Pharmacology of the Somatic Nervous System IV

Why do most drugs tend to stay in the body for a long time?

Unionized/ partially ionized

Lipid soluable

Bound to plasma proteins

A bound drug is unable to be?

Excreted in urine or feces

What is metabolism?

Process of increasing hydrophilic or foreign molecules to increase the rate of excretion

Where do we see most metabolic function?

Liver

Why does the liver do a lot of metabolism?

Widest breath of metabolic enzymes

Large endothelial surface

Distribute products to blood or bile for excretion

Phase I will typically have what types of reactions?

Demethylation

Oxidation

Reduction

Hydrolysis

Phase I will ____ of metabolites and provide ____ for phase II enzymes?

Increased polarity;

reactive sites

What are the major enzymes that handle phase I reactions?

P-450 (CYP)

Dogs will have _____ P-450 enzymes to humans

Cats will have _____ P-450 enzymes in general

Similar;

Fewer

Cats will have slower ____?

Demethlyation and hydroxylation

Why is salicylates in cats so dangerous?

Salicylates like Aspirin, have a very long half life in cats due to slow aromatic ring hydroxylation

Phase II reaction typically involve what?

Conjugation reactions of drugs and other molecules in order to increase molecular weight or polarity

Dogs can get sulfonamide (antibiotic) toxicity and have problems metabolizing pro-drugs due to a lack of what?

NAT1 and NAT2

Cats can typically metabolize pro-drugs and antibiotics better than dogs because they have?

NAT1

Cats lack what enzyme that can lead to life threatening bone marrow suppression when azathioprine is used?

Thiopurine methyltransferase (TPMT)

What is GST (Glutathione Transferase)

Necessary for normal RBC function. Requires Glutathione in the liver

What is SULT Sulfotransferase?

An enzyme that attaches sulfur stores in the liver to drug molecules

What animals is SULT less effective in?

Cats and Pigs

What is UGT, (UDP-glucuronotransferase)

Attachment of UDP-glucoronate to a drug molecule.

Cats DO not do what process?

Glucoronate!!!!

A cat is given a drug by their owners and show signs of methemoglobinemia. What drug was it given and what receptor does the cat lack?

Acetaminophen, UGT1A6

A cat presents to the clinic diarrhea and anorexia. After taking blood and getting a history you find the cat had just got under anesthesia for a dental and has anemia. What drug was the cat given that cause the problem and what enzyme does the cat lack that caused this?

Propofol, UGT1A9

What can induce metabolism?

Increased transcription,

Stabilization of mRNA

Stabilization of protein

Induction of metabolic is a ____ change that occurs ___?

Long term

Slowly

An activating molecule can activate _____ metabolic enzyme?

More than one

What can inhibit metabolism?

Competitive and non-competitive inhibition

An inhibiting molecule will usually only inhibit ___ enzyme and can be _____ term?

One;

Short or long term

Define microsomal inducible enzymes?

Molecules coming from the ER

Where do non-microsomal enzymes come from?

Cytoplasm

Where do we find the most important inducible enzymes? (P450, glucuronidation and glutathione conjugation)

rough ER

Dogs and cats typically metabolize medications ____ than humans?

Faster

Because dogs and cats usually metabolize medications faster what must be done?

Increasing the dosage of medications or frequencies

What would we want to consider if a patient had hepatitis, liver cirrhosis or hypothyroidism?

They likely have slower or impaired metabolism, so that may need a decreased dose

How is a drug excreted?

Usually from renal or hepatic sites due to them receiving most of CO

A drug is conjugated in the liver w/ a glucose molecule, it is approximately 360Da. Where will it be excreted?

Liver, needs to be less than 350 to be excreted in the kidney

How does Enterohepatic recirculation of a drug occur?

Bacteria in the gut will metabolize the conjugated sugars off the drug allowing it to be reabsorbed by GI tract

If a drug undergoes Enterohepatic recirculation what happens to the half life?

Prolonging of the half life

What are examples of drugs that undergo enterohepatic recirculation?

Opioids and benzodiazepines

If you give an oral antibiotic to a dog with a collapsing trachea that is on hydrocodone (an opioid) what might we see happen to the hydrocodone in the dogs system?

The antibiotic will kill gut bacteria meaning more of the opioid will stay conjugated and be excreted

Where are drugs often reabsorbed in the kidney?

PCT

What are the main organic acid transporters that reabsorb drugs?

SLC solute carriers that are nonspecific and reabsorb weak acids