plasma levels
when given at higher doses than the elimination rate, will accumulate in the body and produce excessive plasma levels and TOXICITY
First order
certain % of drug is eliminated per time
can accumulate and reach steady state (Css)
Zero order
certain fixed AMOUNT of drug is eliminated per time
Alcohol 10g/hour
If you drink this much each hour, it will not accumulate and you will not reach steady state.
HOWEVER, if you exceed levels, will build up in plasma and produce TOXICITY= drunk
Cytokine receptor- JAK (kinase activity in a separate protein)
Growth hormone
Erythropoetin
Interferons
Interleukons
Gq- activates PLC
alpha 1 receptors
PIP2 is cleaved into DAG and IP3
DAG activates PKC
IP3 releases intracellular Ca2+ stores