Tx of allergic rhinitis and histamine responses. 

Anti-emetic (promethazine)

Sedative (antihistamine and anticholinergic)

Adjunct in Parkinson's Dx (anticholinergic)

Local anesthetic (diphendryamine ONLY) - blockade of Na+ channels in sensory nerves when used topically

1. Noncytolic process: energy and Ca2+ dependent.  Morphine, vancomycin, tubocurarine, and anaphylaxcotoxins stimulate release/influx of Ca2+ raising intracellular Ca2+ concentrations through GPCR causing histamine release

2.  Cytolytic process: antigens act via this mechanism by cross-linking their receptors

Cardio: dilation of vessels, increased force of contractions via SA & AV node

Resp: bronchoconstriction, increased fluid secretion, bronchospasm, cough

GI: contracts smooth muscle

Cuta. nerves: pain & itching

Adrenal: increased Epinephrine release

CNS: increase wakefullness, inhibits appetite, regulation of drinking, body temp, secretion of ADH, control of BP and nociception

Cardio: combine with H1 to increase peripheral blood flow

Resp: bronchodilation

GI: increases acid secretion, relaxes smooth muscle

Cutaneous nerve endings: pain & itching

CNS: unknown

List the 1st generation Anti-histamines

Side effects, Important interaction

diphenhydramine, chlorpheneramine

SE: SEDATION, anticholinergic effects (dry mouth, urinary retention)

Impt. interaction: Paradoxical stimulation in children

List 2nd generation Anti-histamines

Side Effects

cetirizine, fexofenadine, loratadine

SE: anticholinergic effects, minor sedation

What is the anti-emetic antihistamine agent? 

Side effects?

Important interaction?

Promethazine - D2 antagonist

SE: hyperprolactinemia, EPS

II: synergistic w/ CNS depressants

Azelastine: used for allergic rhinits

SE: drowsiness and sedation

What drugs do you use to treat migraines ACUTELY?

What drugs do you use to treat migraines PROPHYLACTICALLY?

"Triptans" - e.g. sumatriptan - increase vascular tone, prevent neurogenic inflammation

Methylsergide - prevents the release of substance P and prevents neurgenic inflammation

Name receptor and therapeutic actions & SE of

BUSPAR

5-HT 1 agonist - anti-anxiety

SE: chest pain, dizziness, headache

May increase haloperidol plasma levels

Give receptor target, action and SE of

SUMATRIPTAN

5-HT1B/D receptor

Used for ACUTE migraines

SE: coronary vasospasm

Synergistic action with ergots

Receptor, action and SE of

METHYLSERGIDE

5-HT2 antagonist

PROPHYLACTICALLY for migraines, carcinoid tumors

SE: peripheral ischemia (due to interaction with beta blockers), chest pain, dizziness, insomnia, nausea

Receptor, action and SE of

TEGASEROD

5-HT4 agonist

GI prokinetic: Irritable bowel syndrome, constipation

SE: mild

Receptor, action and SE of

CLOZAPINE & RISPERIDONE

5-HT2 antagonist (and dopamine antag)

Anti-psychotic

SE: agranulocytosis

Additive effects with anticholinergics and potentiation of hypotensive effects

Receptor, action  of

KETANSERIN

5-HT2 antagonist (partial alpha1 antag)

Hypertension

Receptor, action and SE of

ODANSETRON & GRANISETRON 

5-HT3 antagonists

Nausea/vomiting (and chemo-induced N/V)

SE: headaches

Receptor, action and SE of

FLUOXETINE & SERTRALINE

SSRI

Anti-depressant

SE: hotflashes, heart palpitations, agitation, insomnia, decreased libido

Inhibits the metabolism of carbamazepine and hydantoins.  Potentiate effects of MAO-I. 

Receptor, action and SE of

SIBUTRAMINE

5-HT, DA, and NE uptake inhibitor

Obesity

SE: increased CV response, headache, agitation, dry mouth, vomiting

Additive effects with MAO-I. 

Receptor, action and SE of

MIRTAZAPINE

Increase NE/5-HT release and 5-HT2/3 antagonist

Depression

SE: agranulocytosis, hypotension, agitation, abnormal thought patterns

Typical antipsychotics treat "positive" symptoms (hallucinations).  Their efficacy relates to their affinity at D2 receptors.

Atypical drugs block 5-HT2 and have efficacy in treating negative symptoms (depression, social withdrawl) with schizophrenia.   

Describe the MOA for

amine ergots

amino acid ergots

atypical ergots

Smaller, amine ergots: more selective partial agonists/antagonists at 5-HT Rs ONLY

Larger AA ergot: less selective and similar affinity as partial agonists/antagonists at 5-HT, alpha-adrenergic, and dopamine Rs

Atypical: primary DOPAMINE agonists  

Peripheral vasoconstriction: up to 24 hr w/ ergotamine (long-lasting agonist at alpha-1 R's & 5-HT R's)

Cerebral vasoconstriction: ergotamine - agonist at 5 HT 1 D/B Rs (acute migraine)

methylsergide - 5-HT2 A/C antagonist (prophylactic)

Stimulation of uterine muscle: due to agonist effects at alpha-1-adrenergic and 5-HT2 R's; pregnant uterus is more sensitive; greater 5-HT R sensitivity

Ergonovine, Methylergonovine - used for labor induction if oxytocin doesn't work, also used for post-partum bleeding

GI Tract: variable effects of nausea, vomiting, diarrhea agonist action at 5HT3 R's in BS emetic center

agonist action on 5HT3 R's GI sensory and vagal afferents agonist action at 5-HT4 R's enhance ACh and increase GI contractions

AMINE ERGOTS

Use, SE, Interaction

Ergonovine, Methylergonivine

Use: post-partum bleeding, induction of labor if oxytocin doesn't work

MOA: Uterine smooth muscle contraction due to agonist /partial agonist effects at alpha-1-adrenergic and 5-HT2 R's

SE: ergotism (vasoconstriction) leading to gangrene and bowel infarction

Interaction: CI in CV diease and pychosis

Methylsergide

Use: Migraine prophylaxis, diarrhea, malabsoprtion of carcinoid

MOA: antagonist at 5-HT2 A/C R's takes 1 to 2 days to develop and 1-2 days for effects to disappear when stopping therapy

AMINO ACID ERGOTS

Use, MOA, SE, CI

Ergotamine, Dihydroergotamine, Bromocriptine

Use: acute treatment for migraine

Bromo - hyperprolactinemia, parkinson's, acromegaly

MOA: agonist at 5-HT1D/B; Bromo - D2 agonist

SE: ergotism (vasoconstriction) leading to gangrene and bowel infarct

Interactions: contraindicated in patients w/ CV disease & psychosis

ATYPICAL ERGOTS

Use, MOA

Pergolide, Cabergoline

Use: hyperprolactinemia, parkinson's, acromegaly

MOA: dopamine D2 agonist - inhibits the secretion of prolactin in humans; replaces lost dopamine in parkinson pts

in pts with acromegaly it lowers elevated blood levels of growth hormone

Migraines: acute tx - vasoconstrictive effect - Ergotamine, dihydroergotamine

prophylactic tx: methylsergide

Hyperprolactinemia: dopamine inhibits prolactin release, so use D2 R agonist such as bromocriptine, pergolide, cabergoline

Postpartum bleeding/labor: ergot alkaloids used for vasoconstriction of uterus after birth; ergonovine, methylergonovine

Antiparkinson agent: dopamine agonist ergots replace loss of dopamine: bromocriptine, pergolide, cabergoline

Carcinoid crisis: carcinoid tumors of GI secrete copious amount of 5-HT - methylsergide

Dx of variant angina: prinzmetal's or variant angine from spastic responses of coronary BVs - ergonovine IV used during coronary angiography

Normal doses: diarrhea, N/V

High doses: CNS stimulation, hallucinations

Ergotamine, ergonovine: prolonged vasospasm leading to gangrene of extremities, bowel infarction

Methylsergide: chronic use see fibroplastic changes in retroperitoneal space, pleural cavity, and endocardial tissue

CI: obstructive vascular and/or collagen disease; HTN; pregnancy; psychosis

AT1 Receptor

AT2 Receptor

AT1: high affinity for losartan and low affinity for PD123177

PREDOMINANT type in vascular smooth muscle

Most actions mediated by AT1: GPCR activation of PLC and generation of IP3 & DAG causing increased intracellular Ca2+ causing constriction

AT2: high affinity for PD123177 low affinity for losartan

Dif transduction system: serine/tyrosine phosphatases, PLA2, nitric oxide, cGMP

High levels of AT2 during development and less abundant in adults - involved in tissue development

High levels in adrenal medulla

Upregulated in heart failure and infarction

Clonidine, Propranolol

Block sympathetic outflow and receptors on kidney

Captopril, Enalapril

Decrease vascular resisitance W/O increasing HR

Promote natriuresis

Rx for HTN, decrease damage and death due to cardiac infarction and delay diabetic neuropathy

INHIBIT degradation of bradykinin, Sub P, and enkephalins - increase vasodilation

SE: hypotension, cough, CP. Anapylactiod rxn and potentially dangerous angioedema. 

 Peptide antagonists (substitute sarcosine for phenylalanine)

Saralasin: limited use due to IV admin. & ability to elicity pressor responses when A-II is low

Nonpeptide antagonists

Losartan, valsartan - HTN

Good oral bioavailability, lower SE than enalapril, selective for AT1, disinhibits renin (lose feedback) and increased A-II levels will stimulate AT2 R's

POTENT vasodilator peptides

The kinin-kallikrein system synthesizes bradykinin

Formed enzymes are kallikreins

Substrate: kinongen - precurosr to kinins

Kallikriens: serine proteases that liberate kinins from the kinongens

Two forms of kinogens: LMW (80-85%) and HMW (15-20%)

B1: [des-Arg9]bradykinin > [Tyr(Me)8]bradykinin > bradkynin

limited distribution, m/b involved in inflammation

B2: [Tyr(Me)8]BK > BK > [des-Arg9]BK

Wide distrib., GPCR

Increase Ca2+, Cl-, NO, PLC, PLA2, cAMP

ANP- atrial naturetic peptide

Released due to stretch and volume expansion

Increases Na excretion & urine flow, GFR increases w/ no change in renal blood flow, inhibits the secretion of renin/aldosterone and vasopressin, vasodilation of arteries

BNP - brain naturetic peptide

Isolated from porcine brain but synthesized in heart, regulation and physical response similar to ANP just lower levels

ANPA, ANPB, ANPC

Both ANP and BNP act at ANPA whereas CNP acts at ANPB

Short T1/2 - metabolized by neutral endopeptidase

Also removed by binding to ANPC which internalizes the protein

Nesiritide (BNP analog) can be administered by constant IV infusion, better approach could be to block endopeptidase

Endothelins are potent vasoconstrictors - 3 isoforms

ET-1: predominant endothelin secreted by vascular endothelium.  Produced in the CNS

ET-2: produced in kidney and intestines

ET-3: highest concentration in the brain. Also in GI tract, lungs, kidneys

Actions: transient lowering of BP (NO via ETB) followed by prolonged increase (ETA receptor); decrease GFR and Na+ excretion

Inhibitors of Endothelin Synthesis & Action

Antagonists for ETA & ETB R's

BOSENTANT

Use: pulmonary HTN

SE: headache, nasopharyngitis, flushing, potentially seriously liver damage

Impt. intraxns: interactions w/ any drugs metabolized by CYP2D9 and CYP3A4.  Inhibited by OC's, cyclosporine A, glyburide, category X during pregnancy

PG pathway: AA (arachidonic acid) acted on by COX to make various PGS & Thromboxanes: PGE1, PGE2, PGF2alpha, PGI2, TXA2

COX exists in 2 isozymes: COX-1 (consitutive) and COX-2 (inducible)

LT Pathway: AA acted on by 5-lipoxygenase to make LTs: LTC4, LTD4 (mixture of these = slow-reacting substance of anaphylaxis)

Vascular: arterial sm. m. relaxed by PGE2 and PGI2 results in vasodilation; TXA2 and PGF2 alpha vasoconstrictors; all immediate breakdown so effects serve to regulate the microcirculation

GI Tract: effects of PG and TX on gut m. vary; administration of clinically-used PGs often leads to colicky cramps; diarrhea, N/V

Airways: respiratory sm. m. is relaxed by PGE2 and PGI2; but contracted by TXA2 and PGF2alpha

Repro. system: FEMALE: stimulate uterine contractions and cervical ripening

MALE: role unknown; low PG in seminal fluid is assoc. w/ infertility

CNS: FEVER: pyrogens cause release of PGE2 in brain which produces fever; PGE2 synthesis is blocked by aspirin

SLEEP: PGD2 produces sleep when infused into cerebral ventricles

NEUROTRANSMISSION: PGEs inhibit the release of norEpi from sympathetic nerve endings; NSAIDS increase vasoconstriction due to increased release of norEpi as well as inhibition of endothelial synthesis of PG vasodilators (PGE2 & PGI2)

Types of prostaglandin receptors and their primary therapeutic actions

(PGE2, PGF2alpha, PGE1, PGI2)

PGE2 - cervical ripening

PGF2- control of postpartum bleeding and open angle glaucoma/ocular HTN

PGE1: patent ductus arteriosus, erectile dysfunction, mucus secretion in hyperacid secretion

PGI2: primary pulmonary HTN

PGE2 - cervical ripening or termination of pregnancy from wks 12 - 20

SE: uterine hyperstimulation, fetal distress, bradycardia/syncope, headaches/flushing

PGF2alpha - Control postpartum bleeding

SE: N/V, diarrhea, increased GI contractions, vasospasm

PGE1 - patent ductus arteriosus, ED, impotence

SE: sleep apnea in neonate or priapism for ED/impotence

PGI2 - pulmonary HTN

SE: dizziness, headache, myalgia, flushing, tachycardia

Increased risk of bleeding w/ coagulants

PGE1 - GI protection in hyperacid secretion

Prevent PUD in NSAID users and Rx of ulcers unresponsive to H2 antagonists

Few SE - headache, diarrhea, cramps, uterine contractions

PGF2alpha - open angle glaucoma and ocular HTN

SE: increased bronw color in iris due to melanocyte stimulation

LK CysLT1 antagonist

Asthma (1X day)

SE: well tolerated

Avoid in NSAID sensitive pts.

PGF2alpha agonist

Open angle glaucoma, ocular HTN

SE: increased melanin - increased brown color in iris

Lk CystLT1 antagonist

Asthma (2X a day)

SE: diarrhea. laryngitis, otitis media, nausea, rash and/or neuropathy similar to Churg-Strauss

Increases warfarin effects,

5-Lipoxygenase inhibitor - inhibits LK synthesis

Use: asthma prophylaxis

SE: well tolerated, m/b headache

Zil increases the plasma concentration of propranolol, theophylline, and warfarin