Pharm 2

Most drugs are ____ and tend to remain _____ at physiological pH.

lipophillic, un-ionized

True/ False: Lipophillic drugs can remain in fat stores and lipid bilayers for a long time

True

Biotransformation aids in most drugs being readily reabsorbed from the glomerular filtrate. If they do not biotransform, what can happen?

The drug remains bound to the plasma protein and are not filtered at all at the glomerulus

Metabolism provides an alternative to?

Renal excretion for the termination of the active form of a drug

Where is the primary site of drug metabolism?

Liver

What happens in phase 1 reactions of biotransformation?

The parent drug is converted to a more polar (water soluble) metabolite by introducing or unmasking a functional group (OH, NH2, SH)

If phase 1 metabolites are sufficiently polar, they may be _____ ?

Readily excreted

Phase 1 reactions include?

oxidation, reduction, hydrolysis

What enzymes are responsible for phase 1 reactions? Where are they located?

Mixed function oxidases; smooth endoplasmic reticulum

What happens during a typical reaction of mixed function oxidases?

One molecule of oxygen is consumed per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water

True/ False: some phase 1 metabolites are not sufficiently polar and undergo a subsequent reaction

True

What happens during phase 2 biotransformation?

An endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with the newly incorporated functional group to form a highly polar compound (so that the molecule can be eliminated/excreted)

True/False: In some instances, phase 2 reactions may occur before phase 1

True

First Pass Affect

Following oral administration, drugs are absorbed from the small intestine, and transported via the portal system to the liver where they undergo extensive metabolism.

What is the principal site for biotransformation?

Liver

What other organs can biotransformation some drugs?

Lungs, GI tract, skin, kidneys

Which two liver enzymes make up ~75% of drug metabolism?

CYP3A4/5 and UGTs

Prolonged exposure to certain drugs will increase the activity of the mixed function oxidases (CYPs) resulting in ______ metabolism of the drug.

accelerated

Examples of drugs that induce CYP3A4 metabolic enzymes (enzyme induction) CYP3A4 is a subtype of CYP450

Carbamazepine, Oxcarbamazepine, Phenobarbital, Phenytoin, Rifampin, smoking,and St. John's wort

Examples of drugs that will inhibit cytochrome P450 systems (enzyme inhibition)

Clarithromycin, erythromycin, azole antifungals, amiodarone, diltiazem, verapamil, protease inhibitors, cyclosporin, grapefruit juice

Reactions that are primarily conjugated and result in the formation of highly polar compounds are?

Phase 2 Reactions

Phase 2 reaction conjugate formation involves?

High energy intermediates and specific transferase enzymes which may be located on the smooth endoplasmic reticulum(SER) or in the cytosol

Phase 2 reactions

Glucuronidation, Acetylation, Glutathione conjugation, Sulfation, Methylation, Water conjugation

Occasionally the metabolism of drugs produces _______ metabolites

toxic

An example of a toxic metabolite is?

Acetaminophen (most common OTC analgesics in US)

The therapeutic dose for acetaminophen

325-1000mg every 4-6hrs. Never more than 4g per day

Toxic exposure of acetaminophen is possible when:

140mg/kg is ingested in a single dose OR when more than 7.5g is ingested in 24hrs.

Acetaminophen metabolism occurs primarily in the liver by ______ and ________. It is then excreted in the urine.

Sulfation (20-46%) & Glucuronidation (40-67%)

A small percent of acetaminophen is metabolized by the _______ enzyme and produces a toxic metabolic (NAPQI)

CYP-450

The toxic metabolite NAPQI is detoxified by

Hepatic glutathione

What happens during the OD of acetaminophen?

hepatic metabolism through glucuronidation and sulfation is quickly saturated shunting acetaminophen to the CYP-450 pathway, producing NAPQI and depleting glutathione. NAPQI binds to hepatic proteins and enzymes causing injury. Hepatic failure develops over 3-4 days.

Treatment of acetaminophen OD

fluids, anti-nausea medication, activated charcoal, N-acetylcysteine (NAC) (patients at risk for liver damage, 100% hepatoprotective within 8 hours)

Who is at risk for hepatotoxicity when taking acetaminophen?

Pts with insufficient glutathione stores (alcoholics and AIDS pts)
-pts with induced CYP-450 (alcoholics and those taking anticonvulsants and anti-TB meds)

What causes variations in drug metabolism?

-genetic factors
-smoking
-diet high in charbroiled foods & cruciferous veggies will induce CYP1A enzymes
-grapefruit juice inhibits CYP3A

The 3 types of CYP2D6 genetic polymorphism are

Poor metabolizer, ultrarapid metabolizer, extensive metabolizer

CYP2D6 poor metabolizers

-3-10% of caucasians
-Higher risk of relapse in breast cancer patients taking tamoxifen

CYP2D6 ultrarapid metabolizers

-up to 1⁄3 of Ethiopians and Saudi Arabians.
-Require 2 to 3 times higher doses of nortriptyline
-codeine is metabolized much faster to morphine and can become toxic quicker

CYP2D6 extensive metabolizers

normal function

CYP2C19 genetic polymorphism

-3-5% of Caucasians and 18-23% Japanese populations
-show toxicity with mephenytoin
-show increased efficacy of omeprazole

CPY2C19 * 17 variant allele

-Higher metabolic activation of prodrugs like tamoxifen, chlorproguanil and clopidogrel.
-Enhanced elimination of drugs like escitalopram, imipramine and voriconazole.

CYP29 genetic polymorphism

-3-5% of Caucasians and 18-23% Japanese populations
-show toxicity with mephenytoin
-show increased efficacy of omeprazole

CPY2C19 * 17 variant allele

-Higher metabolic activation of prodrugs like tamoxifen, chlorproguanil and clopidogrel.
-Enhanced elimination of drugs like escitalopram, imipramine and voriconazole.

CYP29 genetic polymorphism

CYP29*3-much higher risk of side effects of side effects from warfarin

CYP3A5 polymorphisms

Affects metabolism of Midazolam

CYP2A6

tobacco smokers have a lower incidence of lung cancer

CYP2B6

affects metabolism of cyclophosphamide, bupropion, selegiline, and propofol

Age related changes in metabolism:

- Phase I reactions (mixed function oxidase system) reduced
-Phase II reactions (Conjugation) preserved
-Decreased hepatic blood flow
-Decreased ability of the liver to recover from injury

Diseases affecting drug metabolism

-Cirrhosis of the liver
-Hypothyroidism will slow the metabolism of digoxin

The nervous system is divided into:

central nervous system and peripheral nervous system

The peripheral nervous system is divided into:

-autonomic nervous system (involuntary) (smooth muscle, exorcise glands, cardiac muscle)

-somatic nervous system (voluntary) (skeletal muscles)

The autonomic nervous system is divided into:

-sympathetic (short preganglionic fibers; diffuse activation; fight/flight, adrenergic, thoraco-lumbar)

-parasympathetic (long preganglionic fibers; cranio-sacral outflow; discrete activation, rest/digest)

Sympathetic nervous system:

-anatomically is thoracolumbar
-Fibers leave the CNS through the thoracic, lumbar, and sacral spinal nerves.

Parasympathetic nervous system:

-anatomically is craniosacral
-Fibers leave esp. through cranial nerves III, VII, IX, & X.

short sympathetic fibers are ________ chains around the spinal column

paravertebral

longer fibers reach the ______ ganglia.

prevertebral

preganglionic parasympathetic fibers go to the ____

Organs (ciliary, submandibular, otic ganglia and in the walls of innervated organs.)

______ganglia are innervated by sacral preganglionic nerves similar to sympathetic

pelvic

enteric nervous system (ENS) is the collection of neurons that make up the _______. Sometimes considered a 3rd division of the ANS.

GI System

The ______ contains the myenteric plexus and the submucous plexus.

enteric nervous system

The 2 main transmitters found in the autonomic nervous system are

Acetylcholine (ACh) & Norepinephrine (NE)

Acetylcholine (ACh) has which kind of fibers?

cholinergic

Norepinephrine (NE) has which kind of fibers?

noradrenergic

Five key features of neurotransmitter function represent potential targets of pharmacologic therapy includes

Synthesis, storage, release, activation of receptors, termination of action

What is rapidly hydrolyzed by cholinesterase to choline and acetate?

acetylcholine

Acetylcholine also _________ pre-synaptic autoreceptors that inhibit the further release of Acetylcholine

activates

Acetylcholine stimulating at all autonomic ganglia

nicotinic

Acetylcholine stimulating at muscarinic receptors of sweat glands

sympathetic

Acetylcholine stimulating at sympathetic neuro-effector junctions of vasodilator fibers in skeletal muscle

muscarinic

True/False: Acetylcholine is stimulatory at nicotinic sites at neuro-muscular junctions

true

VAMPS are

Vesicle-associated membrane proteins

SNAPS are

synaptosomal nerve-associated proteins

VAMPS and SNAPS are called

fusion proteins

_______ blocks VAMPS and SNAPS so that ACh can not be released

botulinum toxin

Catecholamine transmitters consist of

Dopamine, norepinephrine, epinephrine

In postganglionic neurons ______ is the final product.

norepinephrine

Adrenergic transmission sites of drug action include

Metyrosine; reserpine alkaloids; cocaine, solriamfetol, & some antidepressants; amphetamines & ephedrine

Metyrosine

-inhibits catecholamine transmitter synthesis.
-Used in adrenal gland tumors

reserpine alkaloids

-cause depletion of transmitter stores.
-Rarely used for BP

Cocaine, solriamfetol, and some antidepressant drugs

-increases transmitter activity in the synaptic cleft by blocking the reuptake of norepinephrine

Amphetamines and ephedrine

releases stored transmitter from the nerve endings

Cholinergic receptors include (acetylcholine receptors)

muscarinic and nicotinic

Muscarinic receptors (types & location)

-5 subtypes
-located in the brain

Nicotinic receptors (types & location)

-2 subtypes
-located in skeletal muscle & autonomic ganglia

Activation of muscarinic receptors on presynaptic autonomic nerves ______ further neurotransmitter release

inhibits

Muscarinic receptors are found on?

presynaptic sympathetic nerve terminals

Muscarinic receptors inhibit the release of?

norepinephrine

Which receptor is located at all autonomic ganglia, at somatic neuromuscular junctions, and in the CNS?

Nicotinic receptors

At autonomic ganglia, the activation of nicotinic receptors is ________?

stimulatory

At neuromuscular junctions, the activation of nicotinic receptors causes?

muscle contraction

Organophosphate poisoning in the eye causes

miosis (constricted pupil) and increased aqueous humor flow

Atropine (muscarinic) in the eye causes?

opposite actions of organophosphates (dilated pupil & decreased aqueous humor flow)

Alpha agonist in the eye cause?

Mydriasis (dilated pupil), phenylephrine

Beta blockers in the eye cause?

Decreased secretion of aqueous humor & decrease intraocular pressure. Seen in pts w/ Glaucoma.

Ocular Cholinergic Effects

Lacrimation, miosis, accommodation

Cardiac Cholinergic Effects

Decreased heart rate, increased conduction at the AV node

Vascular Cholinergic Effects

Vasodilation (M3 receptors)

Pulmonary Cholinergic Effects

Bronchoconstriction, Increased mucus production

GI Cholinergic Effects

Increased HCl production, Increased contraction, Increased saliva production

GU Cholinergic Effects

Increased bladder tone, Decreased internal bladder sphincter tone

Ocular Cholinergic Inhibition

Mydriasis, Loss of ability to accommodate for near vision