Pharm - Block 1

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DIAZEPAM

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Valium
Tx: Pain, Grand mal seizure (15-30min) after 2 hrs halflife changes to 2 hours (gets into brain)

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ED50

Back 2

Lower ED50 == Higher potency / Higher affinity

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Antagonist

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Minimal efficacy
Has affinity for receptor
Binds and deactivates
Increases conc. of agonist required to produce a response

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Efficacy

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Amplitude of maximal response acheived at very high concentrations

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Drug affinity is equivalent to

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Drug affinity is equivalent to Potency

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Receptors vs Inert binding site

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Difference is signal transduction

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Partial agonist similar to

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Competitive antagonist

Compete with binding site for full agonist and behave as competitive inhibitors

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Very few drugs are _____
We worry about _____

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SPECIFIC

Selectivity

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Range of concentrations that drug is therapeutic

Back 9

Therapeutic window

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Quantal doe response relationship (vs) graded/conventional

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SD for patient POPULATION

Both have maximal and ED50

only SD can come from quantal

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To avoid first pass effect

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Sublingual or transdermal to avoid presystemic clearance by enzymes and transporters in GI tract and liver

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Formulation for stable plasma level

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Extended release
Transdermal patch

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AC
PC

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Ante cibum: Before meals

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QD

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Quaque die

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PO

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By mouth

Per os

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Zero order

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Alcohol and phenytoin: concentration doesn't matter, a certain rate (not amount) will be metabolized over time

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Factors increasing lipid solubility (↑↑ drug absorption)

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adding an alkyl group (e.g. methyl, ethyl, propyl, CH2CH2CH3)

adding an aryl group (e.g. benzene ring(s))

replacing O with S

addition of a halogen (F, Cl, Br, I)

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Factors decreasing lipid solubility (↓↓ drug reabsorption in kidney tubules)

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- additions commonly produced by metabolism to enhance excretion

- these groups increase hydrogen bonding with water (↑↑ hydrophilicity)

Addition of:

-COOH
-OH
-NH2
-O-CH3
-SO42-
-glucuronic acid

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Examples of Drugs with Significant First Pass Effect or Low Bioavailability

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PMN

Drug: Propranolol- ~26% Bioavailability because 75-85 % is metabolized by the liver before it can reach the circulation when taken orally. (increased BA with cirrhosis)

Drug: Morphine-~30% Bioavailability because 70% is metabolized via 1st pass effect if taken orally. Morphine is therefore usually given via s.c. injection to bypass this mechanism.

Drug: Nitroglycerin- is typically taken sublingually (buccal cavity) where it enters the circulation and is rapidly delivered directly to the heart (without having to go through the liver first), thus avoiding the First Pass Effect.

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Variables that can affect Bioavailability include:

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consumption of grapefruit juice, which can destroy GI epithelial P-450

drugs which induce P-glycoprotein (e.g. rifampin, St John's wort)

drugs that inhibit P-glycoprotein or P-450 (e.g. cimetidine, fluoxetine)

Liver disease (e.g. cirrhosis), which destroys liver tissue

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Drugs: Rifampin & St. John's wort

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Drug's modulating distribution by inhibiting P-glycoprotein

Mechanism of Action: Inducers of Intestinal P-glycoprotein (& hepatic cyt-P450)
Background: P-glycoprotein is a membrane-bound protein that is thought to play a protective role, functioning to prevent entry and promote removal of xenobiotics (foreign compounds) from the body by translocating them from intracellular to the extracellular environment. P-glycoproteins have a broad substrate specificty. P-glycoprotein is expressed in intestinal mucosa, renal proximal tubules & in capillary endothelial cells comprising the blood-brain-barrier, and in tumor cells (where it functions as a multi-drug resistance mechanism).
Pharmacokinetics: Induction of P-glycoprotein can result in decreased intestinal absorption of cationic drugs, reduced entrance into the CNS across the blood-brain-barrier, and increased secretion of drugs into renule tubules. Cyt-P450 induction by these two drugs also enhances the metabolism of a wide variety of drugs including couramin, oral contraceptives & metoprolol (amongst others). Induction of both mechanisms by rifampin & St. John's wort increases elimination of other drugs from the body.

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Drugs: Cimetidine & Grapefruit Juice

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Drug's modulating distribution by inhibiting P-glycoprotein

Mechanism of Action: P-glycoprotein inhibitors (& inhibitors of cyt-P450)
Pharmacokinetics: Cells in the intestinal tract contain a P-glycoprotein that acts as a reverse transporter which actively pumps drugs out of the cells in the gut wall back into the gut lumen. Inhibition of P-glycoprotein can result in substantially increased drug absorption.
Major drug interactions: These compounds can elevate plasma levels of various drugs by inhibiting their metabolism by cyt-P450, and by enhancing their oral bioavailability by inhibiting intestinal P-glycoprotein. They can also increase the fraction of drug crossing the blood-brain-barrier into the CNS.

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Drugs with Unusual Drug Distribution Patterns

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Quinacrine

Thiopental

Digoxin

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Quinacrine

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is largely deposited into the liver and gall bladder. It has an exceptionally high (620 L/kg)“apparent” volume of distribution because most of the drug ends up being in tissues and not in plasma.

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Thiopental

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is highly lipid soluble and rapidly distributes to the brain after a single IV injection. After a single dose, thiopental levels in the brain increase for a few minutes, then decline in parallel with the plasma level. Anesthesia ends rapidly as the drug redistributes to more slowly perfused tissues. If plasma concentration is monitored long enough, a third phase of distribution, in which the drug is slowly released from fat, can be distinguished. With continued administration of thiopental, large amounts may be stored in fat, resulting in prolongation of anesthetic plasma concentrations. Apparent Vd = 2.3 L/kg.

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Digoxin

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is also concentrated in tissues and therefore has a large apparent volume of distribution (Vd 6.3 L/kg) in healthy patients.

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pH Effect on Drug Elimination

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ASA

Amphetamine

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ASA

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example of a weak acid (RCOO- + H+ ↔ RCOOH )

If a drug is in a lipid-soluble form during passage through the renal tubule, a significant fraction will be reabsorbed by passive diffusion across membranes and back into the blood.
Therefore, >>>weak acids are excreted faster in alkaline urine<<< because it causes a greater fraction of drug to be in a charged form (which cannot be reabsorbed).

Drug Interactions: Drugs that alkalinize the urine (e.g. sodium bicarbonate, potassium or sodium citrate, thiazide diuretics, carbonic-anhydrase inhibitors) increase the rate of salicylate renal excretion.

You will lose more of the drug in excretion and less bioavailable

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Amphetamine

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Drug Class: example of a weak base (RNH2 + H+ ↔ RNH3+)

Drugs that acidify the urine (ascorbic acid, aluminum chloride) can increase the renal elimination of weak bases by keeping them in their charged form (see figure below).

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Inhibitors of Cytochrome P450 (CYP)

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Example Drugs & CYP's they inhibit or act as competitive substrates for:
Cimetidine (moderate: CYP 1A2, 2C19, 2D6, 3A4)
Erythromycin & other Macrolides (major: 3A4, weak: 1A2, 2B6)
Ciprofloxacin (strong: 1A2; weak: 3A4)
Ketoconazole (strong: 1A2, 2C9, 3A4; moderate: 2A6, 2C19, 2D6)
Fluoxetine (Prozac ®) (strong: 2D6; moderate: 1A2, 2C19; weak: 2B6, 2C9, 3A4)


Characteristics:

These drugs act either as inhibitors, or competitive substrates for several Cyt-P450 isoforms.
When given, these drugs will cause an immediate inhibition of Cyt-P450 mediated metabolism of other drugs (substrates).
The inhibition is typically reversible,

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Inducers of Cyt-P450 (CYP)

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Rifampin (strong: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 3A4).
Phenobarbital (barbiturates) (strong: 1A2, 2A6, 2B6, 2C8, 3A4)
Carbamezepine (strong: 1A2, 2B6, 2C8, 2C9, 2C19, 3A4)
Phenytoin (strong: 2B6, 2C8, 2C9, 2C19, 3A4)
St. John's wort (induces: 3A4, 2C9, 1A2 & P-glycoprotein)


Characteristics:

Chronic administration of these drugs will cause increased levels of selected CYP isoforms by enzyme induction.
Increased levels of CYP will increase the rate of metabolism of drugs metabolized by their respective isoforms.
Enzyme induction is a relatively slow process (e.g. it typically takes a week or more to reach steady state).
Enzyme induction is slowly reversible -

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Important Drugs Metabolized by Cyt-P450 (CYP)

Back 32

Drug Examples:

Warfarin (major substrate of 2C9 & minor:1A2, 2C19 & 3A4
Theophylline (major substrate of 1A2, 2E1 & 3A4; minor substrate for: 2C9 & 2D6)
Oral contraceptives (Ethinyl estradiol & levonorgestrel) (major: 3A4; minor: 2C9 & 3A5-7)

Characteristics:

Approximately half of all drugs are metabolized by cyt-P450.

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Sulfa drugs & Phenobarbital

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In newborns, sulfa type drugs (e.g. antibiotics) can displace bilirubin from binding sites, leading to jaundice, kernicterus & mental retardation. Coadministering phenobarbital to the mother can induce cyt-P450 mediated conjugation of bilirubin, making it more water soluble and more readily excreted.

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Phenobarbital & Warfarin

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Administration of phenobarbital to a patient (e.g. to calm them down after an MI) can cause induction of cytP40, thus altering the metabolism of warfarin. Withdrawal of phenobarbital will have the opposite effect due to reduced enzyme induction.

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Phenobarbital & Phenytoin

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Administration of phenobarbital to a patient (e.g. to help them sleep) taking the anticonvulsant phenytoin (Dilantin ®) will cause increased metabolism of phenytoin (by induction of cytP40), thus reducing the plasma level of phenytoin, and increasing the chances of seizure in a patient with epilepsy.

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Ethanol & Disulfuram (antibuse)

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Disulfuram inhibits aldehyde-dehydrogenase. When ethanol is metabolized, alcohol dehydrogenase rapidly converts acetaldehyde to acetic acid. Disulfuram prevents this breakdown, causing acetaldehyde to accumulate, which makes the patient ill (nausea, vomiting, decreased BP) & hopefully encourages the patient to stop drinking ethanol.

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MAO inibitors & Tyramine containing foods

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MAOi-type antidepressants will prevent the metabolism of tyramine, which is present in blue cheese & beer. Tyramine in such foods is normally metabolized by MAO in the gut before it can be absorbed. MAO inhibitors prevent this breakdown, resulting in elevated tyramine levels after ingestion of such foods. Tyramine can cause a dangerous increase in blood pressure.

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The 2 Primary Pharmacokinetic Parameters:

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Vd - Volume of Distribution
the volume in the bucket of water (L) that you dump your drug dose (mg) into (see Figure below).

Cl - Clearance (Elimination Clearance)
the volume of bucket water per unit time that is filtered completely free of drug (see Figure below).

Front 39

4 Important Equations:

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Vd = Loading Dose/Co

t1/2 = 0.69 Vd / Cl

t (0.90) = 3.3 t1/2

Css = Dosing Rate/ Cl

Front 40

Examples of 3 Drugs with Dose-Dependent Kinetics of Elimination

Back 40

Phenytoin (Dilantin ®)

ASA

EtOH

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Drug: Phenytoin (Dilantin ®)

Back 41

Phenytoin has dose-dependent kinetics of elimination. Phenytoin is hydroxylated in the liver by an enzyme system that is saturable at high plasma levels, hence small incremental doses may increase the half-life and produce very substantial increases in serum levels,

wide inter-patient variability in phenytoin serum levels with equivalent dosages.

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Drug: Ethanol (Jack Daniels, Budweiser, Cuervo Gold ®)

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Vd is similar to total body water content.

The rate of metabolism is dose-dependent, but at levels usually achieved in the blood, the rate of oxidation follows zero-order kinetics (i.e. is independent of time & concentration).

A typical adult can metabolize 7-10g (150-220 mmol) of ethanol per hour (the equivalent of 10oz of beer, 3.5 oz of wine or 1oz of 80 proof spirits).
Chronic ethanol consumption can induce cyt P450; this can increase the hepatotoxicity of acetaminophen

Acute alcohol use may inhibit the metabolism of other drugs due to decreased metabolism &/or decreased liver blood flow

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Drug-induced Hemolysis in G6PD Deficiency

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Primaquine

G6PD (Glucose-6-phosphate dehydrogenase) is an enzyme present in the Red Blood Cell (RBC). G6PD deficiency leads to shortening of the red-cell life span and hereditary non-spherocytic hemolytic anemia.
G6PD deficiency results in reduced GSH levels, which is required for maintaining the structural integrity of RBC membranes.
G6PD deficiency also results in an increased sensitivity to drug-induced hemolysis.

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Drugs known to cause hemolytic anemia include:

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primaquine, chloroquine, dapsone, quinine, quinidine (antimalarial drugs)
Sulfonamide drugs such as Sulfametoxazole or Cotrimoxazole
aspirin - possible risk at very high doses
some Vit K analogs - possible risk

Patients should be tested for G6PD deficiency before these drugs are prescribed.

Genetic Prevalence: There is a high incidence of severe G6PD-deficiency in individuals of Mediterranean (Sardinians, Sephardic Jews, Greeks, Iranians) and Asian ancestry.

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Drugs Metabolized by Acetylation:

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Isoniazid (Antimycobacterial_

Procainamide (antiarrhythmic)

Sulfa drugs (e.g. sulfonamide antibiotics)

Dapsone (anti-leprosy, antiparasitic)

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Fast vs. Slow Acetylators

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Approximately 50 percent of African Americans and Caucasians are ”slow acetylaters”, and the rest are ”rapid acetylaters”;

the majority of Eskimos and Asians are “rapid acetylaters.”

The defect in slow acetylators of isoniazid and similar amines appears to be caused by the synthesis of less enzyme rather than an abnormal form of it. The rate of acetylation does not significantly alter the effectiveness of isoniazid.

Slow acetylation may lead to higher blood levels of the drug and thus, to an increase in toxic reactions.

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Succinylcholine

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Skeletal Muscle Relaxant (blocks transmission on the muscle side of the NMJ)

Patients homozygous for atypical plasma cholinesterase gene (1 in 2,500 patients) are extremely sensitive to the neuromuscular blocking effect of succinylcholine.

”dibucaine number”.

Front 48

Imatinib (Gleevac ®)

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CML is caused by an abnormal chromosomal translocation that results in the formation of the Bcr-Abl fusion protein. This fusion protein is present in up to 95% of patients with this disease. Hence it is a selective target for drug action against this form of cancer.
Mechanism of Action: an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein. Imatinib prevents the phosphorylation of the kinase substrate by ATP.

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5-Fluorouracil (Efudex, Fluoroplex ®)

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Commonly used cancer drug against solid tumors (colorectal cancer primarily)

a genetic mutation or SNP (single nucleotide polymorphism) of DPD present in up to 5% of cancer patients increases the half-life of 5-FU from 13-15 mins to 160 mins (2.6 hrs)

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Prednisone, generic, Meticorten ®

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Drug Class: Glucocorticoid (synthetic), Immunosuppressant, Anti-inflammatory steroid

MECHANISM
alter the transcription of various target genes

Approximately 20% of expressed genes in a cell are regulated by glucocorticoids
They inhibit the production of inflammatory mediators, including PAF, leukotrienes, prostaglandins, histamine and bradykinin.

inhibition of phospholipase A2 as well a downregulation of the expression of Cox-2

INDICATIONS
treatment of inflammatory disorders in many organ systems

prevent transplant rejection
minimize allergic reactions
treat autoimmune diseases (e.g. Crohn's disease, systemic lupus, psoriasis)

treatment of severe asthma

SIDE EFFECTS
severe toxicities
osteoporosis
aseptic necrosis of femur heads (hip fractures)
peptic ulcer with possible perforation and hemorrhage
growth inhibition
cataracts & glaucoma
tendon rupture (particularly of the Achilles tendon)
muscle weakness, loss of muscle mass (myopathy)
sodium retention & fluid retention
hypertension
worsening of diabetes
depression & psychoses
pancreatitis
impaired wound healing
thin fragile skin
menstrual irregularities
development of Cushingoid state
secondary adrenocortical and pituitary unresponsiveness

Corticosteroids may mask some signs of infection, and new infections may appear during their use

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Cyclosporine, Sandimmune, Neoral, SangCy

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Drug Class: Immunosuppressant

Mechanism of Action: Cyclosporine is a fat-soluble cyclic polypeptide antibiotic that acts at an early stage in the antigen receptor-induced differentiation of T cells and blocks their activation. Cyclosporine binds to and forms a complex with the intracellular protein cyclophilin,

Side Effects: Numerous toxicities, including

nephrotoxicity
hypertension
hyperglycemia

Cyclosporine should be administered with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

Major drug interactions: Numerous!

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Tacrolimus [FK506] Prograf

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its mechanism involves the inhibition of calcineurin.

Drug Class: Immunosuppressant (Proliferation Signal Inhibitor)

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Sirolimus [rapamycin] Rapamune

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NOT FOR LUNG or LIVER PTs

inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukins IL-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants.

has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase.
This inhibition suppresses cytokine-driven T-cell proliferation,

Indications:

prophylaxis of organ rejection in patients receiving renal transplants.
It can be used in combination with other immuosuppressants

Side Effects:
Profound myelosuppression (esp. thrombocytopenia)
Increased susceptibility to infection & possible development of malignancies (e.g. lymphoma & skin cancer)

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Azathioprine, Imuran

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It interferes with purine nucleic acid metabolism at steps required for lymphoid cell proliferation that follows antigenic stimulation. The purine analogs are thus cytotoxic and destroy stimulated lymphoid cells.

Pharmacokinetics:

Azathioprine is a prodrug that is metabolized to mercaptopurine (the active form).
Xanthine oxidase splits much of the active material to 6-thioruric acid prior to excretion in the urine (hence the drug interaction with allopurinol).

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Cyclophosphamide, Cytoxan, Neosar ®

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an alkylating agent that is one of the most efficacious immunosuppressive drugs available. (Destroys proliferating lymphoid cells. Greater effect on B cells than on T cells.)

Indications:

Treatment of autoimmune disorders (systemic lupus erythematosus & multiple sclerosis) & in patients with autoimmune hemolytic anemia. Can inhibit an established immune response. Typically used as a drug of 2nd choice after another drug has been found to be ineffective (because of its greater toxicity).
Broad spectrum anticancer drug that can be given alone, but is more commonly given in combination with other drugs (e.g. CHOP, CAF or CMF). Major indications include non-Hodgkin's lymphoma, leukemias, multiple myeloma, breast & ovarian cancer.

Pharmacokinetics:

Can be given orally (most alkylating agents are given i.v.), and it is well absorbed.
It must be bioactivated by cyt P450 to be effective. Cyclophosphamide in its parent form does not have direct cytotoxic effects. Cyt P450 metabolism produces 4-hydroxycyclophosphamide (an active metabolite) which spontaneously isomerizes to aldophosphamide (a second active metabolite). Aldophosphamide undergoes non-enzymatic breakdown into both acrolein and phosphoramide mustard which are also cytotoxic. Aldophosphamide can be broken down to an inactive metabolite (carxboxyphosphamide) by aldehyde oxidase (aldehyde dehydrogenase).

Resistance:

Aldehyde oxidase (which converts active metabolites to inactive metabolites) can become induced in cancer cells, producing a unique form of drug resistance.

Side Effects:

Impairment of fertility (men & women)
Secondary malignancies following its use (they have most frequently been in the urinary bladder, myeloproliferative, or lymphoproliferative malignancies)
Hemorrhagic cystitis occurs occasionally. Mesna (Na salt of methylethylsulfonate) can be given to protect the bladder from the toxic effects of cyclophosphamide.

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Mycophenolate mofetil

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It inhibits the de novo synthesis of purines by inhibiting inosine monophosphate dehydrogenase (IMPDH).

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Methotrexate Rheumatrex, Methotrex, Trexall ®

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a folic acid antagonist that inhibits dihydrofolate reductase (DHFR), interfering with the synthesis of thymidylate, purine nucleotides & the amino acids serine & methionine, thereby interfering with the formation of DNA, RNA and proteins.
Must be bioactivated intracellularly to polyglutamate derivatives,

Indications:

Psoriasis
Rheumatoid arthritis
Neoplastic diseases:

Contraindications:

Methotrexate can cause fetal death or teratogenic effects when administered to pregnant women.

Major drug interactions:

Leucovorin (folinic acid) is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate.
NSAIDs, penicillins & cephalosporins interfere with the renal clearance of methotrexate.

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Thalidomide

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suppression of excessive tumor necrosis factor-alpha (TNF-α) production
down-modulation of selected cell surface adhesion molecules involved in leukocyte migration

Over 40 different indications including:
multiple myeloma
management of the skin manifestations of lupus erythematosus
cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL)


Side Effects:

Extensive side effects including:
Teratogenesis
Peripheral neuropathy
Hypothyroidism
Thrombosis

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Etanercept, Enbrel

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Monoclonal Antibody / TNF receptor fusion protein
Mechanism of Action:

A dimer of human IgG1 and the TNF receptor.
Etanercept binds to both TNF-alpha and TNF-beta, inhibiting TNF-mediated inflammation.

Indications: Adult rheumatoid arthritis,

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Infliximab, Remicade

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RA, crohns

rug Class: Monoclonal Antibody & TNF-α antagonist
Mechanism of Action:

Neutralizes the biological activity of TNF-α by binding with high affinity to the soluble and transmembrane forms of TNF-α

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Diphenhydramine Benadryl ®

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Drug Class: H1 Antagonist (ethanolamine subtype)

ndications:

Antihistaminic: For allergic conjunctivitis due to foods; mild, uncomplicated allergic skin manifestations of urticaria and angioedema; adjunctive to epinephrine and other standard measures in treatment of anaphylactic reactions - after the acute manifestations have been controlled.
Motion sickness: For active and prophylactic treatment of motion sickness.
Antiparkinsonism: For parkinsonism (including drug-induced) in the elderly unable to tolerate more potent agents.
Local anesthesia: in patients allergic to conventional local anesthetics.
Sedation: used as a mild sedative in Tylenol PM ®.

Side Effects:

Marked sedation; disturbed coordination.
Antihistamine overdosage reactions may vary from central nervous system depression to stimulation.
Stimulation is particularly likely in children.
Atropine-like signs and symptoms, dry mouth; fixed, dilated pupils; flushing, and gastrointestinal symptoms may also occur.

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Hydroxyzine generic, Atarax, Vistaril ®

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Drug Class: H1 Antagonist (piperazine subtype)

ndications:

management of histamine-mediated pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses
for symptomatic relief of anxiety and tension

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Promethazine (previously marketed as Phenergan ®) (

Back 63

antipsychotic

Side Effects: drowsiness, dry mouth, respiratory depression, neuroleptic malignant syndrome
Warnings:

Should not be used in pediatric patients <2 yrs old due to risk of fatal respiratory depression.
When given (accidentally) by intra-arterial injection it has caused several cases of gangrene & limb amputation

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Fexofenadine / Allegra

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Second gen H1 Blocker

Mechanism of Action: antihistamine with selective peripheral H1-receptor antagonist activity.

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Cromolyn Sodium, Intal, Nasalcrom ®

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Degranulation inhibitor

alteration in the function of delayed chloride channels in the cell membrane that inhibits cellular activation in eosinophils & specific mast cells subtypes found in the lung.

Indications:

Prophylaxis for inhibiting asthma caused by allergens or exercise

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Cimetidine Tagamet ®

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Blocks H2 receptors in parietal cells which supresses basal and meal-stimulated acid secretion in a dose-dependent manner

Sideeffects: Endocrine effects: cimetidine inhibits the binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol & increases serum prolactin levels. With chronic use may cause gynecomastia or impotence in men & galactorrhea in women.

Cimetidine inhibits multiple forms of cytochrome P450 (CYP1A2, CYP2C9, CYP2D6 & CYP3A4). Hence the half-lives of drugs metabolized by these pathways may be prolonged.

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Cushings Disease

Back 67

results from a pituitary adenoma that produces large amounts of ACTH, which in turn stimulates the adrenal cortex to release excess amounts of adrenal coritical hormones (cortisol & androgens)

inappropriately high levels of glucocorticoids, no matter what the cause. Exogenous glucocorticoid intake is the most common cause of Cushing's Syndrome.

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Addisons Disease

Back 68

resulting from autoimmune distruction of the adrenal glands) is the most common cause of primary adrenal insufficiency (70-90%) in the US. Worldwide, tuberculosis is the 2nd most common cause (outside of the US).

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Dexamethasone Suppression Tests

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Initial
Purpose: Initial Screening for glucocorticoid excess

DST
: Defines glucocorticoid excess

HighDose
Purpose: to localize the cause of the glucocorticoid excess

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Corticosteroid Side Effects & Mechanisms

Back 70

Avascular Necrosis of Femur Head

Cataract formation & Glaucoma

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Prednisone, Meticorten

Back 71

alter the transcription of various target genes.

Approximately 20% of expressed genes in a cell are regulated by glucocorticoids
They inhibit the production of inflammatory mediators, including PAF, leukotrienes, prostaglandins, histamine and bradykinin.
A mechanism that contributes to the decrease in the synthesis of inflammatory mediators produced by glucocorticoids is an inhibition of phospholipase A2 as well a downregulation of the expression of Cox-2 (but not Cox-1), thus reducing the amount of enzyme available to produce prostaglandins.


Indications:

treatment of inflammatory disorders in many organ systems

transplant rejections, minimize allergic rxns, treat autoimmune dzs (e.g. Crohn's disease, systemic lupus, psoriasis), severe asthma

Side Effects:
High-dose, long-term glucocorticoid therapy can produce severe toxicities that can include effects such as:
osteoporosis
aseptic necrosis of femur heads (hip fractures)
peptic ulcer with possible perforation and hemorrhage
growth inhibition
cataracts & glaucoma
tendon rupture (particularly of the Achilles tendon)
muscle weakness, loss of muscle mass (myopathy)
sodium retention & fluid retention
hypertension
worsening of diabetes
depression & psychoses
pancreatitis
impaired wound healing
thin fragile skin
menstrual irregularities
development of Cushingoid state
secondary adrenocortical and pituitary unresponsiveness

Notes:
Corticosteroids may mask some signs of infection, and new infections may appear during their use

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Hydrocortisone [Cortisol]

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Indications:

replacement therapy in adrenocortical deficiency states such as primary adrenocortical insufficiency (Addison's disease) or secondary adrenocortical insufficiency.
They are also used for their potent anti-inflammatory effects in disorders of many organ systems (e.g. lupus, rheumatoid arthritis, asthma).

Side Effects:

Permanent: aseptic necrosis of femoral & humoral heads, cataracts.
Reversible: fluid retention, hyperglycemia, hypertension, peptic ulcers, osteoporosis, myopathy, mood disorders, impaired wound healing, development of a Cushionoid state (this is the short list).

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Mifepristone [RU-486]

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Drug Class: Glucocorticoid Receptor Antagonist/inhibitor

Indications: Termination of Pregnancy (used in combination with misoprostol).

Indicated for the medical termination of intrauterine pregnancy through 49 days (7 weeks) of pregnancy.

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Metyrapone

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Diagnostic test of pituitary function.

Drug Class: Inhibitor of Glucocorticoid Synthesis

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Celecoxib Celebrex ®

Back 75

Cox-2 inhibitors have analgesic, antipyretic & anti-inflammatory effects similar to non-selective NSAIDs, but with fewer GI side effects.

In general, coxibs have little impact on platelet aggregation (which is mediated by Cox-1) & therefore have minimal cardioprotective effects (e.g. minimal effect on platelet function)

Indications:

relief from the symptoms of osteoarthritis
rheumatoid arthritis in adults

Contraindications:
Patients with severe renal insufficiency (Cox-2 is constitutively active in the kidney).

NSAIDs may diminish the effects of Angiotensin Converting Enzyme (ACE) inhibitors, furosemide and thiazide diuretics.

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Rofecoxib

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Vioxx ® (not available in the US)

increased incidence of myocardial infarctions

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Aspirin

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Aspirin irreversibly inhibits both isoforms of COX

ndications:

Anti-inflammatory. Aspirin interferes with the chemical mediators of the kallikrein system, thus inhibiting granulocyte adherence to damaged vasculature, stabilizing lysosomes, and inhibiting the chemotaxis of PMN leukocytes and macrophages.
Analgesia. Aspirin is effective in reducing pain of mild to moderate intensity through its effects on inflammation and probably because it inhibits pain stimuli at a subcortical (central) site. It is not effective for severe visceral pain.
Antipyretic. Aspirin reduces elevated body temperature (but it has little effect on body temperature in normal healthy patients). This effect is probably mediated by both COX inhibition in the CNS and inhibition of IL-1 (which is released by macrophages during episodes of inflammation).
Antiplatelet Effects. Single low doses of aspirin (81 mg daily) produce a slightly prolonged bleeding time, which doubles if administration is continued for a week. The change is due to irreversible inhibition of platelet COX, so that aspirin's antiplatelet effect lasts 8-10 days (the life of the platelet).
MI Prophylaxis: Aspirin is indicated to reduce the risk of death and/or nonfatal myocardial infarction in patients with a previous infarction or unstable angina pectoris.
Transient Ischemic Attacks: Aspirin is indicated for reducing the risk of recurrent transient ischemic attacks (TIAs) or stroke in men who have transient ischemia of the brain due to fibrin emboli. There is currently no evidence that aspirin is effective in reducing TIAs in women, or is of benefit in the treatment of completed strokes in men or women.

Aspirin may trigger asthmatic symptoms gastric upset, gastric and duodenal ulcers

Front 78

Acetaminophen Tylenol ®

Back 78

A weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant antiinflammatory effects.

It is a preferred drug for the treatment of pain & fever in patients allergic to aspirin, when salicylates are poorly tolerated, in patients with bleeding disorders, history of peptic ulcers, and patients in whom bronchospasm is precipitated by aspirin.
Acetaminophen is preferred to aspirin for the treatment of pain/fever in children with viral infections.

Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with centrilobular necrosis,

Front 79

Ibuprofen generic, Motrin, Rufen, Advil, Nuprin, ® others

Back 79

Analgesic, antipyretic & antiinflammatory.

If taken concomitantly with aspirin it will interfere with the irreversible platelet inhibition induced by aspirin

Ibuprofen can reduce the natriuretic effect of furosemide and thiazides in some patients

Use of NSAIDs in patients who are receiving ACE inhibitors may potentiate renal disease states.

Front 80

Azathioprine, generic, Imuran ®

Back 80

GOUT

It interferes with purine nucleic acid metabolism at steps required for lymphoid cell proliferation that follows antigenic stimulation. The purine analogs are thus cytotoxic and destroy stimulated lymphoid cells.

Front 81

Chloroquine

Back 81

MALARIA

concentrating in parasite food vacuoles, preventing the polymerization of the hemeoglobin product, heme, into hemozoin and thus eliciting parasite toxicity due to the build up of heme.
It is not active against liver stage parasites (and primaquine must be added for the radical cure of these species).

Effective against nonfalciparum and sensitive falciparum malaria
Resistance to chloroquine is now very common against strains of P. falciparum, and uncommon but increasing for P vivax.

Front 82

Penicillamine

Back 82

two or three months may be required before the first evidence of a clinical response is noted

Front 83

Adalimumab Humira ®

Back 83

TNF-α Blocking Antibodies

Drug Class: Treatment of rheumatoid arthritis

a recombinant human anti-TNF monoclonal antibody

Front 84

Infliximab Remicade ®

Back 84

eutralizes the biological activity of TNF-α by binding with high affinity to the soluble and transmembrane forms of TNF-α

RA, crohns

Front 85

Etanercept

Back 85

Enbrel ®

RA

Mechanism of Action:

A dimer of human IgG1 and the TNF receptor.
Etanercept binds to both TNF-alpha and TNF-beta, inhibiting TNF-mediated inflammation.

Front 86

Colchicine

Back 86

GOUT

Binds 
to 
microtubular
 protein 
tubulin
 in
 the 
PMN
 inhibiting 
chemotactic 
and
 chemokinetic 
responses 
of 
the 
neutrophil.

Side Effects:

diarrhea, nausea, vomiting.

Front 87

Allopurinol generic, Zyloprim ®

Back 87

Reserved 
for
 chronic treatment 
of 
severe
 tophaceous gout,
 renal
 urate
 stones, 
hyperuricemia
 not 
controlled 
by
 uricosuric
 agents
.
An important adjuvant in cancer chemotherapy of blood dyscrasias.

Front 88

Probenecid

Back 88

For the treatment of chronic gouty arthritis

Front 89

Summary of Treatment for Chronic Tophaceous Gout

Back 89

Graded
 doses
 of
 allopourinol

Colchicine, 
uricosuric 
agent 
&
 NSAID 
to
 control acute
 gouty
 flare‐up 
and 
pain

Alkalinize
 the 
urine

Diet with 
reduced 
purine 
content