PMC 1

Acetylcholinesterase inhibitors

*Blockage of acetylcholine esterase* increases the concentration Alf acetylcholine at the synapse and produces *muscarinic and nicotinic effects* Also referred to as *indirect cholinomimetics* because they do not bind to cholinergic receptors

Atracurium besylate

*Will undergo Hoffman elimination and will spontaneously decomposed which is useful for patients with hepatic or renal disease* Can also be broken down by plasma cholinesterase Not metabolized in liver or kidneys Duration of action is 30-40 minutes Nondepolarizing Tetrahydroquinoline-based neuromuscular blocking agent

Mifepristone (RU-486)

*antagonsit at glucocorticoid recpetor* Commonly used to treat patients with Cushing's syndrome Can be used to reverse sx of Cushing's syndrome

A2 agonist

*antihypertensives*, antiglaucoma drugs, analgesics 2-arylimidazoline (xylometazoline, oxymetazoline, tetrahydrozoline, napazoline)

Muscarinic receptor blocking drugs

*atropine Scopolamine* Ipatropium Tiotropium Propiverine Cyclopentolate Tropicamide Oxybutynin Trospium Solifenacin Homatropine Darifenacin Tolterodine

Succinylcholine chloride

*dimer of Ach, conjoined at the O-acetyl carbon* Quick acting, very short DOA Rapidly degraded by cholinesterase DOA increases with AchEI

Aldosteronism

*excessive production of aldosterone* by renal adenoma and hyperplastic glands More salt and water retention in blood Excessive renal loss of potassium, hypokalemia, Alkalosis, and increased Na results Tx: aldosterone receptor blocker (spironolactone)

Carbidopa

*inhibitor of aromatic L-Amino acid decarboxylase Inhibit the metabolism of exogenous L-dopa administered in the treatment of Parkinson's disease*

L3

*no controlled studies* in breastfeeding women, *risk possible*

Donepezil (Aricept)

*nonclassical cholinesterase inhibitor* Approved in 1997 for treatment of mild-to-moderate *alzheimer's disease and dementia* Exhibits *greater affinity for brain acetylcholinesterase* than in the periphery *hot hepatotoxic* Undergoes extensive metabolism by O-demethylation, debenzylation, hydroxylation, oxidation to the -N-oxide, and glucuronidation

Fludrocortisone

*one of the most commonly prescribed salt retaining rug* Steroid with both mineral and glucocorticoid activity

Clinical uses of estrogen

-treat primary hypogonadism -postmenopausal hormone therapy (prevent osteoporosis, Alzheimer's, and CV disease but it increases breast and endometrial cancer risk; combining with progestin decreases risk of endometrial cancer) -birth control (ovulation suppression with estrogen and progestin)

First trimester

0.12 weeks *greatest danger for drug-induced developmental defects*

Infant

1 month to younger than 1 year

Child

1 yr to younger than 12 yr

Metabolism of ethanolamine ethers

2 N-dealkylations N-deamination Oxidation of aldehyde Glucourindation

When do postpartum gaps cause a problem in breast milk

3 days Larger drugs can get thru to breast milk

How long can a concieved egg stay in the female Fallopian tube?

3-4 days

Desloratidine

3rd gen antihistamine based on loratidine More potent H1 antagonist and inhibitor of histamine release Duration of action is 24 hours Lacks cardiotoxiict

Terbutaline

3x greater beta 2 receptor selectivity than metaproterenol Tablet, injection, inhalation Resistant to COMT and MAO ADE: palpitation, tachycardia, N/V, dizziness, tremor, headache Short acting

What molecules and enzyme is needed for the synthesis of T4? T3?

4 - 2 DIT with thyroperioxidase 3 - DIT + MIT with thyroperoxidase

Sperm is viable for __ days in the female reproductive system

5

Flunisolide

6-alpha-F group increases glucocorticoid activity but has less left less effect than the 9-alpha-f function on sodium retention Conversion to acetonide derivative whihc cannot hydrogen bond restores biological activity

Which adrenergic receptors physiological effect includes myadrisis? A1 A2 B1 B2

A1

Adrenergic response (SNS) Salivary glands Sweat glands Pilomotor muscles

A1 Increased secretion Thickened, sticky saliva A1 Localized secretion Cold, clammy hands A1 Contraction Hair raising scare

Effect. Receptor. Organ/tissue Increased TPR and BP Increased renin and BP

A1 - blood vessels B1 - kidney

Effect. Receptor. Organ/tissue Urinary hesitancy Localized "nervous" sweat

A1 - trigone and sphincter (bladder) A1 - sweat glands

"Zosin"

A1 antagonist

ADR of prazosin

A1 blocker 1st dose hypotension Weakness/asthenia Orthostatic hypotension (dizziness, lightheaded ness) Fainting/syncope Less common: Loss of bladder control Pounding heartbeat Swelling of legs

Which NT are involved in the parasympathetic nervous system? Norepinephrine and epinephrine Serotonin Dopamine Acetylcholine

Acetylcholine

What is the primary transmitter in cholinergic neurotransmission? Adrenergic? All nerve fibers that originate from the CNS are?

Acetylcholine Norepinephrine Cholinergic

Direct acting cholinomimetic Drugs and preparations

Acetylcholine (opthalmic) - Micohol-E Bethanechol (oral, parenteral) - generic is Urecholine Carbachol (opthalmic solution) -topical: Isopto Carbachol, Carboptic -intraocular: miostat, carbastat Vevimeline (oral) - Evoxac

__ is a popular target in chemical warfare, pesticides, and the treatment of Alzheimer's disease because blocking will allow ACH to stay longer and trigger nerves longer. Deaminase Acetylcholinesterase CYP450

Acetylcholinesterase

Chronic addison's disease

Adrenocorticoid insufficiency (not enough cortisol production) Inability to maintain fasting blood glucose, weakness, fatigue, hypotension Susceptible to renal insufficient and circulatory shock Tx: hydrocortisone and salt retaining hormone such as fludrocortisone Clinical feature - hyperpigmentation in areas of increased friction (palmar creases, dorsal foot, nipples and axillary region, patchy hyperpigmentation of the oral mucosa)

Describe the MOA of bicalutamide, flutamide, and nilutamide

Adrogen receptor blocker

Nedocromil (Alocril, Tilade)

Aerosol inhalation used as a prophylaxis of asthma and reversible obstructive airway disease Opthalmic solution is used for allergic conjunctivitis Discontinued in US

Teratogen

Agent that causes *malformations* *selectivity* for certain target organs *selective* to developmental window *dose-dependent* - (greater dose = greater malformation) Direct effect on developing tissues Secondary effect (first mom, then baby) Diffusion effect (alter oxygen or nutrient diffusion through placenta)

Malathion, cholinesterase inhibitors

Agents/drugs block acetylcholineasterase enzyme so Ach is avaliable longer

MOA of spasmolytic drugs Effects Clinical application Tizanidine

Alpha adrenoreceptor agonist - CNS acting drug Pre and post synaptic inhibitor of motor output Spasm due to MS or stroke

Adrenergic receptors

Alpha, beta, and dopamine

What are the 3 types of receptors in adrenergic neurotransmission? Their location?

Alpha, beta, dopamine Cardiac and smooth muscle, gland cells, nerve terminals, renal vascular smooth muscle, skeletal muscle

Endocrine disruptors

Alter pharmacokinetics of steroids binding to transport proteins Ex. Polychlorobiphenyl derivative and thyroid hormone transport proteins. Kicks thyroid hormone off protien, liver, and kidney remove from circulation

Congenital adrenal hyperplasia

Altered function of adrenocorticoids due to *hyperpalstic adrenal gland leading to defect in cortisol production* Tx: dexamethasone to mother to protect fetus; cortisol replacement using synthetic steroids

Cholinesterase inhibitors Preparations avaliable

Ambenonium (oral) - Mytelase Demecarium (opthalmic) - humorsol Donepezil (oral) - Aricept Echothiophate (opthalmic) - Phospholine Edrophonium (parenteral) -generic, Tensilon Galantamine (oral) - Reminyl Neostigmine (oral, parenteral) - prostigmin Physostigmine, eserine (opthalmic, parenteral) Pyridostigmine (oral, parenteral) - Mestinon, Regonol Rivastigmine (oral) - Exelon Tacrine (oral) - Cognex

Mixed acting sympathomimetics Phenylisopropylamines

Amphetamine and methamphetamine No phenolic substituent and no side chain hydroxyl No COMT Lipophilic enough to cross BBB readily and cause CNS stimulation Serious abuse potential Central appetite suppressant effects

Reuptake inhibits: target potency = NET > DAT >>> SERT Amphetamines Clonidine Cocaine

Amphetamines

Nafarelin, buserelin

Analogies of GnRH

Flutamide

Androgen receptor blocker Used for the treatment of prostate carcinoma Can cause mild reversible hepatic toxicity Highly metabolized in the liver

Clinical uses of androgens

Androgen replacement therapy, some gynecomastia disorders, anemia, osteoporosis, anti-aging, growth stimulator

Actions similar to sex hormones produced by gonads

Androgens

Things synthesized from cholesterol

Androgens Estrogens Progesterone Gluticocorticoids Mineralocorticoids Choline acid Vitamin D3 Androgen and estrogen are sex hormones

The immediate precursor to testosterone is

Androstenedione

Spironolactone

Antagonist at mineralocorticoid receptor in kidney Results in diuretic response: increased Na excretion and K retention K sparing diuretic

Post partum depression tx

Antidepressants (sertaline and paroxetine is preferred; fluoxetine and citalopram have higher passage into breast milk) Hormone therapy Non-pharm (exercise, light, cognitive behavioral therapy) CAM (Omega-3- fatty acids, St. John's wort)

Tropisetron group indicates

Antimuscarinic drug

Which enzyme turns testosterone to estrogen?

Aromatase

What drug can be used to prevent some of the CV adverse effects of neuromuscular blocking agents

Atropine

Antimuscarininc for respiratory disorders Secretion accumulation due to administration of pre-operative anesthetics Drugs MOA

Atropine, scopolamine Blocking post synaptic muscarinic cholinergic receptors. Leads to decreased secretions

Antimuscarininc for respiratory disorders Laryngospasms due to involuntary muscle contraction Drugs MOA

Atropine, scopolamine Blocking post synaptic muscarininc cholinergic receptors. Lead to relaxation of smooth muscles

Direct acting drugs MOA

Bind To the receptor and mimics or modulate the effect of acetylcholine

MOA of aldosterone blockers

Bind to aldosterone receptor and block the actions of aldosterone Spironolactone Extensive blocking leads to: -hyperkalemia -metabolic acidosis -hyponatremia -hypotension

Molecular mechanism of steroids

Bind to receptor inside cell Receptor bind to DNA to regular transcription and translation

Mechanism of action of estrogen

Bind to receptors Transcription of growth factors Activation of cell signaling pathways Proteins necessary for cell growth and proliferation Cell growth, survival development of secondary sexual characteristics, endometrial lining build up, influence other hormone secretion

Alpha-bungarotoxin

Binding to nicotinic receptors is almost irreversible Snakes from bungatus genus have toxin Found in India and china Reversible but tight Competitive Nicotinic antagonist Nondepolarizing

Identify two characteristics that result from unique interactions between IgE and Fc epsilon receptors

Binds essentially irreversibly Cells not restricted to single antigen

Which of the following is a prodrug? Bitolterol mesylate Albuterol Salmeterol Colterol

Bitolterol mesylate

Cardiac muscles, smooth muscles, gland cells, and nerve terminals are innervated by: Only adrenergic neurons Only cholinergic neurons Both adrenergic and cholinergic neurons

Both adrenergic and cholinergic neurons

Organ system effects of indirectly acting cholineomimetics CNS Eye, respiratory, GI, urinary CV

CNS: low - Alert; high - convulsions, coma, respiratory arrest Eye: constriction of pupil Respiratory - constrict GI urinary: contracts muscles and makes you need to go to the bathroom CV: fall in cardiac output, bradycardia, and decrease contractility

Identify the determinants of cardiac output

CO = HR x SV

Metabolism of monteleukast

CYP3A4 and CYP2C9 metabolism Metabolism by cytochromes Drug interactions with phenobarbital, rifampin, and phenytoin

What family does estrogen 2/4-hydroxylase fall into?

CYP450 An oxidizer

Classical muscarinic agonists

Carbachol chloride Bethanechol

Effects of muscarinic agents

Cause tremor, convulsions, hypothermia Blockers do the opposite

Depolarizing neuromuscular blocking agents Bind to the Ex.

Cholinergic receptor holding it open The loss of membrane potential prevents future activation Decamethonium bromide and succinyl chloride

Clinical pharmacology of the cholinoreceptor agonist drugs Alzheimer's disease

Cholinesterase inhibitors such as tacrine, donepezil, galantamine, and rivastigmine can be used *severe loss of nicotinic receptors found in disease. We need cholinesterase inhibitors so Ach can stay in the synaptic cleft for longer time to bind to the few available receptors*

Reversible cholinesterase inhibitors effects can be reversed by

Cholinesterase regenerating compounds Cholinoreceptor blockers

Hormonal control of glucocorticoid (cortisol) prodiction

Circadian rhythm and stressors, fever, hypoglycemia, hypotension influences hypothalmus to produce CRH Hypothalmus secreted corticotropin-releasing Hormone (CRH) CRH acts on pituitary gland Pituitary secretes adrenocorticotropic hormone (ACTH) ACTH acts on adrenal cortex Cortisol is released from adrenal cortex Negative feedback loop. CRH and ACTH production inhibiton (cortisol inhibits both CRH and ACTH production)

Beta means (cis/trans)?

Cis

Indomethacin in babies

Closes ductus arteriosis

Progesterone is secreted from the

Corpus luteum

Aspirin blocks

Cyclooxygenase and forces more leukotrienes to be synthesized Worsens asthma

What first gen antihistamine blocks serotonin receptors?

Cyproheptadine

Which antihistamine has significant serotonin (5HT) receptor antagonist effects? What unique uses does this lead to?

Cyproheptadine Counter side effects of antidepressants Increase appetite and weight gain

Nondepolarizing neuromuscular blockers

D-tubocurarine Atracurium Pancuronium Pipecuronium Rocuronium Cisatracurium Doxacurium Gallamine Metocurine iodide

Which of the following is called the youth hormone? DHEA Cortisol Estrogen Testosterone

DHEA

Explain the baroreceptor reflex

Decrease in BP Baroreceptor in aortic arch and carotid are less active and sends info to medulla SNS sends signal to increase HR and TPR to restore BP Increase TPR occurs via an a1 receptor mediated vascular smooth muscle contraction

B2 effects on Bronchiole smooth muscle Intestine Liver Uterus Lungs

Dilation Decreased motility Increase gluconeogenesis and glycogenolysis Relaxation Bronchial dilation

First generation antihistamines

Diphenhydramine Dimenhydrinate Clemastine Carbinoxamine Pyrilamine Antazoline Triprelennamine Chloropheniramine Bromopheniramine Triprolidine Promethazine Meclizine Hydroxyzine Cyproheptadine Phenindamine

Which 1st gen antihistamines have the most sedative/anticholinergic properties

Diphenhydramine Promethazine

Which first gen antihistamines have pronounced alpha1-AR blockade? Side effects?

Diphenhydramine and promethazine Orthostatic hypotension (dizziness)

Differentiate between direct acting, indirect acting, and mixed acting sympathomimetic drugs.

Direct - bind directly to receptor Indirect - enhances release of NE from vesicle Mixed - combo of direct and indirect

MOA of spasmolytic drugs Effects Clinical application Dantrolene

Direct acting, block Ca release in the skeletal muscle Weaken skeletal muscle contraction by reducing actin-myosin interaction Spasm due to MS, cerebral palsy, or spinal injury

Scopolamine

Drowsiness and amnesia Toxic doses can cause excitement hallicunations, agitation, and coma Effective in attenuating motion sickness Used in the form of injection, by mouth, or transdermal patch SE: dry mouth and sedation Chemically and pharmacologically similar to atropine Combination with morphine produces a twilight effects (relaxes and puts out) Treat N/V associated with motion sickness and post surgery

Vesamicol

Drugs can inhibit Ach transport to the vesicle

Organophosphates (except __) __ absorbed

Echothiophate Well absorbed from all sites and make them highly toxic to human

Triamcinolone hexacetonide

Ester of triamcinolone acetonide and neohexanoic acid

Given the structure of a steroid molecule containing a lipophilic ester at the 17th carbon, describe the purpose of this modification. What is the enzyme that will typically transform? What are the two chemical species that result? Where is this enzyme? What ROA? How does it work?

Esterase Carboxylic acid and alcohol Everywhere Depot The steroid is placed in the skin and esterase cleave the medication which releases the steroid with a carboxylic acid and the steroid goes into the blood stream and provides the desired effect

Major hormone product of the ovary

Estradiol

Estrogen induced effects

Female growth and maturation Building of endometrial lining Enhance blood coagulation CV effects such increases HDL and lower LDL Cardioprotective effects Enhance production of protein (CBG, fibrinogen, TBG) resulting in metabolic changes Cell growth and proliferation

Valproic acid in pregnancy

Fetal hydration syndrome

Which of the following is not an androgen receptor blocker? Finasteride Flutamide Bicalutamide Spironolactone

Finasteride (5-alpha reductase inhibitor that blocks the conversion to testosterone to DHT)

5 alpha reductive inhibitors

Finasteride and dutasteride Inactivate 5-alpha-reductase by irreversible modification of 5-alpha reductase

Treatment of asthma

Increase adrenergic tone by adding an adrenergic agonist Decrease cholinergic tone by adding an anticholinergic *Corticosteroids block prostaglandins and leukotrienes Most cell stabilizers block degranulation Leukotriene modifiers block leukotrienes Anti-IgE antibodies block IgE*

Adverse CV effects of pancuronium

Increase in HR

Spasticity

Increase in stretch reflexes.increased basal muscle tone with muscle weakness Muscle weakness you need to increase stretch reflex

Adrenergic neurotransmission

Involves catecholamine transmitters Norepinephrine, dopamine, epinephrine Tyrosine comes from presynaptic nerve terminal and is converted to dopa > dopamine > norepinephrine which binds to adrenal medulla to release epinephrine Catecholamine biosynthesis are potential sites fro drug action

Which halogen, amino acid, and protein are utilized for thyroid synthesis?

Iodine Tyrosine Thyroglobulin

Nicotinic receptor signaling

Ion channel

What drugs are mast cell stabilizers?

Khellin, chromodynamics sodium, nedocromil, lodoxamide, pemitolast

GnRH stimualtes

LH and FSH secretion

Discuss pharmacokinetic difference during pregnancy

Lipid solubiltiy Drug ionization PH/pKa Placental transporters Protein binding Drug metabolism

Blockade of a1 on radial muscle? B2 on ciliary muscle? B2/A2 on Aquarius humor?

May decrease pupil size Decrease aqueous humor Decrease aqueous humor

Which of the following is a glucorticoid receptor blocker (antagonist)? Aminoglutethimide Ketoconazole Metyrapone Mifepristone

Mifepristone

Pseudophedrine

Mixed acting sympathomimetics Phenylpropanolamine Diasteromer of ephedrine No direct activity and fewer CNS side effects than ephedrine Nasal decongestant

Carvedilol

Mixed alpha and beta antagonist Beta blocking activity is 10-100 fold its alpha blocking activity Antihypertensive agent

Labetolol

Mixed alpha/beta adrenergic antagonists Beta blocking activity is approximately 1.5 fold that of its alpha blocking activity Antihypertensive agent

Cholinergic poisoning

More Ach due to direct acting or indirect acting cholinergic drug overdose Medical emergency Both nicotinic and muscarinic effects are life threatening Wild mushrooms have a high concentration of muscadine and causes cholinergic excess

Formoterol fumarate

More water soluble than salmetrol Racemic mixture Onset less than 20 min Duration 12 hours Inhalant powder only Do not take capsule orally Long acting Beta agonsit

Clinical applications of epinephrine

More widely used clinically than norepinephrine Hypotensive crisis, stimulate heart during cardiac arrest Used in inhalers to relieve bronchoconstriction in asthma, nasal decongestant (vasoconstriction of blood vessels in mucous membrane)

Post partum depression

Most women experience depression that resolves after 4/5 days but can last over a year Anger, anxiety, guilt, hopelessness, loss of interest or pleasure in activities, mood swings, or panic attack, crying, irritability, or restlessness, fatigue or loss of appetite, weight gain/loss, lack of concnetration or unwanted thoughts, depression, fear, insomnia, repeatedly going over throughts

CNS have both muscarinic and nicotinic receptors. Brain has more of? Spinal cord has more of?

Muscarinic Nicotinic All 5 subtypes are present

2 kinds of cholinoreceptors (cholinergic receptors)?

Muscarinic and nicotinic

In cases of renal failure or liver disease several of the beta blockers

Must be dose adjusted in patients with impaired renal fucntion

Theraputic application of acetylcholinesterase inhibitors

Myasthenia gravis Open angle glaucoma Alzheimer's disease Insecticides Chemical warfare

Big difference between muscarinic and nicotinic receptors

N-channels M-G protein culled receptors

Dyphylline

N7 dihydroxylpropyl theophylline Less effective than theophylline Comes in elixir and tablet

Excretion in babies

Neonatal kidney immaturity Changes in glomerular filtration rate and tubular secretion (reach about 100% by 6-12 months) Decreased perfusion rate of the kidneys may reduce excretion of drugs

Why is acetylcholine a poor theraputic agent?

Nonselective (binds to both nicotinic and muscarinic agonists) Quaternary ammonium salt (poorly absorbed across biological membranes) Poor bioavailability Hydrolyzed (ester group) under acidic or basic conditions

Imidazolines

Nonselective alpha-antagonists Tolazoline and phentolamine Imidazoline dictates selectivity for alpha *does not have ortho substituents required for agonist activity* Phentolamine was created from molecular modeling hence the unique exception to standard imidazolines

Transmitter at the nerve endings of the sympathetic nervous system

Norepinephrine Catecholamine SNS also called adrenergic nervous system

Given the structure of 2 corticosteroids with an 11-OH and an 11-keto, which one is active and which one is the prodrug?

OH active Ketone - prodrug

Terfenadine

Once widely used Associated with cardiac arrythmias when used in combo with CYP3A4 inhibitors *at high concentrations binds to K+hERG channel* whihc is responsible for correct repolarization of cardiac action potential *metabolizes for fexofenadine in the body whihc is the active form* Omega oxidation and oxidation of alcohol and aldehyde to carboxylic acid

Androgens Origin Effects

Originate in adrenal cortex and gonads Maturation and function of sex organs (male sexual determination)

Blockade of a1 on baroreceptor reflex

Orthostatic hypotension

Estradiol is secreted from the

Ovarian follicles

Estradiol is produced by

Ovarian follicles in response to FSH and LH

Cushing's syndrome can occur as a result of Over production of glucocorticoids Insufficient production of glucocorticoids Over production of mineralocorticoids Insufficient production of mineralocorticoids

Over production of glucocorticoids

What is the significant of the day 14 in the menstrual cycle?

Ovulation

Adrenocorticoid biosynthesis reactions are mostly

Oxidation

What reactions are catalyze by thyroperoxidase?

Oxidation Coupling ?organification?

What are the phase 1 reactions for estrogens

Oxidation by estradiol dehydrogenase or 16-alpha-hydrolysis

Receptors of ANS Spinal cord > 1 > 2 Parasympathetic Sympathetic (sweat glands) Sympathetic (cardiac and smooth muscle, gland cells, nerve terminals) Sympathetic (renal vascular smooth muscle) Adrenal medulla Somatic (skeletal muscle)

P- nicotinic > muscarinic Sweat- nicotinic>muscarinic Cardiac-nicotinic>norepinephrine (alpha beta) Renal-nicotinic>dopamine Medulla-nicotinic>epi, norepinephrine Somatic-nicotinic First releases ACH to nicotinic receptors Parasympathetic and sweat glands also release acetylcholine to muscarinic receptors Cardiac 2nd release norepinephrine to alpha and beta receptors Kidneys second release dopamine to dopamine receptors

Glucocorticoids contraindicated in patients with

Peptic ulcer and heart disease

Oral contraceptives may treat

Period cramps Moderate acne Irregular menstural cycle or bleeding Heavy menstural flow Abnormal uterine bleeding Acne, depending on type of pill Polycyclic ovarian syndrome Endometriosis Iron deficency anemia Premenstural syndromes, including premenstural dysphoric disorder

Function of encapsulation of placenta Eating or taking placenta pills

Provides emotional balance Replenishes hormones and nutrients Encourages healthy breast milk supply Reduces postpartum bleeding

Fluvestrant and ICI 164, 384

Pure estrogen receptor antagonist (blocker) Treatment of ER positive breast cancer

Echothiophate iodide

Quaternary ammonium salt Used topically and the only irreversible acetylcholinesterase inhibitor for the treatment of glaucoma *effects can last up to 4 weeks*

"Azoline"

Quinazoline derivative A1 antagonist

Mineralocorticoid MOA

Reabsorb Na and water in the kidney and put back into blood

Allergy

Reaction to something present in the enviornment More prevelant in industrialized nations

What is the mechanism underlying rebound hypertension upon abrupt discontinuation of beta blockers? How do you handle that as a clinician?

Receptors upregulate to get physiologic control with the addition of blockers but unable to gain full control Sudden stop leads to sudden loss of blockers Still have upregualtion and agonists only to fill receptors Larger effect possible due to excess receptors and no blockers TAPER instead of stopping abruptly

CNS effects of atropine

Recommended doses cause minor stimulant effects In form of belladonna extract can reduce tremor in Parkinson's Toxic doses can cause excitement, hallucinations, agitation, and coma

Signs of asthma

Recurrent episodes of dyspnea, coughing, wheezing Pharmacist observes

GI effects of antimuscarinics

Reduce GI motility Effective for travelers diarrhea in combination with other drugs such as opoids

Anti-inflammatory and immunosuppressive effects of glucocorticoids

Reduce function of leukocytes and other inflammatory lipid mediators (cytokines, prostaglandins, and leukotrienes) Reduce function of macrophages When applied to skin they produce vasoconstriction by suppressing mast cell degranulation Large doses of steroids can cause decreased antibody production

Antimuscarinics for urinary disorders

Relieve urgency due to incontinence, inflammaotry bladder disorder, and bladder spasms after urologic surgery Oxybutynin Trospium Darifenacin Solifenacin Tolterodine Propiverine

Clinical pharmacology of the cholinoreceptor agonist drugs Urinary system

Relieve urinary retention after surgery, labor, or neurogenic bladder Both direct and indirect acting cholinoreceptor drugs can be used (neostigmine, bethanechol) Contract bladder wall smooth muscles *detrustor muscles*

C16 substitution to corticosteroids

Removes mineraloactivity

Which of the following is a function of the placenta? Secrete estrogen Secrete antibodies Store lactose Secrete progesterone

Secrete progesterone

Cholesterol is converted to pregenolone via

Side chain cleavage mediated by a CYP450 enzyme

What makes something more selective for b2

Steric hinderance

L5

Studies demonstrate significant risk to infant based on experience or high risk for causing damage to infant *risk outweighs benefit*

What is another name for an irreversible enzyme inhibitor?

Suicide substrate

What are the phase 2 reactions for estrogens

Sulfination with Sulfotransferase Glucuronidation by UGT

Hydrocortisone acetate

Superior to cortisone acetate when *IM* Systemic absorption from intra-articulated injection sites usually is complete 24-48 hours

Hydroxyzine

Supplied as dihydrochloride and pamoate salts Pamoate is longer acting Duration of action is 6-24 hours 1st gen antihistamine Used for itching and is sedating (used as anxiolytics) Oxidized to cetirizine in the body

Treatment for Cushing's syndrome

Surgery and hydrocortisone

Location of muscarinic receptors

Sweat glands, heart, GI, bladder, smooth muscle, respiratory Cholinergic receptor CNS, endothelium, heart, and smooth muscle

Muscarinic are in

Sweat glands, heart, gut, bladder, smooth muscle, respiratory

Can you make sense of side effects of B2 AR selective agonists side effects due to adrenergic receptor function? Tachycardia Tremor Nervousness Insomnia Cough Airway irritation Hyperglycemia

Tachycardia - b1 Tremor - b1 Nervousness - a1 Insomnia — less adrenal release Cough - a1 (thickly sticky saliva) Airway irritaiton due to drug Hyperglycemia (a1/B2)

Bioisosteric replacement for carboxylic acid

Tetrazole Better penetration and bioavailability Acidic Size and electronic arrangement allow them to be bioisoteres of carboxylic acid

In the estrogen/testosterone pathway, what happens if you block 3 beta-dehydrogenase isomerase

The follicular phase can produce only progeneolone, 17-hydroxyprogenolone, and DHEA The luteal phase can only produce progenolone

In the estrogen/testosterone pathway, what happens if you block 17 alpha hydroxylase

The follicular phase product is only progenolone The luteal phase can only produce pregenolone and progesterone

Homeostasis

The maintenance of a relatively constant internal enviornment

Cholinergic neurotransmision

The primary transmitter is ACH Almost all fibers leaving from CNS are cholinergic

Adrenergic neurotransmission

The primary transmitter is norepinephrine/noradrenalin

How does progestin prevent E2 induced breast cancer in HPT patients?

The studies in the textbook indicate that there is no real risk reduction in breast cancer, and that there may be an increase in risk for breast cancer when used as a combination therapy. Theoretically progestin is used to restrict the cell growth caused by estrogens.

Methylxanthines

Theophylline and pyphlline

What do testosterone esters do in the body? What enzyme is used?

They are broken down by esterase slowly in the body which allows them to be used as depot injections

Sympathetic Site Activity

Thoracolumbar Fully activated during fight or flight response Epinephrine and norepinephrine

List the thyroid binding globulins. What is the relative affinity for T3/T4 for each?

Thyroid binding globulin (high T3/T4) TransThyRetin (low T4/ no T3) Albumin (low for each; higher for T3)

Topical H1 antihistamines

To eye relieve itching and prevent congestion of the conjunctiva (involved in lubriation of the eye) *density of mast cells in the conjunctiva are high* Olopatadine, azelastine, and ketotifen are "dual acting" - *prevent histamine relapse and antagonize the H1 receptor*

Alpha means (cis/trans)?

Trans

Tautomers

Two isomers of a compound that exist in equilibrium, and are readily interchanged by migration of an atom or group within the molecule

Antiandrogens

Tx for advanced prostate cancer Hormone blocking drugs Goal is to block effect of testosterone and DHT on androgen receptors Not a cure because the cancer can advance in presence of therapy Bicalutamide, flutamide, nilutamide

Asthma Related to smoking Reversible? Persistent? Progressive? Due to?

Unrelated to smoking Reversible Properly controlled asthma is asymptomatic Often outgrown Due to mast cells and eosinophils; minor neutrophil cause

Alkylamine antihistamines

Widely used for OTC for seasonal allergies Duration of action is up to 24 hours *less sedative effects* compared to ethylenediamines and ethanolamine ethers *decreased anticholinergic* properties compared to ethanolamine ethers Sold as enatiomers or racemic mixtures, sold as E- isomer S-enantiomers have greater affinity for H1 receptors and more potent Most have a long half-life (24 hours) N-dealkylation is major metabolism pathways

Toxic drug actions to fetus - opoids

Withdrawl

Permissive effects of glucocorticoids

Without these many normal functions become deficient *administration of cortisol can restore the proper vascular and bronchial muscle tone*

How d blood pressure medications reduce MAP?

Work on CO or TPR CO (inhibit HR and contractility; decrease ventricular filling pressure (increase venous capacitance, decrease blood volume)) TPR (vasodilation of arterioles, interfere with vasoconstriction medicated by SNS and RAAS)

Polychlorobiphenyls (PCBs)

Xenoestrogens Used as electrical insulators Persistent environmental contaminant Some shown to have estrogenic or antiestrogenic activity BPA banned from baby bottles in 2013 (very weak estrogen - estrogen mimic) -safe at the current levels occuring in foods -still used in liners of food cans and lids

Receptor with good affinity for norepinephrine

a1, a2, b1

Prednisolone acetate

avaliable in suspension and ointment forms for use externally

Phenoxygenzamine (clearly)

beta-haloalkylamine Undergoes intramolecular reaction to form a highly reactive aziridinium ion Nucleophile from amino acid (Cysteine, serine, or lysine) attacks the reactive ring *Longer DOA because it covalently binds to the receptor* Alleviates the sympathetic effects of *pheochromocytoma* (tumor of adrenal medulla produces large amounts of EPI/NE)

Metyrosine

blocks conversion of tyrosine to DOPA

Mydriasis

dilation of the pupil

Uveitis

inflammation of the iris, ciliary body, and choroid

Reserpine

inhibits VMAT that carries dopamine to the vesicle

Sympathomimetic

mimics the sympathetic nervous system

Eplerenone

mineralocorticoid antagonist Approved for the tax of HTN No effects on androgen receptor

What is depolarization?

the inside of the membrane becomes less negative due to Na coming in

Mecamylamine

Reduce nicotine craving Ganglion blocking drug Crosses BBB SE: tremor, sedation, mental aberrations Cycloplegia GI motility and secretion inhibited (constipation) Urianry retention, impairment of sexual function in men, reduced sweating

Spasmolytic drugs

Reduce stretch reflexes Muscle tone is due to some stretch Stress releases cortisol while causes too mush muscle stretch Diazepam Baclofen Tizanidine Dantrolene Botulinum toxin "Muscle relaxants"

Effects of b1 blockade on heart? Kidneys? Affect to kidney affects what parameters of MAP?

Reduction in contractility, HR, and CO Decrease renin secretion Decrease blood volume and TPR

Cortisol PK

Regulate growth, cardiovascualr function, and immunity Synthesized from cholesterol, enzyme P450c17 (17-alpha-hydroxylase) is involved In normal adults (not under stress) daily secretion is 10-20 mg Cortisol secretion follows the rhythm of fluctuations of ACTH secretion Under stress more cortisol is secreted If you could not get enough sleep at night your cortisol rises Bound to corticosteroids binding globulin (CBG) in plasma (90% bound) Albumin bound to cortisol is considered as free cortisol In situations such as hyper/hypothyroidism and pregnancy CBG level changes Metabolized primarily in liver, some in kidney In kidney it is converted to cortisone

COPD Related to smoking Reversible? Persistent? Progressive? Due to?

Related to smoking Not completely reversible Persistent Progressive Bronchitis due to neutrophils and infection scarring Emphysema due to alveoli elastin damage *increased elastase*

How do we relieve asthma? How do we do that? How does the body naturally do this?

Relax bronchial smooth muscle Activate sympathetic adrenergic B2 receptors Adrenaline

Effect of a1 blockade on vascular smooth muscle B2

Relaxation, decreased resistance, decrease BP Contraction

Urinary effects of antimuscarinics

Relaxes smooth muscles of bladder wall causing urinary retention Slows voiding/emptying

Uterus effects of antimuscarinics

Relaxes uterus Keep baby inside uterus

Catalytic triad for site of acetylcholinesterase

Ser, his, glu Most other serine proteases use asp instead for glu

Hydrolysis of acetylcholine

Serine attached to acetylcholineasterase attacks Carbonyl to break double bond and from alcohol OH reforms carbonyl and choline molecule comes off but the enzyme is inactivated Water comes in and liberates enzyme and acetic acid

Serine > > choline

Serine decarboxylase > removes carboxyl group Choline N-methyltransferase SAM > forms choline

Vercuronium bromide

Steroid-based neuromuscular blocking agent Nondepolarizing neuromuscular blocker Immediate duration of action Does not have a significant cardiovascular effect

Andropause

"Man-opause" 30% of men in 50s 50% of men older than 65 Testosterone levels are low enough to cause noticeable symptoms

Discovery of beta blockers

*replacememnt of catecholamines groups with chlorine* led to discovery of new antagonistic activities Dihlororisoproterenol (DCI) was discovered in 1958 but had no clinical utility Led to the production of other derivatives with similar characteristics

Breast feeding

*risk for exposure to drug consumed by the mother* Usually drug concentration is low Take 30-60 min after nursing and 3-4 hours before next feeding Shorter acting drug so you can clear it before nursing session If no data on safety available, avoid or pump and dump Recommend consulting medications and mothers milk

Ethylenediamines

*sedation* Compounds with several different but very closely related aromatic rings are useful (phenyl, 2-pyridyl, pyrimidyl, thiophenyl, etc) Metabolism: N-demethylation followed by deamination, N-glucourination *2 rings and an ethyl linker group*

Second-generation nonsedating H1 antihistamines

*selective* *nonsedating* May or may not resemble first gen Do *not cross BBB because of zwitterion* form at physiologic pH Usually given once a day because o long duration of action, slow rate of dissociation from H1

Long term toxicity of glucocorticoids - other

Adrenal suppression, peptic ulcers, acute psychosis, and complications associated with salt and water retention such as alkalosis, fluid retention, BP changes, and heart failure

Finasteride and dutasteride What enzyme did they work at? Function of enzyme? How does its function contribute to the pathology of BPH? What kind of inhibitor

5-alpha-reductase inhibitor Converts testosterone to DHT which leads to cell growth Irreversible

Acute effect of Lugol's solution

1-2 days Inhibits thyroid release MOA unclear

What enzyme produces leukotrienes? What are th 2 main leukotriene receptor subtypes and their function? CysLT receptor inhibitors? Which agents inhibits leukotriene synthetic enzyme?

5-lipoxygenase BLT (chemotaxis) and Cys-LT (bronchoconstriction, vasodilation, mucus secretion) Zorfirlukast and monteleukast Zileuton

Fluoxymesterone

9 alpha fluro group on testosterone 20x anabolic and 10x androgenic activity as 17-alpha-methyltestoststerone Half life of 9 hours and less than 5% is excreted unchanged Na and water retention that could lead to edema

Testosterone can be turned into dihydrotestosterone using the enzyme

5-alpha-reductase

What is theophylline's theraputic window? 10-15 mcg/ml 10-20 mcg/ml 5-15 mcg/ml

10-20

Acetylcholine metabolism

10^ 3 Ach is released 10^8 acetylcholine esterase is in the synapse to cleave acetic acid from choline Choline is recycled back into the nerve terminal

What is the immediate precursor to cortisol?

11 beta deoxycortisol

11 keto to 11 OH Enzyme? Reaction type?

11-beta-hydroxysteroid dehydrogenase Reduction when going from ketone to OH

What enzyme converts hydrocortisone to cortisone?

11-beta-hydroxysteroid dehydrogenase (oxidation to ketone - inactive)

How long can an unconcieved egg stay in the female Fallopian tube?

12-24 hr

2nd trimester

13-28 weeks Function organs, muscles, and nerves Baby begins to move

The optimal time to conceive is

14-21 day in cycle

Betamethasome

16-alpha-methyl in dexamethasone converted to 16-beta methyl Rx of dermatological and rheumatic disorders As effective as dexamethasone Possbily best for short term use -increased appetite, facial mooning, weight gain

Dexamethasone

16-alpha-methyl reduces the *na retaining properties* of the corticosteroids and *increases antiinflammatory activity* by increases lipophilicity and receptor affinity Activity 20x hydrocortisone 5x anti-inflammaotry activity of prednisolone Peake plasam levels after 10-20 min IV

Outstanding feature of corticosteroids

17-beta ketol or esterified 17-beta ketol

Major form of estrogen present in reproductive age females?

17-beta-estradiol

The __ and __ functions are found in clinically used adrenocorticoids, and these groups contribute to the potency of agents

17-beta-ketol 4-3 ketone

The immediate precursor to DHEA is

17-hydorxypregenolone

Estrogen structure features

18 C Aromatic A ring with 3OH

Androgen structure features

19 C O at C3 and C17 (OH or keto)

Acetylcholine receptor binding to nicotinic receptor

2 molecules of Ach can bind concurrently Induces opening permitting Na and K to diffuse Leads to a depolarization of the post synaptic membrane initiating an action potential After 1-2 milliseconds the Ach spontaneously dissociate from the receptor and the channel closes

SAR for muscarininc antagonists

2 rings -one is aromatic other is saturated typically -may be fused rings -as steric hinderance increases, potency decreases -can be carocyclic or heterocyclic Other subsistent of Center atom -hydroxyl and hydroxymethyl work well -can also be hydrogen or amide Between central atom and linker -esters are most potent -can also be ether or methylene N substituent -quaternary ammonium for max potency -can be tertiary amine Carbon linker -2 C for most potent -2-4 carbons

Transient effects of Lugol's solution

2-4 weeks Inhibits organification Inhibits thyroid hormone synthesis Decrease gland size and vascularization

Tricyclics antihistamines

2-carbon spaces between aromatic rings Has anticholinergic, antiserotonergic, and appetite-stimulating properties, which are useful in treatment of anorexic nervous a and in cachexia

Progestin structure features

21 C 3-keto-4-ene 21 keto

What is the airspeed velocity of an unladen swallow?

24 mph 11 m per sec

3rd trimester

29-40 weeks *greatest percent of maternally absorbed drug* to fetus Enhanced placental blood flow Baby is pretty much mature and just packing on weight

Responsible for changes that occur in puberty

5 alpha DHT Synthetic androgens are used for their anabolic effects and to treat testosterone deficiency

Fludrocortisone

9-alpha-F group nearly prevents metabolic oxidation of the 11-beta-OH group to a ketone (inactive form Glucocorticoid activity increased 11 fold Mineralocorticoid activity increases 300 to 800 fold Because of its tntense Na-retaining activity, its contraindicated in all conditions except those that require a high degree of mineralocorticoid activity because it leads to edema

Where is cortisol bound in the plasma

90% bound to corticosteroid binding protein Some bound to albumin is considered as free cortisol

Discuss pharmacokinetic difference for pediatrics. What physiological changes may affect drug ADME?

A - less acidic gastric acid, slow gastric emptying, irregular IM absorption D - BBB immature, more water at younger age, more water less fat, low protein binding = free drug increases M - liver immature (decrease clearance rate, increase half life), watch longitudinal drugs, maternal induced fetal hepatic enzyme production E - neonatal kidney immaturity, changes in glomerular filtration and tubular secretion, decreased perfusion rate of the kidneys may reduce excretion of drugs

When choosing a bronchodilator, which one would you reccomend as a pharmacist? Nonselective or selective B2 agonsit

A nonselective B-agonsit has undesireable cardiacs stimulators properties because of its B1-activity The undesireable cardiac stimulators properties are greatly diminished in a selective B2 agonist

Cevimeline

A quinculidine derivative Nonclassical muscarininc agonist Partial agonist at M1 receptor in the CNS Agonist for M3 receptor in salivary glands Used orally in Xerostomia (dry mouth)

Adrenergic response (SNS) GI tract

A, b decreased motility and muscle tone A contraction of sphincters and inhibition of secretion

Impulse generation and propigation in excitable cells

Ach bind to post synaptic AchR in skeletal muscle cells Ion channel opens Action potential generation and propagation leading to muscle contraction Inside of membrane is negative and outside is positive Depolarization makes the inside less negative Depolarization - sodium moves inside and makes less negative Plateau - closing of Na and Ca Repolarization -Na and Ca blocked; Cl goes out and K goes in Charged go back and repolarization occurs and another potential can occur

Adrenergic response (SNS) Blood vessels

A1 causes vasoconstriction B2 causes vasodilation Dopamine causes vasodilation in renal artery and arterioles

What are the indications for tamsulosin and alfuzosin

A1 reversible competitive inhibitor BPH

Effect. Receptor. Organ/tissue Increased blood glucose Mydriasis

A1, B2 - liver A1 - radial muscle of iris (eye)

Clonidine

A2 adrenergic agonist 2-aminoindidazolines Was originally synthesized as a vasoconstriction game nasal decongestant In clinical trials it was found to have dramatic hypotensive effects *vasodilation* as clonidine penetrates the BBB and interacts with CNS A2-receptors Imidazoline ring is part of guanidino group (tautomer) Antihypertensive, ADHD, nicotine/opiate withdrawl, and glaucoma Most of it is protonated at physiologlcal pH

Cholinergic neutrotransmission

ACH is made inside the nerve terminal from Acetyl COA (from the liver) and choline Nerve impulses come to axon and opens up voltage-mediated calcium channel to move vesicles and outside of the axon into the synapse Binds to choline receptors in the postsynaptic cell and brings effect Unbound ACh gets broken down to choline and acetate by acetylcholineasterase

Histrionicotoxin

Ach noncompetitive antagonist Binds to delta subunit of cardiac nicotinic receptors Causes heart palpitation, weakness, blurred vision, cardiac paralysis leading to death Reversible Noncompetitive Nondepolarizing Harlequin poison frog

Acrivastine

Acidic analog of triprolidine Ionized carboxylic acid limits BBB penetration Less sedating that triprolidine Used in combination with a decongestant

Physostigmine

Active part of *calabar bean* High affinity for the catalytic site of the enzyme Reversible acetylcholineasterase inhibitor that carbamylates the enzyme at a slow rate Tertiary amine rather than a quaternary ammonium salt More lipophilic than other inhibitors Able to cross th eBBB due to lipophilicity Used in treatment of glaucoma and alzheimer's disease Used to treat overdoses of anticholinergics *aqueous solutions are subject to hydorlysis* to form eseroline, which undergoes light-catalyze oxidation to form rubreserine, a red colored compound > inactive products

Storage of acetylcholine

Actively transport to cytotoxic storage vesicles located in *presynaptic nerve endings*

Differentiate between when the pre-formed and induced mediators of hypersensitivity reactions are released. Which ones sustain acute v chronic reactions? What is the primary preformed mediator? What are the primary indices mediators?

Acute- preformed Chronic - induced Pre-formed > histamine Induced > leukotrienes

Metacholine Clinical uses Toxicity Clinically important

Administered cautiously by inhalation for the diagnosis of bronchial airway hyperreactivity Parasympathetic effects if absorbed systemically Emergency resuscitation and medications to treat every bronchospasms must be on hand Direct acting

Cortisone

Administered orally or by injection as 21-acetate (cortisone acetate)

Nonselective beta blockers increase the risk of hypertensive events upon

Administration of (high dose) epinephrine or other stimulants Discontinuation of clonidine (A2 agonist)

steroid hormones are synthesized in

Adrenal cortex under influence of ACTH -gluticocorticoids -mineralocorticoids Gonads, under influence of LH and FSH -testosterone (mainly LH) Dihydrotestosterone (mainly LH) Estrogen (mainly FSH)

What are the theraputic uses of glucocorticoids?

Adrenal insufficiency (addison's disease), *rheumatoid diseases, allergic symptoms*, Cushing's syndrome Mineralocorticoids are also used for Addison's disease Cortisol is used as replacement therapy after pituitary tumor removal (Cushing's syndrome)

Which nervous system is involved in the fight to flight reactions? What is the NT molecule involved? Effects of NT? Released from? Stress hormone?

Adrenergic Norepinephrine Increase HR, energy, sugar in blood, and blood supply to muscles. Decreased GI movement. Adrenal medulla Cortisol

Atropine, cholinoreceptors blocker

Agents/drugs can block Ach from binding to cholinoreceptors

Botulinum toxin

Agents/drugs can inhibit Ach vesicles fusion with the surface membrane and emptying Ach to the cleft

Verapamil

Agents/drugs can inhibit Ca channel so Ach vesicles cant fuse with the surface membrane

What is the special thing about serms

Agonist in some tissues (bone) and antagonists in others (breast)

What is the most endogenous mineralocorticoids?

Aldosterone

Galantamine hydrobromide (Razadyne)

Alkaloid Tertiary amine and can cross the BBB Treatment of mild-to-moderate Alzheimer's disease and dementia *dual cholinergic action: acetylcholinesterase inhibitor and binds to nicotinic receptors*

Teratogens - heroin Trimester Effect

All Chronic use leads to neonatal dependence

Teratogen - tetracycline Trimester Effect

All Discoloration and defects of teeth and altered bone growth

Teratogen - streptomycin Trimester Efffect

All Eighth nerve toxicity (ototoxicity)

Teratogen - tamoxifen Trimester Effect

All Increased risk of spontaneous abortion or fetal damage

Teratogens - smoking Trimester Effect

All Intrauterine growth retardation; prematurity; sudden infant death syndrome; perinatal complications

Teratogens - ethanol Trimester Effect

All Risk of fetal alcohol syndrome and alcohol-related neurodevelopmental defects

Girls have ___ eggs when they are born

All When they reach puberty eggs will mature, usually one at a time Ovulate once a month

Teratogens - ACE inhibitors Trimester and effect

All, especially second and third Renal damage

Discuss how competition of IgE for binding sites may limit the development of allergies (and auto-immune disorders) in areas where parasites are endemic.

Allergen competes with parasite specific IgE for mast cell, basophils, and eosinophil activation (runs out of room) Limits allergic and anti-parasite response This is why those with parasites have less allergies

First generation antihistamines Use Receptor binding Side effects

Allergic responses (hay fever, rhinitis, urticaria, food allergy) R: cholinergic, adrenergic, dopaminergic, serotonergic S: sedation, decreased cognitive ability, somnolence, blurred vision, dry mouth, urinary retention, constipation Useful in treatment of allergy/inflammatory disorders Generally *2 aromatic groups linked through short chain to a tertiary alipathic amine

State the hygiene theory

Allergies and increased longevity are both consequences of reducing infectious stressors during early childhood

Blockade of a1 on prostate smooth muscle

Alleviates BPH sx

Prednisone

Almost completely absorbed Bioavailability >80% Interconverted in liver by 11-beta-hydroxysteroid dehydrogenase

Alpha receptor with highest expression in prostate

Alpha 1a

What receptor is yohimbine relatively selective for? Agonsit or antagonist? Sympatholytic or sympathomimetic?

Alpha 2 Antagonist Sympathomimetic

Theraputic/side effects for H1 blockade

Decrease vasodilation, blood vessel permeability, bronchoconstriction, mucus secretion, and cough Sedation

Corticosteroid General rule 9-alpha F 9-alpha Cl 9-alpha-Br Causes increased retention of urinary sodium with the order of

F>Cl>Br

Doxylamine (unisom)

Arya group: phenyl and 2-pyridyl Addition of methyl group to carbinoxamine *very strong sedative properties and one of the most potent antihistamines* Safe to use for mild insomnia

Carbinoxamine (Arbinoxa, Palgic)

Arya groups p-Cl-Ph and 2-pyridyl Duration of action is 3-6 hours Para substituted chloride helps factor selectivity towards antihistamine over anticholinergic

What type of molecule is Omalizumab? What 3 effects does it have?

Anti IgE "humanized" monoclonal antibody Attenuated IgE mediated responses, depletes free IgE, and down regulates Fc epsilon receptors on mast cells and basophils

Omalizumab (Xolair)

Anti-IgE monoclonal antibody for asthma Designed to attach to an antibody Does not bind to IgE already bound to mast cells SQ injection has 62% bioavaliable Mechanism is unknown

Bicalutamide

Antiandrogenic activity resists almost exclusively in R Cyano group and trifluromethyl group are associated with high androgen receptor affinity Half life is about 6 hours Antiandrogen

Process of sensitization

Antigen recognized by T helper and B cells IgE Fc region binds to Fc epsilon receptor on mast cells/basophils Expression induced on eosinophils after activation by cytokines Antigen cleared from system Antigen specific IgE remain bound to mast cells

Parkinson's disease

Antimuscarinic drugs were developed before L-dopa Still used as an adjunctive therapy in some patients Nasty toxicity Antimuscarininc drugs can reduce muscle contraction in these patients

Rx for cholinergic poisoning

Antimuscarininc therapy (repeated doses of atropine) Cholinesterase regenerator compounds (Pralidoxime (PAM) and diacetylmonoxime (DAM))

Drugs with a ketone at C11 rather than an OH

Are prodrugs Transformed to OH in *liver by 11-beta-hydroxysteroid dehydrogenase* (reduction) *not administered locally* Not recommended in hepatic insufficiency

Anastrozole, letrozole, fadrazole, exemestane

Aromatase inhibitor

What is the MOA of exemestane, Letrozole, and anastrozole?

Aromatase inhibitor

Which of the following drug can cause facial hair development in post menopausal women? Estrogen Fulvestrant Danazole Anastrozole

Aromatase inhibitor

The endometrial lining is the thickest

Around day 21

Curare

Arrow poison used by native Americans Produces death by muscle paralysis D-tubocurarine was developed from this

Finasteride

At steady state, depresses DHT levels by approx 70% in plasma and as much as 85-90% in the prostate Can reduce urinary retention or surgery with long term therapy Has no affinity for androgen receptor Text-butyl group undergoes extensive metabolism giving a half life of 5-6 hours 5-alpha-reductase inhibitor

3 antimuscarinics to know A I T

Atropine Ipatropium bromide Tiotropium bromide

Drugs may transfer into human milk if they

Attain high concentrations in maternal plasma Low in molecular weight (<500) Low in protein binding Pass into brain easily Other factors: -oral bioavailability of medication to infant -may be destroyed in infants gut -fail to be absorbed through gut -rapidly picked up by liver

Describe the etiology and Pathophysiology of Grave's Disease

Autoimmune disorder Mediated by TH2 T-helper cells Production of anti-TSH receptor IgG antibodies > function of TSH receptor agonist Excessive synthesis and release T4/T3 in absence of CNS input > goiter

Describe the etiology and Pathophysiology of Hasimoto's disease

Autoimmune disorder TH1 helper T cells Lymphocytes infiltrate thyroid Destroy tissue and appear to be converting the thyroid gland into a lymph node No longer synthesizes T3/T4 Goiter due to lack of negative feedback

Nicotinic are in

Autonomic ganglion and skeletal muscle

Location of nicotinic receptors

Autonomic ganglion and skeletal muscle Cholinergic receptor

Describe the process of iodine uptake at the basolateral membrane and apical membrane

B - uptake of iodide by sodium-iodide symporter (NIS) A - oxidation of iodide to iodine by thyroperoxidase

Describe the oral bioavaliabiltiy of testosterone

Bad

In whihc location within the thyroid gland does thyroid hormone synthesis occur?

Follicle on thyroglobulin

Formation of testosterone and estradiol

Follicular phase: Cholesterol > pregnenolone > DHEA (fountain or youth hormone) > testosterone > estradiol Luteal phase: Cholesterol > pregenenolone > progesterone > testosterone > estradiol

Effect. Receptor. Organ/tissue Increased HR (chronotropic) and BP Increased contractility (inotropic) and BP

B1

Which adrenergic receptors physiological effect includes increased heart rate and blood pressure? B1 B2 A1 A2

B1

Dopamine

B1 adrenergic agonist Metabolized by COMT and MAO IV infusion Stimulates cardiac B1 receptor for CHF or MI Acts on dopamine receptor > dilate renal vessels, increase renal blood flow

Dobutamine

B1 adrenergic agonist N-substituted dopamine analog with no b-OH group Used in racemic mixture: primarily B1 activator S is a1 and b1 agonsit R is a1 antagonist Leaves b1 antagonist effect Half life is 2 mins due to COMT metabolism Cardiac stimulant post surgery or CHF

Adrenergic response (SNS) Kidney Liver

B1 causes increased secretion and raises BP A1/B2 increase gluconeogenesis and glycogenolysis to release stores of energy

Adrenergic response (SNS) Rate of contraction Force of contraction Conduction velocity

B1 increase cause tachycardia and positive chronotropic effect B1 increased and positive inotropic effect B1 increased

To treat asthma we want to increase __ activity and increase __ levels

B2 CAMP

Adrenergic response (SNS) Lung

B2 Relaxation of tracheal and bronchial smooth muscle

Effect. Receptor. Organ/tissue Open airways Relieve nasal congestion

B2 - tracheal and bronchial smooth muscle A1 - nasal blood vessels

Relative affinity for epinephrine

B2 > a1, a2, b1

Adrenergic response (SNS) Bladder

B2 relaxes detrusor muscle *a1 causes contraction and leads to urinary hesitancy*

Distribution in babies

BBB is immature so more things can get into brain more easily Younger the age the more TBW of baby Increase TBW decreases fat content Decrease protein binding leads to more free drug

Identify the determinants of mean arterial blood pressure

BP=CO x TPR

Risk factors for breast cancer

Being a women Age Genetics (BRCA1 and BRCA2 mutations) Factors that affect hormone (estrogen) levels

Metaproterenol

Beta agonist Good oral bioavaliability Onset of 30 min (5 min inhaled) *4 hour duration* - short acting Resistant to monoamine oxidase and COMT Avaliable in tablet, syrup, and inhalation ADR: palpitation, tachycardia, N/V, dizziness, tremor, headache

"Olol"

Beta blocker

What is intrinsic sympathomimetic activity? How does partial agonist explain this phenomenon? What are the physiologic differences you see when using this type of agent?

Beta blocker specific - typically 3rd gen Ability to activate beta receptors partially With a strong agonist they appear as antagonist due to crowding out of the strong agonist; absence of strong agonist they exhibit their intrinsic activity (modest inhibition of heart inotropy and chronotrophy) Less bradycardia

How does 131I ablate the thyroid gland? Does it damage other tissues? Long term complications?

Beta particles break chemical bonds and excrete ions which damage tissue Does not because it goes only to the thyroid. Hypothyroidism

Difference between alpha and beta receptors

Beta receptors have a larger hydrophobic pocket than alpha receptors

Colterol receptor selectivity: selective __ SERT DAT Beta-2-receptors

Beta-2 receptors

If the delivery is expected before 34 weeks of pregnancy the mother will be given

Betamethasone

Which carbamate is used to treat urinary retention and abdominal distension? Tacrine Bethanechol Galantamine

Bethanechol

Muscarininc antagonists

Binds reversible to muscarininc receptors Have no intrinsic activity Competitive antagonists AKA: anticholinergics, *antimuscarinincs*, cholinergic blockers, antispasmodics, parasympatholytics

Nicotinic antagonists - neuromuscular blocking agents

Binds reversible to the nicotinic receptors but have no intrinsic activity Adjunct to general anesthesia Reduces the depth or requirement from general anesthetics (longer and more in depth damages Brain) Skeletal muscle relaxation that facilitate operative procedures such as abdominal surgery

How can an uncharged molecule form a zwitter ion?

Have acidic and basic part (like an amino acid) The acidic proton comes off and attaches to the base to make the charges inside of the body

Mineralocorticoids

Binds to mineralocorticoids receptors and stimulate reabsorption of Na and H2O in the kidneys Cortisol also binds this receptor with the same affinity. But in kidney mineralocorticoids bind the receptor with high affinity because cortisol is converted to low affinity cortisone Aldosterone is secreted at the rate of 100-200 mcg/d

Agonist

Binds to receptor and produces a receptor response

Monteleukast (Singulair)

Block leukotriene D4, C4, and E4 receptors Rapidly absorbed orally (so better patient compliance than inhaled) 64% bioavaliable, metabolized is the liver, 86% excreted in bile Adverse affects same as placebo

Sweat gland effects of antimuscarinics

Block sweat Suppressed thermoregulatory sweating in children resulting in atropine fever

Aromatase inhibitors

Block the conversion of androgens to estrogens Control reproductive functions Health treat estrogen-dependent breast cancer Anastrozole, letrozole N4 triangle reacts with the heme ring in aromatase and deactivate it

Nondepolarizing neuromuscular Agnents Bind to the cholinergic receptor Ex.

Blocking Ach from binding The cholinergic receptor cannot open No wave of depolarization is ever initated D-Tubocurarine, histrionicotoxin, alpha-bungarotoxin

What is the MOA of zileutin? Blocks phospholipase A2 Blocks 5-lipooxygenase Blocks chloride channels Inhibits phosphodiesterase

Blocks 5-lipoxygenase

Zileutin

Blocks 5-lipoxygenase Leukotrienes pathway inhibitor Benzothienyl and N-hydroxyurea N-hydroxyurea is essential for activity 90% of dose is bioavaliable Metabolized by glucuronidation in liver 95% excreted via urine Half life is 2.5 hour s

Cocaine, tricyclic antidepressants, and amphetamines

Blocks NET so norepinephrine stays longer at the synaptic clef and make you too happy

Zafirlukast (accolate)

Blocks leukotriene D4, C4, and E4 receptors Leukotriene pathway inhibitor Food reduces oral absorption by 40% 90% of metabolites excreted in the feces

Identify how amphetamines can correct deficiencies associated with ADHD.

Boost NE and dopamine Boost vilagance, sustained attention, and focus Optimize rate, amount, and length of time that a stimulant occupies NET and DAT. Occupying enough transporters in the prefrontal cortex at a slow enough onset and long enough DOA to enhance tonic NT

Explain how steroid hormones (and lipophilic drugs) are transported through the bloodstream? How might this be important for drug interactions?

Bound to transport proteins in the plasma (sex hormone binding globulin, corticosteroid binding globulin, and albumin) Albumin is a protein found in the blood that is important for a number of drug-drug interactions due to protein binding Lipophilic molecules are transported in the bloodstream through this way Some drug-drug interactions can occur due to competition for steroid transport proteins (ex. Contraceptives and prednisone)

Pregnenolone

Branch point Made from cholesterol Precursors to all 3 pathways (mineralocorticoids, glucocorticoids, estrogen and androgens)

Respiratory effects of antimuscarinics

Brocnhodilation Reduce secretion Used prior to inhalant anesthetics to reduce secretions in the traches

Which first gen antihistamines have the least sedative/anticholinergic properties

Bromopheniramine Chlorpheniramine

LTD4 causes

Bronchoconstriction, bronchial reactivity, mucosal edema, and mucus hypersecretion

Leukotrienes Physiologic symptoms formed Timing acute or chronic? Preformed or induced? Potency

Bronchocontriction, vasodilation, mucus secretion Chronic Induced 1000 times more potent than histamine

Beta 2 on lungs and uterus

Bronchodilation Relaxation of uterus

Effect of B2 blockade on bronchial smooth muscle

Bronchospasm

Progestin antagonists

Completes with progesterone for its receptor, preventing it from binding and activating its receptor Interfere with pregnancy maintenence

Adding a double bond to corticosteroids a C1-C2

Increases glucocorticoid and decrease mineralocorticoid activity More potent than parent compounds

SAR glucocorticoids

C3, Keto C4-C5 ene C17 beta ketol C11 OH required (C11 keto is prodrug) C1-C2 ene increases glucocorticoid and reduces mineralocorticoid activity C16 substituents hep remove mineralocorticoid activity but keep glucocorticoid activity C9 F increases both glucocorticoid and mineralocorticoid activity

How does certirizne differe from other 2nd gen agents? How does levocetirizine differ from cetirizine? How does acrivastine differ from other 2nd gen agents?

C: some drowsiness reported L: increased potency and less sedation A: mild sedative properties

Identify NE sympathomimetic effects

CNS stimulant, HTN, tachycardia, tremor, restlessness, dizziness, insomnia, appetite suppression

Amphetamines, tyramine, and ephedrine

Can be taken up by NET and VMAT and they can release norepinephrine by a Ca independent process

Synthetic estrogens

Can increase oral bioavailability of estradiol by preventing oxidation of C17. OH to a ketone Adding a C17 alkynyl agroup allows dose to be in the microgram range

Bethanechol

Carbamate form of methacholine Potent muscarinic activity but no nicotinic activity Given orally, IV, IM can lead to cholinergic crisis Treats urinary retention, and abdominal distension

Carbachol chloride

Carbamate of acetylcholine Potent cholinergic agonist at both receptors Far more stable in gastric acid Difficult for acetylcholine esterase to metabolized Used for glaucoma and miosis induction

Carbaryl

Carbamate-derived acetylcholinesterase inhibitor Naphthalene ring system 3rd most common insecticide in the US Used in veterinary medicine

Combination of L-dopa and Carbidopa in Parkinson's disease

Carbidopa inhibits aromatic L-amino acid decarboxylase in the periphery Carbidopa cant cross the BBP so dopamine can be formed in the brain The greater amount of dopamine is formed in the brain after orally administered levodopa/carbidopa L-dopa crosses the BBB, dopamine does not Carbidopa does not cross the BBB

Adverse CV effects of succinylcholine

Cardiac arrythmias Bradycardia

Other effects of progestin

Cause decrease in Na reabsorption via competing with aldosterone for the mineralocorticoids receptor Responsible for the development of the secretary apparatus in the breast Cause decease in plasma amino acids and leads to increased urinary nitrogen excretion

What does aldosterone do?

Cause increased salt and water reabsorption from the collecting duct of the kidney tubule to the blood More Na in the blood Increased CO leading to increased BP H and K are secreted from the blood to the collecting duct of the kidney tubule Less K in blood (hypokalemia) Less H in blood (alkaline) Causes hypokalemic metabolic alkalosis

Rivastigmine (Exelon)

Centrally selective arylcarbamate acetylcholinesterase inhibitors Treatment of Alzheimer's disease Inhibit acetylcholinesterase for up to 10 hours Arylcarbamate that is centrally active

Hormone

Chemical messenger produced by endocrine glands Secreted directly into bloodstream, transported elsewhere in body, exert a specific effect on body as a whole

Acetylcholine esterase is a popular target in

Chemical warfare, pesticides, and treatment of Alzheimer's disease

Symptoms of asthma

Chest tightness, SOB, increased bronchial responsiveness to inhaled stimuli Patient observes

Precursor to pregnenolone: Branch point: Major precursor to mineralocorticoids: Major precursor to glucocorticoids: Major precursor to estradiol: Immediate precursor to estradiol:

Cholesterol Pregnenolone Pregnenolone 17 hydroxypregenolone DHEA Testosterone

__ uptake is the rate determine step in the biosynthesi of ACh. Choline Epinephrine Dopamine

Choline

Identify a2-AR selective agonists What effect does activation of persynaptic a2-Ars have? Indicated for?

Clonidine and guanfacine Inhibit release of NE; sympatholytic effect;help treats the upregulation of NE from the drugs to reduce withdrawl symptoms Alleviate symptoms of withdrawl from depressants and ameliorate unpleasant side effects from stimulants

Pyridostigmine (Mestinon)

Closely related to structure of neostigmine Incorporates charged nitrogen into a pyridine ring Lacks CNS activity Prophylaxis of sarin gas exposure Contracts NM blockers

Reuptake inhibitors: target potency = DAT > NET > SERT Cocaine Amphetamines Clonidine

Cocaine

Cocaine vs amphetamines Order of potency Substrate or antagonist Displacing NT Reversing transport

Cocaine: -more selective for DAT -antagonist -no -no Amphetamines -more selective for NET -substrate -yes -yes

Metyrosine

Competitive inhibitor of *tyrosine hydroxylase* (rate limiting step in NE/EPI biosynthesis) Useful in treating HTN caused by excess catecholamine biosynthesis is in pheochromocytoma tumors Half life is about 4 hours S enantiomer binds to active site but r enantiomer does not Catecholamine production down 35-80%

Hydrocortisone sodium phosphate

Completely and rapidly metabolized by phosphatases Half life of less than 5 min Peak levels in about 10 min *used for IV/IM injection in the management of emergency conditions* that can be treated with anti-inflammatory steroids

Alpha 1 on arterioles and eye and uterus

Constriction Dilates eyes Induces labor

Combination oral contraceptive

Contains estrogen and progestin Come in packs of 21, 28, or 91 pills The last 7 pills may not contain hormone, whihc means you may stop taking the pills for 7 days Menstural bleeding occurs during the week that you do not take the pills or take you take w/o hormones

Mini pill oral contraceptive

Contains progestin only Packs of 28 pills All 28 pills contain hormone You take the pill everyday and at the same time

Autonomic receptors and functions

Contraction and relaxation of muscles in GI tract, heart, blood vessels, eye, bladder, etc Opening and closing of Na and K channels begin the transmission of nerve signal for cholinoreceptors Adrenoreceptors cause modulation of second messenger cAMP

Antimuscarininc effects on eye

Contraction of some of the eye muscles (pupillary constrictor muscle) depends on muscarininc cholinoreceptor activation Blocking constriction by atropine causes mydriasis (extremely dilated pupils) Weaken contraction of ciliary muscles (cycloplegia) Dry eyes because they decrease secretion

Corticosteroids and stimulation of lung attraction in the fetus

Conttoleld by fetal secretion of cortisol at the latter part of pregnancy Needed to produce surfactants in the fetal lung When baby is delivered prematurely, respiratory distress syndrome is common due to lack of enough cortisol Tx: mother treated with betamethasone if the delivery is anticipated before the 34 week of gestation

What is the function of aromatase? What do you give to prevent it?

Convert A ring from 2-keto-4-enology to phenol ring.

C9 fluoridation in corticosteriods

Increases glucocorticoid and mineralocorticoid activity

Identify mast cell stabilizers. What molecular changes take place within a mast cell during degranulation? How do mast cells interfere with the process of degranulation?

Cromolyn and nedocromil Fusion of granules to cell membrane surface so exocytosis can occur and release the granular contents Phosphorylation of cell membrane moesin-like protein (binds to cytoskeleton and prevent changes needed for exocytosis) and inhibit activation of chloride current needed to activate the cell

What are the precursors to aldosterone

Corticosterone in the mineralocorticoid pathway Angiotensin II from the RAAS system

When you are under stress _ secretion increases

Cortisol

Which of the following adrenocorticosteroid is responsible for many functions including providing adequate insulin to the brain and immune suppressive effects? Aldosterone Cortisol Androgens Pepsin

Cortisol

What is the most potent endogenous glucocorticoid? Primary function of glucocorticoids?

Cortisol Maintain blood glucose levels (also minimize inflammatory reactions and suppress immune response)

Fetal lung secretes _ which is needed to produce _ in the lung

Cortisol Surfactant

Parasympathetic Site Activity

Craniosacral Essential, vegetative, rest and digest Always partially on Acetylcholine

Sx of hypothyroidism

Cretinism (defective physcial and mental development) Weight gain Elevated cholesterol Bradycardia Cold intolerance fatigue, lethargy, depression Dry skin Thinning hair Goiter

Sarin

Deadly chemical used as warfare agent Potent inhibitor of acetylcholinesterase Colorless odorless gas Build up of acetylcholinesterase leads to N/V, convulsions, cessation of breathing, and death

Explain what enzyme biosynthesizes histamine and from what precursor. What kind of reaction is this? Can you name the reactant? Product? Enzyme? Cofactors?

Decarboxylation Histidine Histamine Histidine decarboxylase Pyridoxal phosphate (B6)

Blockade of b1 on cardiac muscle and SA & AV node

Decrease CO Decrease BP

Theraputic/side effects for Na channel blockade

Decrease cough reflex and relief from dermatological hypersensitivity reactions Sedation

Blockade of a/b on gluconeogenesis and glycogenolysis

Decrease glucose

CV effects of ganglion blocking drugs

Decrease in arteriolar and vasomotor tone Hypotension Decrease peripheral vascular resistance (vasodilation) Diminished contractility

C6 fluorination in addition to C9 fluorination to corticosteroids

Increases lipophilicity and potency

Biosynthesis of estrogen Follicular phase

DHEA is made from pregnenolone

In target tissues testosterone is convertered to

DHT Dihydrotestosterone

Albuterol

DOC for acute bronchospasm Aerosol, solution, tablet, syrup Inhalation onset 5 min Duration 6 hours Mixture of R and S enantiomers Short acting Beta agonist

17-alpha-methyltestosterone

Daily doses between 10 and 50 mg, which is equivalent to a 400 mg oral dose of testosterone Reduced susceptibility to hepatic oxidative metabolism, thereby increasing oral bioavaliability by slowing metabolism Increases half life from 30 mins to 3 hours

Given dashes and wedges which is alpha/beta

Dashes alpha (trans) Wedges beta (Cis)

Day 1-23 of pregnancy

Day 1 - fertilization 2 - cleavage 3 - compaction 4 - differentiation 5 - cavitation 6 - zone hatching 7 - implantation 9 - cell mass differentiation 12 - bilaminar disc formation and mesoderm formation 18 - mesoderm spreading 23 - amniotic sac enlargement Highly controlled and rapid cell growth

Have to have what steps for muscles to contract?

Depolarization, plateau, and repolarization

Succinylcholine

Depolarizing neuromuscular blocker Duration of action is short (10 minutes) due to the hydrolysis by cholinesterase Onset of effect is about 30 seconds

Cons of oral contraceptives

Depression Trouble sleeping Headache N/V Breast tenderness Irregular bleeding or spotting during the first several months Bloating or fluid retention Weight gain Increase BP Combo pills increase risk of blood clots, heart attack, and stroke Increase risk of hepatic adenomas, jaundice, malignant tumors, etc

Pharmacological effects of hormonal contraception

Depression of ovarian function, morphology, and follicular development Hypertrophy and polyp formation of the cervix Estrogen causes CNS excitability. Useful in therapy of postpartum depression, and premenstural tension. Estrogen also causes alertness, good for bone health Endocrine function - increase corticosteroids binding globule and thyroid binding globule Effects on liver function and alterations in lipid metabolism

Major function of androgens

Development and maintenence of male sex characteristics Protein synthesis and muscle growth (anabolic) Quantity of androgens produced by adrenal is small compared to gonads

What first gen antihistamines block cholinergic receptors

Diphenhydramine Clemastine Promethazine

Choline esters

Direct acting cholinoreceptor drugs Water loving Poorly absorbed and distributed to CNS SAMe as acetylcholine but cross bilayer better A large amount of acetylcholine must be infused to get a detectable effect and the duration of action is very short Others are more resistant to hydrolysis (through acetylcholinesterase) and duration of action is longer Ex. Bethanechol, carbachol, metacholine

Malathion

Dithiophosphate ester Bioactivated in insects to its toxic phosphate ester metabolite Less toxic in humans because plasma esterase hydrolyzes the esters to carboxylic acid metabolites

Edrophonium chloride

Does not have a carbamate Phenol derivative IV for diagnosis of myasthenia gravis Reverse action of neuromuscular blockers

Mivacurium chloride

Does not undergo Hoffman elimination Tetrahydroisoquinoline-based neuromuscular blocking agents Orientation of ester to the quaternary ammonium group Undergoes *rapid hydrolysis by plasma cholinesterase) DOA 12-18 min *short acting* Shortest acting tetrahydroisoqunioline based NMB

Which NT is associated with abuse potential/addiction?

Dopamine

Which neurotransmitter is associated with abuse potential/addiction? Dopamine Norepinephrine Epinephrine

Dopamine

L2

Drug studied in limited number of breastfeeding women w/o observed adverse effects and/or evidence of demonstrated *risk is remote*

L1

Drug taken by a large number of breastfeeding women w/o observe adverse effects *fail to demonstrate risk*

Hemicholiniums

Drugs can inhibit choline transport to the nerve ending

Toxicity of antimuscarininc drugs

Drugs target to one organ system indices undesireable effects in other organ systems Higher doses block all parasympathetic functions (complete block of GI motility, increased HR) Atropine poisoning and atropine fever in children

Cholinomimetic drugs, bethanechol

Drugs that mimic Ach

GI effects of antimuscarinics

Dry mouth Some blockade of gastric secretion GI motility (tone and propulsive movements) diminished

Common anticholinergic effects (McCune)

Drying (mouth, respiratory passages, urinary retention) Constipation Blurred vision Tachycardia Palpitations Thickening of mucus in COPD

Metabolic effects of glucocorticoid

Due to direct action in the cell Dose related effects on carbohydrate, protein, and fat metabolism Required for *gluconeogenesis, glycogenolysis, and glycogen synthesis in the fasting state* (in the fasting state glucocorticoids mainly increase gluconeogenesis and glycogenolysis) - stimulate many enzymes involved in these processes

Cetirizine

Duration of action 12-24 hours 2nd gen Zwitter ion Non-sedative because it doesnt cross BBB due to charge Higher selectivity for H1 receptors based on hydroxyzine

Circadian rhythm and cortisol production

During night both ACTH and cortisol levels are low ACTH and cortisol levels peak in the morning (highest around 7-9 am) ACTH and cortisol levels are somewhat high during lunch-dinner (1-7)

Which drugs block testosterone to DHT conversion?

Dutasteride, finasteride Antiandrogen

Organ system effects of muscarinic blockers Eye Skin GI CV Respiratory Genitourinary CNS

E - mydrasis (dilation) and cycloplegia (blurred vision) S - reduced sweating, flushing GI - reduced motility and secretions ("constipation") CV - increased HR (at high doses) R - bronchial dilation and decreased secretion Gen - urinary retention CNS - drowsiness, hallucinations, coma

Responses from muscarinic receptor activation Eye Cardiovascular Respiratory GI Glands Genitourinary

E: miosis (constriction of pupil) CV: decrease heart rate, BP, and peripheral vascular resistance R: bronchial constriction (cause asthma symptoms) GI: increased motility, secretion, and relaxation of sphincters G: secretion, sweating, salivation GU: bladder wall contraction, uterine contraction, relaxation of sphincters (you have to pee)

In the pathogenesis of asthma, which is being released as a part of the late phase reaction? Eosinophil cationic protein (ECP) Tryptase Histamine IgE

ECP

Blockade of B2 in erectile tissue

ED

Muscarinic receptor

Early SAR hypotheses of Ach thought that there was an H bond at the ester oxygen and nitrogen charge was repelling. They actually found out that they are G protein coupled receptors

Pathogenesis of asthma

Early reaction -1 hour -due to mast cell mediators (*histamine, tryptase, prostaglandin D2, leukotriene C4, platelet activating factor*) -IgE receptors on mast cells bind to allergen and cause degranulation -mast cells and T cells release *cytokines* (IL4, granulocyte-macrophage colony stimulating factor, TNF, tissue growth factor) which *attract and activate eosinophils and neutrophils -during this time FEV1 recovers* Late reaction -about 5 hours -help has arrived (eosinophils and neutrophils) -eosinophil cationic protein, Major basic protein, PAF, proteases -*cause edema, mucus hypersecretion, smooth muscle contraction, increased bronchial activity*

Clinical pharmacology of the cholinoreceptor agonist drugs Heart

Edrophonium used for tachyarrythmias Atropine and over dose of tricyclic antidepressants can block muscarinic receptor resulting in arrythmias in adults and behavioral symptoms in children Need to use cholinesterase inhibitors to increase the Ach at the receptor Physostigmine DOC

Adrenergic drugs act on

Effector cells by binding to the adrenoreceptor that are activated by norepinephrine Neurons that release the neurotransmitter

Nerve fibers originate from different regions of the spinal cord and terminate inthe

Effectors/organs Divides into sympathetic and parasympathetic. Nerve fibers start from two different locations of the spinal cord

Maternal drug actions

Effects of drugs on *reproductive tissues* sometimes altered by changes in endocrine system Effect of drugs on *maternal tissues* (heart, lungs, kidney, CNS) do not change significantly *physiological changes* Pregnancy vs non-pregnancy state

Smoking increases

Elastase Keeps losing elastin and lung function

Corpus luteum

Endocrine organ that is produced to ovarian follicle when ovulation occurs Produces estrogen and progesterone

Day 14 of menstrual cycle

Endometrium is getting thicker LH (larger) peak Estradiol peak Ovulation occurs (egg is released) and corpus luteum is formed

As a general rule for corticoidsteroids Conversion of 17-alpha OH to 17-alpha-ether

Enhances anti-inflammatory potency and receptor affinity

Cevimeline Clinical uses Toxicity Clinically important

Enhances lacrimal secretions May have fever side effects than pilocarpine Caution in those with asthma, COPD, urinary/GI obstruction, CV disease, hypotension, or bradycardia Direct acting

Androgens will be converted to estrogens using

Enzyme aromatase

FSH and LH stimulate

Estrogen and testosterone secretion

How does estrogen work?

Estrogen binds to estrogen receptor causing translocation of estrogen bound to receptor to the nucleus and cause gene transcription resulting in multiple effect

Estrogens role in breast cancer

Estrogen induced cell proliferation plays a major role in causing breast cancer Promote cell replication by binding to the nuclear estrogen receptor (ER) Estrogen receptor regulates the transcription of key growth factors and nuclear proteins necessary for cell proliferation

Triamcinolone acetonide

Ether formed from the 16-alpha and 17-alpha OH groups Frequently used by inhalation for treatment of lung diseases Conversion fo 17-alpha OH to 17-alpha ether greatly enhances antiinflammatory potency and receptor affinity

Phytoestrogens

Ex. Isoflavones Notably found in soy Estrogenic and antiestrogenic compounds Have been studied in breast cancer survivors Results in one study (nonsignificant reduced risk of breast cancer specific mortality and a statistically significant reduced risk fo recurrence)

Alkaloids

Ex. Muscarine, pilocarpine, nicotine M and P are agonists of muscarinic receptors N is an agonist of nicotinic receptor Absorbed well from most sites of administration N is lipid soluble and can be absorbed through the skin

Metyrosine excretion

Excreted unchanged in urine Limited water solubiltiy due to intramolecular ion-ion interactions within the zwitterion Can lead to *crystalluria*

Estradiol

Exhibits high affinity for the estrogen receptor and high potency when administered *parenterally* Promptly conjugated in the intestine and oxidatively metabolized by the liver resulting in low oral bioavailability and theraputic effectiveness

Flutamide

Extensive 1st pass metabolism Major metabolite (2-hydroxyflutamide) has a half life of 8 hours and higher affinity for androgen receptor than flutamide Antiandrogen

Orally adminsted testosterone is ineffective in the treatment of male androgen deficency due to

Extensive first pass metabolism Oral preparations have reduced first pass metabolism

Asthma shows decreased __ & __

FEV1 and FVC (the lungs wont expand as much)

What causes ovarian follicles to get developed

FSH Usually one follicle matures per month

Androgens

FSH controls gametogenic (sperm making) function LH is important in endocrine (hormone production) function Testosterone, DHEA, DHEAS, androstenedione Bind to the androgen receptor and brings the action In target tissues testosterone is converted to DHT Metabolized in the liver Prevention against atherosclerosis

T/F Progesterone is produced in the follicular phase.

False Produced in the luteal phase

Steroid

Fat soluble organic compound found in plants and animals Class of lipid characterized by "steroid nucleus"

Ing's rule of 5

For maximal muscarinic potency, there should be no more than 5 atoms between the N and their terminal H

Teratogen - warfarin Trimester Effect

First Hypoplastic (shortened) nasal bridge, chondrodysplasia

Teratogens - methotrexate Trimester Effect

First Multiple congenital malformations

Teratogens - organic solvents Trimester Effect

First Multiple malformations

Teratogen - thalidomide Trimester Effect

First Phocomelia (shortened or absent long bones of the limbs) and many internal malformation

Tacrine hydrochloride (Cognex)

First drug approved in 1993 for the treatment of *alzheimer's disease* Limited use due to *hepatotoxicity* Use is greatly decreased because of the recent developement of safer AChEIs

When do postpartum gaps close

First week

Teratogens - Cytarabine Trimester Effect

First, second Various congenital malformations

The monthly prescribed sal retaining drug is

Fludrocortisone

What of the following is not a change that occurs with asthma? Increased sensitivity to trigger Inflammation Smooth muscle contraction Fluid build up

Fluid build up

Atropine Natural sources ADME

Found in nightshade, jimsonweed, and thorn apple Tertiary amine ester or tropic acid Well absorbed thru all routes Well distributed throughout body and reach CNS w/n 30 mins Half life is 2 hrs 60% of drug is excreted unchanged. Rest appears as products of hydrolysis and conjugation products Effects lasts short term in the eye

Introduction to Autonominc Nervous System (ANS)

Functions are not under direct conscious control Happen without thinking Cardiac function, endothelial function, digestion, blood flow to organs, etc Signal start from brain/spinal cord, signals transmit through nerves to distal parts of the body. NT is involved in transmission of signals

Why give babies zidovudine?

HIV

Indications of prazosin

HTN (not first line), as adjunct in severe CHF Alone or in combo with beta blockers in the preoperative management of signs and symptoms of pheochromocytoma Off label: PTSD

Can you link the theraputic effect, side effects, contraindications, and precautions to an adrenergic receptor function? MAOI HTN CAD, ischemia heart diseases Urinary complications Mydriasis

Further anticholinergic effect Raise in BP and HR due to b1 CAD and ischemic due to b1 Urinary and BPH due to a1 Mydriasis and glaucoma due to a1

Adrenergic receptors are what type of receptors?

G protein

Adrenergic receptors are __ receptors

G protein coupled receptors

Muscarinic receptor signaling

G-protein coupled receptor

Leukotrienes receptors are __ receptors

G-protein coupled receptors

MOA of spasmolytic drugs Effects Clinical application Diazepam

GABA (inhibitory neurotransmission pathway) - CNS acting drug Central sedation Acute spasm due to muscle spasm. Chronic spasm due to cerebral palsy, stroke, or spinal injury

MOA of spasmolytic drugs Effects Clinical application Baclofen

GABA (inhibitory pathway) - CNS acting Pre and post synaptic inhibition of motor output Space city due to cerebral palsy, MS, stroke (stress induced muscle tightness)

Ach binding to nicotinic receptors to activate the release of several neurotransmitters such as

GABA, dopamine, glutamine, and norepinephrine

Trimethaphan

Ganglion blocking drug Treatment of hypertensive emergencies (occasional use)

Tissue distribution and function of H2 receptor subtype

Gastric parietal cells, smooth muscle, mast cells, CNS Increase stomach acid, mucus production, smooth muscle relaxation

Which of the folllowing is FALSE of a teratogen? Targeted selectivity to organ Dose dependent Time frame of vulnerability Genetic heritability

Genetic heritability

Clemastine (Tavist)

Has an additional C between O and N, in the form a pyyrolidine ring Marketed in the form of R, and is the most potent compound *less sedative properties relative to diphenhydramine/doxylamine* duration of action is 12 hours

Olopatadine (patanol)

Has structural similarity with tricyclics High selectivity for H1 receptors and prevents relapse of transmitters from mast cells *limited penetration* and lack of muscarininc acitivity becuase of the carboxylic acid presence Rapid onset of action and long duration of action Dual activity

Spermatogenesis

Germinal diploid cell differentiates into primary spermatocyte (diploid) Primary spermatocyte undergoes meiosis I to form 2 secondary spermatocytes (haploid) Each secondary spermatocyte undergoes meiosis II to form 2 spermmatids (haploid) each - total of 4 spermatids Spermatids lose excess cytoplasm and gain tails so they can swim and form spermatozoa

Depolarizing relaxant drugs

Get depolarized and depolarize but cannot depolarize again Producing excess of depolarizing agent Succinylcholine only clinically useful drug of this type Occurs in 2 blocks Phase 1 block: -continuous depolarization by binding to Ach receptors and initially preventing repolarization -repetitive firing results in muscle paralysis Phase 2 block: -with continued exposure the end plate repolarizes but cant depolarize again (becomes desensitized)

Phenytoin in pregnancy

Gingerval hyperplasia

How are the natural thyroid products derived?

Glands of domesticated animals

Carbachol Clinical use Toxicity Clinically important

Glaucoma and induce miosis Parasympathetic effects if absorbed systemically Caution in those with asthma, COPD, urinary/GI obstruction, CV disease, hypotension, or bradycardia Direct acting

Pilocarpine Clinical uses Toxicity Clinically important

Glaucoma, induce miosis, treatment of dry mouth Parasympathetic effects if absorbed systemically Caution in patients with asthma, COPD, urinary/GI obstruction, CV disease, hypotension, bradycardia I react acting

Triamcinolone

Glucocorticoid activity equivalent to prednisolone but decreased mineralocorticoid activity 16 alpha OH counteracts high mineralocorticoid activity from 9 alpha fluoride Used as ester and ether derivatives

Regulate carbohydrate metabolism

Glucocorticoids

Hypothalamus secrets __ hormone

GnRH (gonadotropin releasing hormone)

Dutasteride

Greater and more consistent reduction of plasma DHT than finasteride Inhibits multiple types of 5-alpha-reductase enzymes Longer half life of 5 weeks 5-alpha-reductase inhibitor

Guanidines

Guanabenz Guanfacine Ring opened analogies of clonidine Phenyl ring with 2 ortho chlorine's Antihypertensive agents Acts same as clonidine

What is the difference between hypotension and orthostatic hypotension

H - globally low BP no matter what the body is doing OH - fall in BP after getting up (may cause dizziness or fainting)

Histamine is an agonist of? Antihistamines?

H1 receptor Blockers

What properties or uses are associated with: -hydroxyzine -promethazine -cyproheptadine

H: antipruritc/antianxiety P: antiemetic, combo with antitussives/decongestants, sedation, anticholinergic effects C: decrease sexual and other side effects of antidepressants, increase appetite and weight gain

2-arylimidazolines Imidazolines

Have a *hetrocyclic imidazoline nucleus* *linked to aromatic moiety* via a bridge unit Commonly lipophilic groups found ortho to bridge unit Bridge unit is usually *single methylene or an amine* A1-adrenergic agonist Ionized at physiological pH Used in topical preparations as nasal decongestants and eyedrops Systemically they are potent vasoconstrictors

GI changes in pregnancy

Heartburn Decreased motility > constipation Increase reflux

Nilutamide

Hepatotoxic nitroaromatic hydantoin compound Nitro group gets converted by NO syntheses to nitro free radicals Reduction of nitro to hydroxylamine may lead to toxicities Half life of about 50 hours Antiandrogen

What are the bladder effects of a cholinergic antagonist? Cholinergic agonist

Hesitancy Urgency

Which of the following fill not allow for easier transfer of drug into breastmilk? Low molecular weight Lipophilic Low protein binding High protein binding

High protein binding

Neuromuscular blocking drugs

Highly polar and inactive orally Do not readily cross cell membranes Must be administered parenterally

Budesonide

Highly potent glucocorticoid intended for local treatment of lung diseases and rhniitis Unique retention in lung, undergoes reversible formation of fatty acid resters from free fatty acids in the lung Prolongs effec due to slow release of parent drug Inhaled once daily Rapidly deactivated in systemic circulation

Mechanism of action of atropine

Highly selective for muscarinic receptors Reversible blockade (if we add enough agonists) Prevents muscarinic agonist mediated signaling Doesn't distinguish b/t muscarininc receptor subtypes

Adverse effects of androgens

Hirsutism in women (changes in external genitalia of women. Replacement therapy in men can cause hepatic failure, behavioral effects, increase LDL and decrease HDL

Mast cell mediators

Histamine Tryptase Prostaglandin D2 Leukotriene D4 Platelet-activating factor

Blockade of __ & __ receptors in the __, __, and __ yields anti-emetic properties.

Histamine and muscarinic Vestibular apparatus, vomiting center, and chemoreceptor trigger zone

Histidine is converted to histamine by

Histidine gets converted to histamine by the enzyme histidine decarboxylase with pyridoxal phosphate

Clinical uses of estrogen

Hormone contraception (estrogen alone may lead to breast cancer) Thx of bleeding disorders and endometriosis when estrogen therapy is contraindicated

Synthetic preparation of cortisol is

Hydrocortison

Treatment for chronic Addison's disease

Hydrocortisone and fludrocortisone

Adverse effects of depolarizing neuromuscular blockers

Hyperkalemia Increased IOP Increased intragastric pressure Muscle pain

Spironolactone causes Hypokalemia and metabolic alkalosis Hyperkalemia and metabolic acidosis No change in blood K levels No change in blood pH

Hyperkalemia and metabolic acidosis

Manifestations of aldosteronism

Hypernatremia Increased BP Increased CO Hypokalemia Metabolic alkalosis

Cushing's syndrome

Hyperplasia of adrenal glands contribute to *increased ACTH release* *excessive production of glucocorticoids leading to Cushing's syndrome* Sx: round face, skinny arms and legs, mental disorders, osteoporosis, central obesity and stretch marks, thin and brittle skin, hyperpigmentation of knuckles due to ACTH excess Can be caused by pituitary adenoma or other tumors Tx: surgical removal of tumors and resection of adrenal glands follows by hydrocortisone

Too much aldosterone can cause Hypokalemia and metabolic alkalosis Hyperkalemia and metabolic acidosis No change in blood K levels No change in blood pH

Hypokalemia and metabolic alkalosis

Adverse CV effects of tubocurarine and atracurium

Hypotension through histamine receptor via release of histamine

GnRH is produced from the

Hypothalmus

Control of androgen secretion

Hypothalmus produces GnRH GnRH acts on pituitary Pituitary LH LH acts on testis Testis produces testosterone Testosterone can turn into dihydrotestosterone using the enzyme 5-alpha reductase Both testosterone and DHT binds to androgen receptor Gene induction in androgen responsive cells

Reversible inhibitors of acetylcholinerase

I: reacts with acetylcholineasterase but is capable of undergoing hydrolytic regeneration whihc is much slower than the acetylated form. *the rate of hydrolytic regeneration is measured in munutes* II: binds to acetylcholine with greater affinity than acetylcholine

Methylprednisolone sodium succinate

IV Slowly and incompletely hydrolyzed Peak levels attained in 30-60 min

How does the pharmacy and medicinal chemistry of the synthetic thyroid hormone replacement drugs differe from that of androgynous human thyroid hormone?

Identical Na salt

Hormonal control of menstural cycle

If a baby gets conceived endometrial lining will not get shed Progesterone and estrogen levels are high Otherwise hormone levels decline, and the endometrial lining will be shed periodically

Will drug pass into bloodstream? If drug passes into bloodstream will it get into breastmilk? If drug gets into breastmilk will survive in baby's stomach? If drug survives in baby's stomach, will it get into baby's bloodstream?

If yes to all the drug may cause harm to baby

Mediators of type 1 hypersensitivity

IgE Mast cells Histamine

Explain how a1-AR blockade relates to orthostatic hypotension

Impairs baroreceptor Drop in BP cannot be adjusted for when getting up

Khellin

Natural product traditionally used in Mediterranean N/V Search for analogues w/o side effects lead to chromones Natural mast cell stabilizers

Testosterone replacement therapy (TRT)

Improvement in muscle mass and strength, cognitive function, mood and sexual function CV system and blood (increased hematocrit and hemoglobin level) and prostate cancer

Clinical pharmacology of the cholinoreceptor agonist drugs Myasthenia Gravis

In disease Ach binding to nicotinic receptors will be blocked in the skeletal muscle neuromuscular junction Less Ach receptors are here and flattened post synaptic folds due to autoimmune attach (less receptors and surface area) Cholinesterase inhibitors are used here > we do not need to make more Ach, we have enough. We need to keep this Ach longer in the synaptic cleft Edrophonium (short term), neostigmine, or other pyridostigmine can be used for this disease

Beta 1

In heart Increase HR and BP Activation in heart increase Ca to increase force and rate of contraction

Sertoli cells

In seminiferous tubules Produce activin and inhibin Activin increases FSH release Inhibin plays a role in feedback inhibition

Beta agonists to know for asthma M T B A L S F A I O

Metaproterenol sulfate Terbutaline sulfate Bitolterol mesylate Albuterol Levalbuterol Salmeterol xinafoate Formoterol fumarate Arformoterol Indacaterol Olodaterol

Male hypogonadism

Inability of the testes to produce sufficient testosterone to maintain: -sexual function -muscle strength -bone mineral density -fertility (spermatogenesis)

Symptoms of chronic Addison's disease

Inability to maintain fasting blood glucose Weakness Fatigue Hypotension Hyperpigmentation in areas of increased friction (palmar creases, dorsal foot, nipples and axillary regions, patchy hyperpigmentation of the oral mucosa)

Catecholamine

Included based on structure Norepinephrine - main transmitter of sympathetic postganglionic fibers Epinephrine - primary hormone released from adrenal medulla Dopamine - predominant NT of extrapyramidal system

CV changes in pregnancy

Increase CO, blood volume, HR Decrease TPR and BP (2nd trimester)

Why give phenobarbital to babies?

Increase CYP450 To clear bilirubin in jaundice

Adrenergic system and cholinergic system effects on asthma

Increase adrenergic relaxes smooth muscle tone Decrease cholinergic relaxes smooth muscle tone

Why give corticosteroids to babies?

Increase lung development

Beta 1 on heart

Increase rate and force

Respiratory changes in pregnancy

Increase respiratory rate Decrease function capacity Respiratory alkalosis

Protein synthesis in liver and release of amino acids in muscle metabolism effects of glucocorticoids

Increase serum glucose levels Increase insulin secretion and lipogenesis Increased release of fatty acids and glycerol (lipolysis) into circulation These help *maintain adequate level of glucose to the brain*

Breast tissue changes in pregnancy

Increase size Increase estrogen and progesterone

Other effects of glucocorticoids

Increased amounts cause depression and behavioral disturbances Important in development of fetal lung Required for proper Renal function Chronic adminstration cause suppression of ACTH, GH, thyroid hormone, and LH Large doses cause peptic ulcer, promote fat redistribution, and decrease calcium absorption

Beclomethasone

Increased urinary sodium retention Has half the potency of its fluro analogue as a glucocorticoid Used as dipropionate derivative in inhalation aerosol therapy for asthma and rhinitis

What is meant by "enterohepatic cycling". How is it relevant to the bioavaliability of steriods? What enzyme is relevant to this? What produces this enzyme? Where is it? How might antibiotics affect enterohepatic cycling? What would be the effect on bioavailability?

Increases the amount of steroids in the body Beta-glucouronidase by bacteria in the large intestine Antibiotics inhibit Decreases the bioavaliability becuase the polar group is not able to be taken off and recycled

Ultra long acting beta 2 agonists

Indacaterol and olodaterol Derivatives of formoterol DOA 18 hours stays bound to beta 2 receptor Inhalation allows once daily dosing

Acetylcholine esterase antagonists are

Indirect cholinergic agonists

Adverse effects of beta blockers

Induction of HF in suceptible patietns Bradycardia (heart block) Exercise intolerance Bronchoconstriction CNS effects for lipid soluble agents like propranolol (fatigue, depression, insomnia, nightmares) Impotence Metabolic effects (elevated lipids, low or high blood glucose)

Three changes that occur with asthma

Inflammation (swelling, mucous secretion) Smooth muscle constriction Increased sensitivity to trigger

Modification of the ethylene bridge of acetylcholine

Ing's rule of 5: for maximal muscarinic potency, there should be no more than 5 atoms between the N and terminal H Extending the ethylene to a longer carbon chain leads to a longer carbon chain leads to decreased or antagonist activity Steroselectivity for the optical isomers of acetyl-a-methylcholine -less active at both receptors -greater nicotinic potency in relation to muscarinic potency Putting a methyl on the B carbon leads to muscarinic agonist with very little acitivity at nicotinic receptors > s enantomer is 20X more potency at muscarinic (m3) receptors and is hydrolyzed much slower -R entantomer is not hydrolyzed by acetylcholinesterase (longer duration of action than acetylcholine) - induces bronchoconstriction

How do amphetamines affect DAT? Affect storage of NTs?

Inhibit DAT (antagonist) Reduce storage of NE which causes high doses of NE in synapse

Explain how the release of T4/T3 is regulated by the hypothalmus? Pituitary? T3 itself?

Inhibit TRH Suppress TSH Negative feedback

Cyproterone

Inhibit androgen action at the target organ Androgen receptor blocker

MOA of majority of adrenocorticoid antagonists

Inhibit one of more CYP450 enzyme complexes involved in adrenosteroid biosynthesis

MOA of spasmolytic drugs Effects Clinical application Cyclobenzaprine

Inhibition of muscle stretch reflex in spinal cord. MOA not clear. CNS acting drug Reduction in hyperactive muscle reflexes. Antimuscarinic effects Acute spasm due to muscle injury/inflammation

Spironolactone

Inhibitor for both aldosterone and androgen receptor

Sympathomimetic blockers

Inhibitors of catecholamines reuptake Inhibitors of catecholamines metabolism A2 antagonist

Sympatholytic blockers

Inhibitors of catecholamines synthesis Inhibitors of catecholamines storage A1 antagonist B blockers

Indirect acting drugs MOA

Inhibits acetylcholinesterase so acetylcholine cant be broken down and the acetylcholine levels increase Inhibit the hydrolysis of acetylcholine because acetylcholinesterase aids hydrolysis and it is blocked so we can keep acetylcholine.

Mifepristone (RU-486)

Inhibits activity of progesterone via progesterone receptor Bind to and act as antagonist at the GR

Ketoconazole

Inhibits fungal CYP450 enzyme Potent inhibitory of fungal sterol biosynthesis at low concentrations Higher doses *inhibits CYP3A4 in adrenosteroid biosynthesis (Cushing's syndrome off label)*

Danazol

Inhibits many enzymes including P450c17 in steroid synthesis pathway Suppresses secretion of FSH and LH Partial agonist/antagonist of ER, PR, GR

Alpha 2

Inhibits norepinephrine rlelase Activation prevents Ca influx

Release of histamine

Inital contact with antigen dads to specific IgE synthesis by B cells Secreted IgE binds to receptors on mast cells On subsequent exposureto antigen, immediate hypersensitivity reaction triggered

Release of acetylcholine

Initated by action potential Voltage-dependent calcium channels open and calcium comes inincrease in intracellular Ca induces fusion of acetylcholine storage vesicles Each vesicle (*called a quantum* 10^3 acetylcholine per vesicle Fuse to nerve terminal and get released

SAR for muscarinic agonist: for maximum potency, the size of the alkyl groups should not exceed a Methyl group Thio group Alcohol group

Methyl group

Parathion and malathion What are they? Which one can we detoxify more effectively?

Insecticides Malathion

Methylprednisolone

Insertion of *alpha-methyl groups at C6 increases glucocorticoid activity* Lacks significant mineralocorticoid activity Extensively metabolized, only 10% found unchanged un urine

Carbamates (eg neostigmine) relatively __ in lipids so

Insoluble Large dose is required for oral administration Barely distribute to CNS

Toxicities associated with acute (less than 2 weeks) tx of glucocorticoids

Insomnia Behavioral changes Acute peptic ulcers (rare) Acute pancreatitis (rare)

Chronic Addison's disease can occur as a result of Over production of glucocorticoids Insufficient production of glucocorticoids Over production of mineralocorticoids Insufficient production of mineralocorticoids

Insufficient production of glucocorticoids

Cholinesterase inhibitors Toxic effects

Intoxication due to pesticide use N/V, sweating, bronchial constriction, D

Steps of thyroid hormone synthesis

Iodide trapping (uptake of iodide by NIS) Oxidation ( of iodide to iodine) Organification (tyrosine to MIT or (DIT) Coupling (attaching 2 DIT or DIT and MIT) Proteolysis of thyroglobulin (thyroglobulin is reabsorbed by follicular cellls and TSH stimulates the breakdown of thyroglobin resulting in thyroid hormone release into circulation)

Give the structure of hydrocortisone esters, which ones have polar groups? What is the purpose of this functional group? How is it likely administered?

Ionic (sodium succinate or phosphate) Speeds up the absorption of the medication from the acetate form IM/IV

Identify the anticholinergic used for allergic rhinitis/COPD. Why may an anticholinergic nasal spray be useful for allergic rhinitis, or post-nasal drip. What side effects would you expect? Are systemic effects going to be common?

Ipatropium bromide Dries it up Drying (mouth, respiratory passage, urinary retention), constipation, blurred vision, tachycardia, palpitations, thicken mucus in COPD Yes - nose and lungs are good places for systemic absorption

Antimuscarinic for respiratory disorders Asthma and COPD Drugs MOA

Ipatropium, Tiotropium Prevent bronchoconstriction

Malaoxon

Irreversible Active metabolite of malathion (less toxic form)

Paraoxon

Irreversible Active metabolite or parathion (more toxic one)

Sarin, tabun, soman

Irreversible Extremely toxic Present in nerve gas

Parathion

Irreversible Insecticide Higher toxicity than malathion

Malathion

Irreversible Insecticide Safter than parathion due to greater detoxification ability by higher organisms

Diazinon, dimpylate

Irreversible Insecticide Use in gardening Banned indoor use in 2005. Phased out outdoor use also

DFP (diisoprophylflurophosphate)

Irreversible Potent irreversible inactivator

Malathion, parathion, sarin, soman, echothiopate are? Which one is used for glaucoma?

Irreversible Very long acting Echo for glaucoma

Chlorpyifos

Irreversible Insecticide with restricted use

Phenoxybenzamine Reversibility Receptor selectivity Indications Theraputic effect Side effects

Irreversible - heavy as an ox Nonselective (slight preference for a1) Pheochromocytoma Reverse EPI/NE medication vasoconstriction (vasodilation) > hypotension Reflex tachycardia, hypotension (decrease TPR), orthostatic hypotension Use before surgery

Antidotes for irreversible acetylcholinesterase inhibitors

Irreversible acetylcholinesterase inhibitors are toxic Designed compounds whihc are capable of cleaving the phosphate ester to regenerate active acetylcholinesterase Searched for stronger nucleophilic than water, whic can efficiently hydrolyze the phosphate ester Led to the development of aldoxime (aldehyde reacted with hydroxylamine

Toxic drug actions to fetus - ACE inhibitors

Irreversible renal damage

Where is cortisol converted to cortisone? With what enzyme?

Kidney 11-beta-hydroxysteroiddehydrogenase type 2

RAAS

Kidneys sense decreased renal perfusion and secrete renin Renin converts angiotensinogen from the liver to angiotensin 1 ACE from the lungs converts angiotensin I to angiotensin II Stimulates release of aldosterone from the adrenal gland Na, Cl, H2O reabsorption K excretion This increased perfusion pressure and decreases renin secretion

Only L-dopa adminsitration in parkinson's

L-dopa is converted to dopamine in the periphery in preference to the brain L-dopa only enters the brain only when administered in high doses to overcome loss by peripheral metabolism

Which lactation category represents a drug contraindicated in lactation? X L1 A L5

L5

Which hormones are elevated/peaked at day 14? Progesterone GnRH Only LH Only estradiol LH and estradiol

LH and estradiol

Select all that apply. Which of the following blocks testosterone production? Aromatase inhibitors LH Danazol Flutamide Ketoconazole

LH, danazol, and ketoconazole Aromatase inhibitors block conversion of testosterone to estradiol (orandrostenedione to esterone) LH is needed for hormone function Danazol inhibits 17-alpha-hydroxylase so testerone cannot be synthesized Flutamide is an androgen receptor blocker Ketoconazole blocks testosterone production.

Phenylephrine

Lack of para-phenol leads to alpha 1 selectivity Nasal decongestant Dilate pupil during eye surgery

Oxandrolone

Lactose susceptible to in vivo hydrolysis 3x anabolic activity of methyltestosterone Slight androgenic activity Used for muscle regrow this and osteoporosis Does not aromatize to estradiol

Tautomerization

Migration of a proton, accompanied by a switch of a single or double bond

Absorption in babies

Less acidic (pH 6-8) -especially in preterm infants -weak acids lower concnetration -acid labile plugs found in higher concentration Gastric emptying -delayed and slow -6-8 hours on first day or so after delivery Irregular IM absoprtion -irregular blood flow -cardiac glycosides, aminoglycosides antibiotics, and anticonvulsants

Block 5-lipoxygenase and you block

Leukotrienes

Monteleukast and zafirlukast block

Leukotrienes D4, C4, and E4 receptors

Lipocortin

Leukotrienes pathway inhibitors Produced by steroids Blocks phospholipids A2 Less leukotrienes, prostaglandins and thromboxane

Musculoskeletal changes in pregnancy

Ligament laxity by relaxin "Rubberbandy ligament connections"

Infant immune system

Linked to bacteria and virus it fights Many do not fully develop until the microbes that colonize the gut First weeks of life depend on antibodies from the mother

Factors affecting maternal drug transfer

Lipid solubility and drug ionization -lipophilic drug diffuse readily -highly ionized diffuse slowly Molecular size (smaller drugs pass more readily) PH of blood -mom - 7.4 -baby - 7.3 -basic drugs will be more ionized in the fetal compartment > ion trapping and lead to higher fetal levels Placental transporters -p-glycoproteins pumps some drugs back into maternal circulation Protein binding Drug metabolism -placenta (site of some drug metabolism, can oxidize but can lead to toxic metabolites) -fetal circulation (umbilical vein (oxygenated), up to 60% can enter fetal liver, umbilical artery(unoxygenated))

Generally more lipophilic drugs are primarily cleared by the __, whereas the more hydrophilic agents are cleared by the__

Liver Kidney

Metabolism in babies

Liver immature (decrease clearance rates, increase half lives) Opoids can speed up CYP Watch longitudinal drugs (dose changes with age) Material induced fetal hepatic enzyme production

Blockade of a1 on bladder wall

Loss of control

Explain the difference in the effect of low dose (physiological) vs high dose (pharmacological) epinephrine on TPR and overall BP

Low - low TPR and no real predictable BP High - high TPR and increased BP due to cholinergic reflex

Parkinson's disease is characterized by

Low levels of dopamine in the brain

Clinical pharmacology of the cholinoreceptor agonist drugs GERD

Lower esophageal sphincter open in disease Increase the tome of the lower esophageal sphincter in patients with reflux esophagitis (heart burn/acid reflux) Direct acting cholinomimetic; Bethanechol Cholinesterase inhibitor: neostigmine

B2

Lungs Bronchial and vascular smooth muscle relaxation Activation lowers Ca levels leading to relaxation

Muscarinic receptor we are concerned with in asthma

M3 Effects we want: Dilates eyes Decelerates SA node and atrial contractility Relaxes bronchiole smooth muscle Relaxes smooth muscle Decrease secretion Contracts sphincter We dont want to activate the receptor for asthma because that would cause more bronchoconstriction

What is the primary physiologic function of mineralocorticoids?

Maintain electrolyte balances by enhancing Na reabsorption and increase K and H secretion in. The kidney Semisynthetic analogs exhibiting high mineralocorticoid effects are not employed in the treatment of rheumatic disorders because of toxic effects resulting from a disturbances of electrolyte and water balance

Major vs minor route of biosynthesis of acetylcholine

Major is recycling Minor is biosyntheiszed from serine

Anticholinergic SAR

Many 1st and 2ns gen have anticholinergic side effects because they bind to acetylcholine receptors Central atom with 2 rings attached, short chain, and amine on other end Alcohol can be attached to central atom Ester or ether can be in the linker chain

Iritis

Many causes Causes red eyes and discharge

Nedocromil sodium (Tilade)

Mast cell stabilizer *thought to act by blocking chloride channel* Stabilizes mast cells Blocks airway nerves (inhibits cough) Stabilizes eosinophils inhibiting inflammation

Cromolyn sodium (Intal, Nasalcrom, Gastrocrom)

Mast cell stabilizer Derived from the chemical Kelvin which is found in the plant am I visnaga (in carrot family) Poor GI absoprtion. Must be inhaled as powder or Aerosol into lungs Thought to act by *blocking chloride channels* *specific to mast cells (no effect on basophils)* Specific to lung and not to skin cells

Storage and release of histamine

Mast cells -skin, mucus membranes of respiratory tract, urinary tract, tissues adjacent to blood, lymph vessels Basophils -type of circulating WBC -releases histamine as an inflammatory response

Glucocorticoid receptors (GR)

Mediates effect of glucocorticoids Member of nuclear receptor superfamily Cytoplasmic receptor Upon binding (on adrenal cortex) it translocates to the nucleus and binds glucocorticoid response elements in the promoters of the genes and cause gene transcription Ligand bound receptors also activates other transcription factors that lack the glucocorticoid response elements leasing to many effects (anti-inflammatory and immune suppressive)

Botulinum MOA

Membrane fusion is initiated by the complex formation of SNARE proteins Botulinum is a protease that cleave the SNARE proteins Alpha helixes are cleaved I depended if they are nicotinic or muscarinic receptors After cleavage the SNARE proteins cannot properly interact and membrane function is blocked Ach release out of the synapse is blocked

B3

Metabolic

Glucocorticoids

Metabolism and immune function Cortisol (hydrocortisone) is the major hormone in this class "Stress hormone"

Metabolism of Zafirlukast

Metabolism by CYP3A4 and CYP2C9 Increases level of warfarin, phenytoin, carbamazepine, cyclosporine, dihydropyridine

Fexofenadine

Metabolite of terfenadine via CYP3A4 (carboxylic acid form) Does not have antarrythmic effects 3rd gen Convert to zwitterion in the body

Regulate Na/K levels

Mineralocorticoid

Aldosterone

Mineralocorticoid - most important one Synthesized in adrenal cortex Salt and water retention in kidneys ACTH and angiotensin stimulate secretion

Drospirinone

Mineralocorticoid antagonist Oral contraceptive and progestin

MOA of ephedra/PSE

Mixed acting A1 mediated vascular smooth muscle contraction B2 medicated relaxation of bronchial smooth muscle B1 mediated positive inotropic/chronotropic effects that may be opposed by cholinergic reflexive response to increased TPR Most selective for B2 but can still bind to other receptors and produce side effects

How do plasma levels of iodine influence iodine uptake

Moderate levels facilitate uptake High levels like pharmaceuticals shut off transporters

CV system effects of antimuscarinic drugs

Moderate to high doses of atropine can cause tachycardia Block vasodilation of coronary arteries and other vessels Does opposite of Ach

Prednisolone

Modifications made for glucocorticoids selectivity -1-ene -11 - OH -glucose:mineralocorticoid activity ratio 4:1 1-2 double bond increases glucocorticoid activity and reduces Na retention Longer half life than hydrocortisone Almost completely absorbed with bioavaliabilty IOP > 80% Converted in liver by 11-beta-hydroxysteriod dehydrogenase

Biosynthesis fo acetylcholine

Most of the choline used is *recycled* following acetylcholinesterase catalyze hydrolysis of acetylcholine in the synapse Small amounts can be biosynthesized from the amino acid *serine* *choline uptake is the rate-determining step in the biosynthesis of Ach* Choline gets acetylated to form acetylcholine Serine gets decarboxylated and N-methylation to form choline that can then get acetylated Choline uptake is *inhibited by hemichlinium*

The effects of the Ach that are mimicked by the alkaloid muscadine and antagonized by atropine are termed ___ and the receptor is called __

Muscarinic effects Muscarinic receptors

Cholinergic receptors Two subclassifications

Muscarinic: naturally occuring alkaloid muscarine from Amanita muscarinic binds to this receptors Nicotinic: naturally occuring alkaloid nicotine binds to this receptor Acetylcholine binds to both nicotinic and muscarinic receptors

Differing in effects of NE, EPI, and isoproterenol (ISO)

NE - alpha and beta agonist EPI - slight alpha and more beta agonist Isoproterenol - beta agonist

Neruromuscular blockers vs spasmolytic drugs

NMB-muscle paralysis S-reduce stretch reflexes and flexor muscle spasms

Given the structure of nilutamide, identify the unusual structural feature (functional group). Why is this functional group unusual in modern drugs?

NO3 Gets converted to NO which is really reactive

Acetylcholine clinical uses

NT at nicotinic and muscarinic sites Topically to induce miosis (constriction of pupil) during opthalmic surgery Direct acting

Pronethalol

Napthylethanolamine (arylethanolamine) derivative Clinical candidate Toxicity tumor induction in animal tests in 1963 Eventually led to the discovery of oxymethylene bridges (OCH2) into the arylethanolamine led more potent beta blockers

What slows the air flow? What makes the lungs have less volume?

Narrowing of airway Lungs cant expand Information works on both

Ephedrine

Natrually occuring stereoisomers having 1R,2S absolute configuration No substituents on phenyl ring so it is not a good substrate for COMT Good oral activity Less polar, crosses BBB, CNS stimulant Mixed acting sympathomimetics Phenylpropanolamine

Progestin

Natural form is progesterone Precursor to androgens, estrogens, and adrenocorticoids Progesterone is produced primarily by the corpus luteum in the ovary.

Botulinum toxin

Naturally produced by clostridium botulinum Minor doses can be fatal (LD50=2ng/kg inhaled) Used cosmetically (Botox) by temporary paralysis of wrinkle causing muscles Prevention of chronic muscle spasms ~ 10 million fold more toxic than cyanide

CNS depressant sensitivity in babies

Neonates are more sensitive to opoids than older children and adults Watch breast milk exposure

Reversible inhibitors of acetylcholinesterase

Neostigmine Pyridostigmine Carabaryl Edrophonium chloride Tacrine Donepezil Rivastigmine Galantamine

Excitable cells

Nerve and muscle cells

Brain and neurons in babies

Neural links need to be pruned Allows for connections necessary for survival Later used to develop motor coordination and speech into more efficient network of connections

LTB4 is a

Neutrophil chemoattractant

Brexanolone

New medication for post partum depression CIV for IV use REMS program IV infusion 2.5 days in hospital GABA receptor positive modulator

Direct acting nicotinic drugs Acute toxicity Toxic effects Chronic toxicity

Nicotine Fatal dose is 40 mg of pure substance TE: convulsions, coma, respiratory arrest CT: lung cancer, CV disease, emphysema, ulcer recurrences, etc Direct acting nicotinic receptor agonists Varenicline is used in smoking cessation

Ach binds the post synaptic receptors (N or M) at the skeletal much and cause contraction of skeletal muscle

Nicotinic If you need to paralyze the muscle, Ach binding to post synaptic receptors needs to be blocked

The effects of the Ach that are mimicked by nicotine and no effect by atropine and block other agents are termed ___ and the receptor is called __

Nicotinic effects Nicotinic receptor

Nicotine is a ligand for __ High exposure leads to

Nicotinic receptor Mind altering actions, tremor, convulsions, coma

Beta blockers ability to induce vasodialtion occurs through

Nitric oxide production

Is norepinephrine selective?

No

Is reverse T3 biologically active? Where is it synthesized? What enzyme is responsible for its synthesis?

No Peripheral tissues Deiodinase enzyme 3

Can T4 be synthesized in the periphery? Can T3? What enzymes catalyze synthesis of T3

No - prohormone Yes Deiodinase 1/2 to form active T3

Is Lugol's appropriate for long term maintenence?

No - thyroid storm

Adrenergic response (SNS) Sphincter muscle of iris Radial muscle of iris Ciliary muscle

No SNS A1 contraction can lead to mydriasis, pupillary dilation, good for fight or flight B2 relaxation, distant vision sharp

Tubocurarine

Nondepolarizing neuromuscular blocker Larger skeletal muscles are more resistant to be paralyzed than smaller ones Hand and feet muscles go first Diaphragm is the last to go Lasts 45-60 mins

Rocuronium

Nondepolarizing neuromuscular blocker Most rapid onset (60-120 seconds)

Metocurine iodide

Nondepolarizing neuromuscular blocking agent Methyl iodide of d-Tubocurarine 4X more potent than d-Tubocurarine

How is atropine hydrolyzed

Nonenzymatic ester hydrolysis Doesn't needs an enzyme to break it down Breaks down on its own Shorter half life

Clinical applications of norepinephrine

Nonselective Rapid metabolism, lacks oral activity Limited clinical application used in hypotensive crises

Which transmitters are involved in the sympathetic nervous system? Acetylcholine Norepinephrine and epinephrine Dopamine Serotonin

Norepinephrine and epinephrine

Metabolism of norepinephrine

Norepinephrine to DOPGAL by monoamine oxidase (MAO) DOPGAL can be broken down by aldehyde reductase, aldehyde dehydrogenase, and *catechol-O-methyl transferase* COMT looks for catechol and puts a methyl on one of the hydroxys

Select the 3 phenylethanolamine drugs Methoxamine Metaraminol Phenylephrine Bethanechol

Not Bethanechol

What type (family) of receptor does the thyroid hormone bind to? Where within the cell is it located? What is a thyroid response element? Explain the difference in receptor activity when it is beyond by T3 verses when it is not. What biological process does T3 receptor regulate at molecular level? Cellular level? Resulting physcial responses?

Nuclear receptor superfamily Cell nucleus Specific DNA sequence T3 activivates it DNA Drive gene transcription More DNA is made

Explain the interaction between non-selective beta blockers and powerful sympathomimetics (ex opposed vs unopposed)

O - physiologic ? Activate a1 and b2 (balance effects U - activation of a1 leads to vasoconstriction > inhibition of B2 leads to hyperconstriction and makes HTN worse -relevant in Administration of (high dose) epinephrine or other stimulants or Discontinuation of clonidine (A2 agonist)

Structure activity relationship of acetylcholine is broken down into 3 sections

O-acetyl group (ester) Ethylene bridge Quaternary ammonium

Long term toxicity of glucocorticoids - metabolic effects

Obesity, muscle wasting, osteoporosis, diabetes (Cushing's syndrome)

Levalbuterol

Only R isomer of albuterol Short acting Aerosol, solution Beta agonist

Sympatholytic

Opposite of sympathomimetic. An agent that opposes the effects of the adrenergic or sympathetic nervous system.

Antagonist

Prevents binding of agonist, prevents receptor response Has no intrinstic ability

Fludrocortisone acetate

Oral adminstration of fludrocortisone Used for mineralocorticoid replacement in patients with adrenocorticoid insufficiency, such as addison's disease

Progestogens Origin Effects

Originate from ovaries Mediate menstural cycle and maintain pregnancy

Gluticocorticoids Origin Effects

Originate in adrenal cortex Affect mainly metabolism in diverse ways; decrease inflammation and increase resistance to stress

Mineralocorticoids Origin Effect

Originate in adrenal cortex Maintain salt and water balance

Estrogens Origin effects

Originate in adrenal cortex and gonads Maturation and function of secondary sex organs (female sexual determination

Cromolyn sodium

Prevents release of histamine, does not block it from its receptor Low bioavailability due to poor absoprtion Nasal solution for allergic rhinitis Topically as eyedrops for allergic conjunctivitis and keratitis

SERM MOA

Prevents translocation of steroid receptor complex to nucleus

Drugs enter breast milk by

Passive diffusion Plasma levels rise and push drug into milk Plasma levels fall and drive drug out of milk Ion trapping in milk at pH 7-7.2 3 days you have postpartum gaps that allow most dugs into milk 1 week prolactin closes the gaps and larger drugs cant get thru

Identify a1-AR selective agonists. Physiologic effect? Indicated for? How does ther MOA relate to their use? Why night they be a problem in those with CV disease?

Phenylephrine and Imidazoline sympathomimetics Peripheral vasoconstriction Eye redness and decongestants, Mydriatic Vasoconstriction relieves pressure for decongestant purposes Still increases BP

What enzyme transforms phosphate esters? Are they prodrugs? What does the addition of the phosphate do to the lipophilicity and water solubility?

Phosphatases Yes - except for antiviral drugs (nucleotides) Decreases lipophilicity and increases water solubility

Irreversible inhibitors of acetylcholinesterase

Phosphate esters are very stable to hydrolysis Phosphoric, pyrophosphoric, and phosphoric acids Acetylcholinesterase enzyme is esterified as phosphate esters Hydrolytic regeneration is measured in hours Duration of action is longer Sarin Echothiophate Malathion Aged phosphates

Factors for placental drug transfer by diffusion

Physicochemical properties Drug transfer rate through placenta Duration of exposure Distribution in fetal tissues Development stage Drug combination effects

Non-classical muscarinic agonists

Pilocarpine Cevimeline Does not adhere to traditional SAR Used to treat open-angle glaucoma and Xerostomia (dry mouth)

Direct acting muscarinic drugs Toxicity Treatment

Pilocarpine N/V/sweating, bronchial constriction Rx: atropine

Direct-acting cholinomimetic Preparations avalaible

Pilocarpine (opthalmic topical, sustained release inserts (Ocuserts), oral) - Isopto Carpine Varenicline (oral) - Chantix

FSH and LH are produced from the

Pituitary gland

Gonadotropin works on? This causes?

Pituitary gland and causes it to secreted FSH and LH hormones which stimulate gonads to secrete sex steroid hormones Estrogen leads to female sex characteristics Testosterone leads to male sex characteristics

Endocrine changes in pregnancy

Placenta is a temporary endocrine gland Increase parathyroid size = calcium At term posterior pituitary produces oxytocin At birth anterior pituitary produces prolactin

Mast cell stabilizers are used?

Prophylatically No use once degranulation has occurred

Tubocurarine Medical chem info

Poison dart frog and Chondrodendron tomentosum Used by native Americans in poison arrows and used as a muscle relaxant but largely replaced by safer alternatives Competitive Reversible Nicotinic antagonist Nondepolarizing Prototype for nondepolarizing neuromuscular blocking agent Natural product extract Relatively long acting Only 1% is metabolized in liver and predominately excreted unchanged

L4

Positive evidence of risk to breastfed infant or milk production, but *benefits may be acceptable despite the risk*

Catabolic/anti-anabolic effects of glucocorticoids

Possess these effects in *muscles, skin, peripheral fat, and lymphoid and connective tissue* High concentrations cause decrease in muscle mass and thinning of skin Long term use of glucocorticoids may cause osteoporosis and Cushing's syndrome Reduce growth in children

Bicalutamide and nilutamide

Potent orally active antiandrogens Used in metabolic carcinoma of the prostate

Ketotifen

Potent selective H1 antihistamine Structurally similar to the cyproheptadine Stabilizes mast cells and prevents degranulation of eosinophils Approved in US for allergic conjunctivitis

2-PAM

Pralidoxime Oxide moiety has strongly nucleophilic oxygen atom capable fo cleaving the phosphate ester bond Pyridine ring is common i na number of biochemical systems Cationic change increase affinity of the compound for the anionic binding site of the phosphorylated acetylcholinesterase *only clinically avaliable antidote for poisoning by phosphate ester acetylcholineasterase inhibitors Is effective only before aging*

The only clinical antidote for poisoning by phosphate ester? Pralidoxine Physostigmine Methyldopa

Pralidoxine

Deocycorticosterone

Precursor of aldosterone, secreted about 200 mcg/d Secretion primarily under control of ACTH Secretion gets enhanced in adrenal hyperplasia and adrenal carinomas Turns into corticosterone whihc serves as an immediate precursor to aldosterone

Complete blocking of __ will terminate all three pathways Pregnenolone Progesterone 17 hydroxypregenolone Testosterone

Pregnenolone

Precursor to all adrenocorticoids pathways is? Made from?

Pregnenolone Cholesterol

Histamine

Present in nearly all mammalian tissues Synthesis occurs in mast cells, parietal cells of the stomach, and neurons of the CNS and periphery Plays a role as a chemical messenger in many pathways Small, hydrophilic molecule *imidazole ring, ethylamine sidechain Pka of 5.8 and 9.4 respectively* At physiological pH, is tautomeric mixture of cations *2 pKa values* N on chain is more basic than those in rings At physiological pH it exist as a mixture of cations (mostly monocation > dictations > nonprotanated species) Trans conformation is preferred at both H1 and H2 receptors

Pros to oral contraception

Prevent pregnancy, easy, and reliable May reduce the risk of endometrial and ovarian cancer Can be used as emergency contraception Prevents ectopic pregnancies (miss located)

Mast cell stabilizers

Prevent release of histamine Do not block effects of histamine at its receptor They are not anatagonist or inverse agonists

Opthalmic uses for antimuscarinics

Prevent synechia (iris adhering to cornea/lens) in uveitis and iritis DOC homatropine Dilation of pupils for ophthalmoscopy -atropine -scopolamine -homatropine -cyclopentolate -tropicamide

What do mast cell stabilizers do?

Prevent the release of histamine

Oral (hormone) contraception

Preventing the ovaries from releasing eggs via inhibition of pituitary function (FSH and LH) Thicken mucus in the cervix which prevents sperm from entering the uterus Thinking the endometrium, which prevents a fertilized egg from attaching to the endometrium

Nondepolarizing relaxant drugs

Prevents Ach from reaching its receptor and prevents depolarization D-tubocurarine, atracurium Most NMB are this type Nerve signal can't transmit to the skeletal muscle > muscle relaxes and causes paralysis

Tiotropium bromide

Primarily used for COPD For use in handihaler only 2 thiophene rings in drug Inhaled 30 min onset 24 hour duration Long acting ADR; blurred vision, dry mouth, tachycardia, urinary difficulty, headache Dilation of eyes can exacerbate NAG

Progestins

Primary sire of action is uterus -stops rhythmic contraction of myometrium -causes endometrium to secrete carbs as food for fertilized ovum Most potent is progesterone Used for contraception, amenorrhea, abnormal uterine bleeding, endometrial hyperplasia, endometriosis and infertility Activity is limited to molecules with a steroid nucleus Ethisterone, norethrindrone, norgestrel, levonorgestrel

Aging of phosphorylated acetylcholinesterase

Process in whihc one or more phosphoester bonds are cleaved by the acetylcholinesterase is phosphorylated Product is an anionic phosphate whihc is less electrophilic and less likely to undergo hydrolytic cleavage Does not undergo uncleophilic attack and regeneration by antidotes

A-methyldopa

Prodrug Methyldopa bioactivation: transported across the BBB Active metabolite acts as an antihypertensive agent by inhibiting the sympathetic via agonizing a2 receptor A-methyl dopa > aromatic L-amino acid decarboxylase > dopamine b-hydroxylase > active metabolite

Bitolterol mesylate

Prodrug activated by esterase s in lung to Colterol Nebulized solution only Onset inhaled is 3 min Duration is 8 hours *Ester is lipophilic, localized to lungs* ADR: palpitation, tachycardia, N/V, dizziness, tremor, headache (less drowsiness and restlessness) Short acting Beta agonist

Inverse agonist

Produces the opposite effect of the normal agonist

Which hormones are peaked at day 21? Progesterone GnRH Only LH Only estradiol LH and estradiol

Progesterone

If a baby gets concieved, the hormones __ & __ will be needed to kept the endometrial lining intact. Among these two hormones __ plays the major role in keeping intact endometrial lining

Progesterone & estrogen Progesterone

Biosynthesis of estrogen Luteal phase

Progesterone is made from pregnenolone

Day 21 of menstural cycle

Progesterone peak Estradiol about half of peak at day 14 LH and FSH is low Period and shedding of endometrium

Mifepristone (Dr. Cox)

Progestin, androgen, and glucocorticoid antagonist For hyperglycemia secondary to Cushing's syndrome

What first gen antihistamine blocks alpha adrenergic receptor?

Promethazine

Anabolic

Promotion of cell growth

Androgenic

Promotion of masculine characteristics

Identify the prototypical nonselective beta blocker? B1 selective, but not specific antagonist?

Propranolol Metoprolol and atenolol (more cardio selective effect)

Ethanolamine ethers

Prototype is diphenhydramine Significant anticholinergic side effects -use in Parkinson's disease due to this -sedation with short half life and wide margin of safety make it OTC Duration of action is 12 hours *amine, 2 rings, N on other side, ether* Carninoxamine, doxylamine, clemastine

Theophylline

Purported to act by inhibiting phosphodiesterase causing increase cAMP Relaxes bronchial smooth muscle Metabolized by C8 oxidation (OH on C between NS in 5 membered ring) and N-demethylation *does not exacerbate gout* Has a narrow theraputic window (10-20 mg/L) Overdose causes quick onset of ventricular arrythmias, convulsions, death Available in tablet, capsule, liquid, and parenteral Drugs that increase concnetration include quinolone, macrolide antibiotics, oral contraceptives, and others

Ipatropium bromide

Quaternary amine is not orally avaliable Too hydrophilic ~17% bio avaliable after inhalation, localized to lungs ~83% swallowed and not absorbed Generally used for COPD not asthma ADR; blurred vision, dry mouth, tachycardia, urinary difficulty, headache Dilation of eyes can exacerbate NAG Inhaled 15 min onset, duration less than 4 hours Short acting

Drugs that increase theophylline levels

Quinolone Macrolide antibiotics Oral contraceptives

Reversible vs irreversible cholinesterase inhibitors

R -water soluble -most end in -ium or -mine -carbamic acid ester, Nero stigma exists, physostigmine I -lipid soluble -more harmful/toxic -parathion, malathion

Arformoterol

R, R enantiomer of formoterol Approved for COPD only Nebulizer only long acting Beta agonsit

Levocetrizine

R-enantiomer High affinity and slower dissociated Sometimes classified as 3rd gen

Autonomic nervous system (ANS)

Rapid adjustments to changes in environment Mediated by neurotransmitters released at ganglionic and postganglionic synapses Actions are integrated by the CNS

Reuptake of Norepinephrine

Release is triggered by depolarization-induces calcium influx Norepinephrine binds reversible with adrenoreceptor on the *effector cells (a or B) and presynaptic neuron (a2 receptors)* *about 95% of released NE is removed from the synapse by active transport uptake* Some undergoes metabolism outside of the synapse

Cholinergic nerurons

Release or accept acetylcholine Neurotransmitter for many neurons (autonomic nervous system, somatic nervous system, and CNS)`

Explain exercise intolerance with respect to their effects on the heart

Relevant for beta blockers Limit hearts ability to compensate for increased energy need

Clinical pharmacology of the cholinoreceptor agonist drugs GI system

Relieve paralysis of stomach or bowel after surgery (increase motility of gut) To release stomach/bowel paralysis in people with congenital mega colon or colonic dilation due to inflammatory bowel disease Direct acting cholinomimetic: Bethanechol Cholinesterase inhibitor: neostigmine Pilocarpine can be used for dry mouth

Modification of the quaternary ammonium group of acetyl choline

Replaced N with P, S, As Some activity but are less active and not used clinically Only compounds possessing a positive charge on the atom in the position of the nitrogen has appreciable muscarinic activity 3 methyls > 3 ethyls leads to antagonist 1 methyl > 1 ethyl - decreased agonist activity Replace methyl with hydrogens - decreased agonist activity

Modification of ester group on acetylcholine

Replacing the acetyl group with a functional group less susceptible to hydrolysis Carbamates (ester and amide mix) -far less reactive -carbonyl is less electrophilic -more stable than esters to hydrolysis

What properties for second gen antihistamines have that gives them a more selective theraputic effect with fewer side effects?

Restrict distribution of drug across the BBB Increase selectivity for H1 receptors Decrease selectivity for other H receptors Decrease selectivity for muscarinic, adrenergic, and serotonergic receptors

Rivarstigmine, donepizil, and galantamine are?

Reversible Treatment for Alzheimer's Immediate acting

Edrophoium is

Reversible Used for myasthenia gravis Short acting

What are the indications for terazosin and doxazosin?

Reversible a1 antagonist BPH, HTN

Phentolamine Reversibility Receptor selectivity Indications Theraputic effect Side effects

Reversible and competitive Nonselective (equal for alpha) Pheochromocytoma Reduces peripheral resistance (vasodilation) Hypotension, orthostatic hypotension, *arrhythmia, tachycardia Reflex tachycardia is greater in this because of the non-selectivity*

Prazosin Receptor selectivity Effects on smooth muscle Effects on blood vessles Effects on BP

Reversible competitive a1-AR antagonist Antagonism in vascular smooth muscle limits ability to the SNS to trigger Ca influx (thru EPI/NE) Decrease TPR and increase venous capacitance (blood redistributed in the periphery) Decease BP

Symptoms of Cushing's syndrome

Round face Skinny arms and legs Mental disorders Osteoporosis Central obesity and stretch marks Thin and brittle skin Hyperpigmentation of knuckles

Identify the B2-AR selective agonist What physiologic effect do they have? How does site of administration affect therapy? Indication?

SABA and LABA Relax bronchial smooth muscle (bronchodilation) Topically applied to lungs but you can still get systemic side effects Asthma

Tamoxifen, raloxefen

SERMs Selective estrogen receptor modulators

FX of SNARE proteins and botulinum

SNARE - membrane fusion of Ach vesicle with presynpatic membrane Botulinum - protease that hydrolyze s SNARE proteins and prevents release of Ach

Compare and contrast SNS and PSNS Function Transmitters

SNS (adrenergic) Fight or flight Epi and NE PSNS (cholinergic) Rest and digest Ach

Of the following adrenergic agonists, which one has the greatest receptor affinity? Colterol Bitolterol mesylate Albuterol Salmeterol

Salmeterol

Mineralocorticoids

Salt and water retaining function Ex. Aldosterone

What is membrane stabilizing activity?

Same agents have local anesthetic/membrane stabilizing activity like lidocaine Block propagation of action potential across nerve cell Relevant in beta blockers - typically 3rd gen

Which first antihistamines are most useful for motion sickness?

Scopolamine Promethazine Meclizine, cyclizine, dimenhydrinate

Major functions of glucocorticoids

Secretion controlled by ACTH Increase gluconeogenesis Increases glycogenolysis Increases protein catabolism Decreased antibody response/inflammatory response

Major functions of mineralocorticoids

Secretion influenced by angiotensin II Increase sodium and water retention Promote potassium loss

What is a SERM? Drugs?

Selective Estrogen Receptor Modulators Triphenylethylene antiestrogens (raloxifene, clomifene, tamoxifen)

Doxazosin

Selective a1 antagonist DOA 18-36 h HTN, BPH

Yohimbine

Selective alpha-2 antagonist Indole alkaloid isolated from Pausinystlia yohimbe bark and Rauwolfia roots Dietary supplement in the treatment of male impotence Induces HTN and increases HR No indications by FDA

Esmolol

Selective beta-1 antagonist Has a methyl ester Acid metabolite generated by hydrolysis is essentially inactive and readily excreted as a zwitterion Short acting Used to control supraventricular tachycardia during surgery

Metyrapone

Selective inhibitor of *steroid hydroxylation*, interfere with cortisol and corticosterone synthesis Commonly used in tests of adrenal function

Effect of isotetinoin in pregnancy

Severe birth defects

Androgens and estrogens

Sex steroids Major adrenal androgen and precursor to estrogen is DHEA and DHEAS (dehydroepiandosterone)

What happens to the unfertilized egg?

Shed during period with endometrial lining

Neostigmine, pyridostigmine, physostigmine, ambenonium are

Short acting Treatment for myasthenia gravis Immediate acting Reversible

Corticosteroids and nonadrenal disorders

Since they suppress inflammatory and immune response they are used in the diseases where immune response is the major manifestation of the disease Ex. Transplant rejection, IBS, allergic reactions, skin diseases, eye diseases

Which is easier to predict, the actions of ganglion blocking drugs or the actions of skeletal muscle relaxants?

Skeletal muscle relaxants because the action is at muscles and not multiple types of receptors

Nicotinic receptors are found at *

Skeletal neuromuscular junctions, adrenal medulla, and autonominc ganglia Comprised of 5 subunits Receptors are combinations of alpha, beta, gamma, delta, and epsilon A large number of receptors exist

Factors affecting pediatric drug dosages

Skin is thin and permeable Lungs have weaker mucus barriers Liver and kidneys are immature, impairing drug metabolism and excretion Stomach lacks acid to kill bacteria Body temperature less well regulated and dehydration occurs easily

Endocrine system

Slow more generalized adaptioation Medicated by hormones released into circulation Effects at distant sites Effects appear over minutes to hours or days Actions are integrated by the CNS

Hydrocortisone sodium succinate

Slowly and incompletely hydrolyzed Peak levels in 30-45 min Used for *IV/IM injection in the management of emergency conditions* that cane be treated with anti-inflammaotry steroids

Acetylcholine

Slows heart and makes you need to go to the bathroom Water, sweat, salivation Contracts gut

What type of molecule comprises most allergens? How is this relate to the immune systems defense against parasitic infections?

Small protein molecules The parasite attaches and damages cells which release small proteins that are recognized by the immune system and histamine and leukotrienes are released to physically expel the parasite

Tissue distribution and function of H1 receptor subtype

Smooth muscle, endothelial cells, and CNS Contractile response (increase permeability) and wakefullness

Where are Cys-LT1 receptors located in the body?

Smooth musclein lungs, intestine, spleen, and peripheral leukocytes

Aminoglutethimide

Steroid synthesis enzyme inhibitor *block conversion of cholesterol to pregenolone* Causes decreased synthesis of all steroids Can be used to treat sx of Cushing's syndrome and to eliminate estrogen production in breast cancer patients

Ketoconazole

Steroid synthesis inhibitor Inhibits cleavage of cholesterol side chain Can be used to treat sx of Cushing's syndrome

Which drugs block testosterone production?

Steroid synthesis inhibitors Ketoconazole Antiandrogen

Azelastine

Some structural similarities to benzimidazoles Used as nasal spray for allergic rhinitis and as eyedrops for allergic conjunctivitis Inhibits mast cell release of inflammatory mediators Oral adminsitration - N-dealkylated metabolite appears to be active High incidence of bitter taste Dual acting

How does tamsulosin differ from other a1 blockers? Is this clinically relevant?

Specificity for alpha 1a and 1d No clear clinical benefit

Differences in actions of steroids are due to

Specificity of steroid receptor proteins Particular genetic process initated Specific cellular proteins produced

Nonoxynol-9/ Gynol II vaginal gel

Spermicidal gel (kills sperm) Can be used with other barrier methods such as condoms, diaphragm Vaginal yeast infections interact with this medication ADR: -allergic reactions (skin rash, itching, hives, swelling, irritation, itching, burning), thick white or curd-like vaginal discharge, chills and fever, pain in bladder or lower abdomen, pain on urination/trouble passing urine or change in the amount of urine

Liver function in babies

Start off low and don't get full CYP3A4 fx until the first year Opoids can kick start the CYP formation and require more of these drugs to get the effect

Mechanism of steroid hormone action

Steroid hormones act on target cells to regulate gene expression and protein biosynthesis via formation fo steroid-receptor complexes Complex interact with particular regions of DNA (inside cell), called hormone-responsive elements (HRE) Binding of the complex to DNA initiates transcription to produce mRNA Elevated levels of mRNA lead to increase in protein synthesis (enzymes, receptors, and secreted factors

Pancuronium bromide

Steroid-based neuromuscular blocking agents Belong to aminosteroids chemical class Long duration of action May cause increase HR and BP Undergoes hydrolysis in the liver Nondepolarizing agent

Steroid nomeculature and structure

Steroids consist of 4 fused rings Chemically these are *cyclopentanoperhydrophenathrenes* -contain a 5 membered cyclopentane(D) ring plus the three rings of phenanthrene

Adrencorticosteroids

Steroids produced and released by adrenal cortex Release is controlled by pituitary release of ACTH Three catagories are gluticocorticoids, mineralocorticoids, androgens, and estrogens

Nonsteroidal estrogens

Still been derivatives found in 1930s have estrogenic effects Diethylstilbesterol was used extensively for pregnancy complications Cancer from in utero exposure Other estrogens in high doses may also increase risk of cancer

Explain why you might see bronchoconstriction/bronchospasm? What would this mean with respect to precautions/contraindications?

Still have some affinity for B2 antagonism even with selective beta blockers (even tho it is less and a less common side effect) Constricts lungs Watch out for asthma and COPD patients

Functions of the thyroid gland

Stimulate lipid metabolism Regulates rate of gluconeogenesis, cellular uptake of glucose, intestinal absorption of glucose, and glucose uptake by adipose tissue Stimulates production of mRNA for growth hormone, Na/K ATPase/beta receptor Inhibits production of mRNA thyrotropin releasing hormone

How to stop estrogen induced breast cancer

Stop: -transcription of growth factors -Proteins necessary for cell proliferation -stop survival and proliferation of breast cancer cells

Neostigmine (prostigmin)

Structural features of both physostigmine and acetylcholine Has quaternary ammonium group Lacks CNS activity Treats urinary retention

Piperazine antihistamine

Structurally related to both ethylenediamines and alkylamines Treatment for motion sickness Anticholinergic side effects (causes sedation) Cyclizine, Chloe cyclizine, meclizine, buclizine, oxatomide, hydroxyzine, ceterizine

Loratidine

Structurally related to first gen tricyclic antihistamines Lacks cardiotoxicity Duration of action is 24 hours Omega-1 oxidation and hydrolysis converts it to desloratidien

Permanent birth control

Surgery to block the Fallopian tubes Having an insert put into each Fallopian tube Surgery to tie off the tubes that carry sperm (vasectomy)

What neuromuscular blocking drugs are used for

Surgical produces Tracheal intubation Control of ventilation Treatment of convulsions

Sum of effects from angiotensin II

Sympathetic activity (fight or flight) Tubule Na, Cl, H2O retention and K excretion Aldosterone secretion (further enhances retention and excretion) Arteriolar vasocontriction > increase in BP ADH secretion from the posterior pituitary > water reabsorption in the collecting duct

Chemical transmission takes place between the nerve cell and their effectors (could be another nerve, or tissue) in the place called

Synaptic cleft The transmitter binds the receptors in the post synaptic cell and activate or inhibit it. Drugs can mimic or block the actions of these transmitters and in turn can modify these autonomic function

Biosynthesis of adrenocorticoids

Synthesized from cholesterol Cholesterol is stored in the adrenal glands as a cholesterol lipid ester ACTH released from pituitary acts on receptors at the adrenal gland G protein receptor binds to ACTH > activation of adenylate cyclase > increased cAMP > activation of cholesterol esterase Cholesterol esterase cleaves ester and gives free cholesterol

PK and PD of synthetic corticosteroids

Synthesized from cholic acid Rapidly and completely absorbed by the mouth Bind to the same intracellular receptors and produce the same effect as cortisol May have a different affinity to the receptors, different ratios of glucocorticoid to mineralocorticoid potency, different metabolic products, excretion rate, etc Can be given as a prodrug (prednisone converted to active prednisolone)

Progestin

Synthetic progestin MOA similar to estrogen (binds to receptor > transcription of growth factor > activation of cell signaling pathways > proteins necessary for cell growth and proliferation > cell growth, survival, development of secondary sexual characteristics, endometrial lining buildup, influence other hormone secretion)

Which thyroid hormone is more potent?

T3 5x more

Tamoxifen

TAM, antiestrogen One of current Tx for breast cancer Can lead to TAM resistance and enhanced risk of uterine cancer

Pilocarpine

Tablet, opthalmic solution, and gel Subjects to hydrolysis and epimerization Solutions can be stored at room temperature, but the gel should be refrigerated and labeled with a 2 week expiration date when dispensed

First drug approved for the treatment of AD Bethanechol Methoxamine Tacrine

Tacrine

Biosynthesis of epinephrine

Takes place in *adrenal medulla* L-tyrosine undergoes 3 steps to be converted to norepinephrine -tyrosine hydroxylase to L-dopa (tyrosine hydroxylase) -L-dopa to dopamine (aromatic L-amino acid decarboxylase) -dopamine to norepinephrine (dopamine beta-hydroxylase) Norepinephrine is converted to epinephrine by phenylethanolamine-N-methyltransferase

Thalidomide

Teratogen 1960's sedative/hypnotic Results in Amelia/phocomelia FDA pregnancy safety catagories development STEPS program (System of Thalidomide Education and Prescribing Safety) Clinical trials species selection with a sensitive window during 4-7 weeks

Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in late trimesters), and the possibility of fetal harm appears remote

Teratogenic category A

Either animal-reproduction studies have not demonstrated a fetal risk, but there is not controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).

Teratogenic category B

Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryo cidal or other) and there are no controlled studies in women or studies in women and animals are not avaliable. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Teratogenic risk C

There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg. If the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Teratogenic risk D

Studies in animals or human beings have demonstrated fetal abnormalities or there is or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Teratogenic risk X

Which short acing b2 adrenergic agonist has an injectable form used off label in the management of preterm labor? Tacrine Bethanechol Terbutaline

Terbutaline

Identify second generation antihistamines (McCune - some may by classed as 3rd gen by Cox)

Terfenadine Astemizole Fexofenadine Loratidine Desloratidine Cetirizine Levocetirizine Acrivastine

2nd and 3rd generation nonsedating H1 antihistamines

Terfinadine metabolizes for fexofenadine in the body Cetirizine > levocetirizine Loratidine > desloratidine Acrivastine *3rd gen derived from a 2nd gen antihistamine- a metabolite or more potent enantiomer*

Which of the following drugs cannot be used to treat prostate cancer? Bicalutamide Testosterone Nilutamide Flutamide

Testosterone

The potent androgen found in the blood is __, with the more potent metabolite formed in certain androgen target tissues being __

Testosterone 5-alpha-dihydrotestosterone (DHT)

Leydrig cells produce

Testosterone Required for sperm production Most important androgens in humans

Common drugs detected in milk

Tetracycline Lithium Barbiturates, diazepam Opoids (heroin, methadone, morphine) Alcohol, nicotine, and caffeine Radioactive iodine Cancer chemotherapy

__ and __ had shown a great deal of interest to performance-enhancing area because their use was difficult to detect

Tetrahydrogestirone (THG) Desoxymethyltestosterone (DMT)

Doxacurium chloride

Tetrahydrosoquinoline based neuromuscular blocker Nondepolarizing Does not undergo Hoffman elimination and not metabolized by plasma cholinesterase Longest duration of action of THIQ NMB

Prostaglandin E1 in babies

Tetralogy of fallot

Biosynthesis of estrogen

There are 2 phases (follicular and luteal phase) Different intermediate products in each phase Luteal phase progesterone is made from pregnenolone Follicular phase DHEA is made from pregnenolone Bothpathways lead to the production of androgens Androgens will be converted to estrogens using enzyme aromatase

How do the thioureal drugs inhibit T3/T4 synthesis? Potentially fatal rxn?

Thiocarbamide Inhibit Rx of thyroid hormones by interfering with synthesis Agranulocytosis (propylthiouracil has lower risk because it occurs in the peripheral tissues

Chemical group that is essential for anti-thyroid activity of thioural drugs.

Thiocarbamide NH - C = S

Clinical pharmacology of the cholinoreceptor agonist drugs Glaucoma

To relieve IOP Direct acting: pilocarpine Cholinesterase inhibitors: physostigmine Combination of those 2 Contract ciliary muscle of the eye leading to outflow of aqueous humor and leads to decreased IOP

Lodoxamide (Alomide)

Topically in the eye, primarily for onjunctivitis and keratitis Structurally similar but still a mast cell stabilizer

Placenta

Transitory organ - only one that the body makes Latin for "cake" Day 26 completed (about 3 weeks) Functions similar to liver -gas, nutrient, waste exchange -produces hormones -accumulate glycogen -produces progesterone (maintains pregnancy)

A1 agonist

Treat *hypotension* during surgery or severe hypotension accompanying shock Phenylethanolamines (metraminol, methoxamine, and phenylephrine) - not substrates for COMT, longer DOA than NE

Why give antiarrythmic drugs (Procainamide) to babies?

Treat fetal arrythmias

Clinical pharmacology of the cholinoreceptor agonist drugs Accommodative esotropia (crossed eyes)

Treated with higher dose of cholinoreceptor agonists

Brimonidine

Treatment of glaucoma probably reducing aqueous humor production and increasing outflow A2-adrenergic agonist 2-aminoimidazolines

Apraclonidine

Treatment of glaucoma probably reduction of aqueous formation Stimulation of a2 receptors in the eye reduces production of aqueous humor and enhances outflow of aqueous humor A2-adrenergic agonist 2-aminoimisazoline

Fluticasone proprionate

Trifluroinated glucocorticoid 17-beta-carbothioate, 17-alpha ester proprionate Designed to be susceptible to metabolic deactivation Thioester rapdily cleaved to inactive carboxylate

Atropine

Tropine chirality insignificant Acid chirality, R 100 fold more active than S Phenyl stereochemistry disrupts carbonyl binding to tyrosine if not in R absolute configuration Really short acting

Biosynthesis fo norepinephrine

Tyrosine is oxidized to L-dopa by *tyrosine hydroxylase (rate limiting step)* L-dopa is decarboxylated to dopamine by *aromatic L-amino acid decarboxylase* Dopamine is stereospecifically hydroxylated to norepinephrine (R configuration) by *dopamine B-hydroxylase*

Bethanechol Clinical use Toxicity Clinically important

Urinary retention, decreased GI motility, decreased lower esophageal sphincter Parasympathetic effects if absorbed systemically Caution in those with asthma, COPD, urinary/GI obstruction, CV disease, hypotension, or bradycardia Direct acting

Sx of hyperthyroidism

Weight loss Decreased cholesterol Tachycardia Heat intolerance Nervousness, irritability Sweating Fine, brittle hair Goiter

Physostigmine ___ absorbed Used in

Well absorbed Can be used topically in the eye Readily distribute to the CNS

Echothiophate used for Duration of action

Used for opthalmic use Duration of action is longer than others

Propranolol

Used in CNS disorders (performance anxiety) becuase of high lipophilicity, penetrates BBB *may induce disturbing CNS effects, including nightmares* antihypertensive properties

Prednisolone tert-butylacetate

Used in suspension form and by IM injection Has a long DOA because of low water solubility and a slow rate of hydrolysis

Hydrocortisone butyrate and buteprate

Used topically

Pemirolast (Alamast)

Used topically in the eye to prevent itching associated with allergic conjunctivitis

Cortisone acetate

Usually corticosteroid of choice (along with hydrocortisone) for replacement therapy in patients with adrenocortical insufficiency, because these drugs have both glucocorticoid and mineralocorticoid properties Slowly absorbed from IM injection sites over 24-48 hours and is reserved for patients who are unable to take the drug orally Increased stability and a longer DOA when administered IM

Antimuscarinincs for vasovagal attack

Vagal discharge associated with MI from too much Ach Causes heart to slow down and sends more blood to periphery Antimuscarinings releive impairment of CO due to depression of SA node Parenteral atropine or any other antimuscarininc drug can be used

Toxic drug actions to fetus - Diethylstilbestrol (DES)

Vagina adenocarcinoma in multiple generations

What are the effects of high or pharmacological doses of epinephrine on: Vascular smooth muscle Vascular endothelial cells Bronchial smooth muscle Heart TPR BP

Vascular smooth muscle - contraction Endothelial - reformation of tight junctions (not permeable) Bronchial - relaxation/bronchodilation Heart - positive inotropic/chronotropic effects (may vary due to cholinergic reflex opposed to peripheral resistance) TPR - increase BP - increase

Alpha 1

Vasoconstriction Activation of of smooth muscle increases Ca levels leading to contraction

How does a1 blockade contribute to therapeutic efficacy?

Vasodilation

Physiological symptoms caused by histamine

Vasodilation Bronchoconstriction Mucus secretion Cough Itching

Blockade of B1 on RAAS

Vasodilation, diuresis

Salmetrol

Very long lipophilic side chain onto albuterol Long acting compared to albuterol Used to treat severe persistent asthma Not a substrate for COMT Long DOA results from specific binding interaction (anchoring) of the phenyl group at the end of the side chain with a specific region of the b2 receptor > affords salmeterol with a unique binding mechanism

Drug interactions of neuromuscular drugs

Volatile anesthetics Antibiotics Local anesthetics and antiarrythmic drugs Other neuromuscular blocking drugs Can potential employers the effects of skeletal muscle relaxants/neuromuscular blocking drugs

What role does histamine play in the sleep-wake cycle

Wake promoting

Prednisolone sodium phosphate

Water soluble salt of 21-phosphate ester Half life les than 5 min due to hydrolysis from phosphatases Peak levels in 10 min after injection Topical used as 1% opthalmic

Phtalates

Xenoestrogens Plasticizers (increase flexibility of plastic polymers) Lipophilic ester of phthalic acid Uncertain modulation of endocrine function High doses in animals change hormone levels and cause birth defects 4 are banned in the European Union as of July 2017 (butylbenzyl phthalate, Di-n-butyl phthalate, Di(2-ethylhexyl) phthalate, and diisobutyl phthalate)

In the estrogen/testosterone pathway, what happens if you block aromatase

You block the conversion of testosterone to 17-beta-estradiol and androstenedione to estrone Prevent formation of the the major form of estrogen in reproductive females (17-beta-estradiol)

Neonate or newborn infant

Younger than 1 month

Preterm infant

Younger than 38 wk gestation

What is DHEA?

Youth hormone

Mark I kit

a two-part auto-injector set the military uses as treatment for nerve-agent exposure; involves the administration of atropine and then pralidoxime chloride. Atropine: cholinergic antagonist Pralidxoine chloride: regeneration of acetylcholinesterase from inactivated state

Tizanidine

a2 adrenergic agonist 2-aminoimidazoline Used in reducing speciality associated with cerebral or spinal cord injury *presynaptic inhibition* of motor neurons at the a2 adrenergic receptors sites, reducing the release of excitatory amino acids and inhibiting facilities ceruleospinal pathwyas

Tamsulosin

alpha 1 antagonist Selective for alpha-1a in the prostate No quinazoline benzenesulfonamide BPH

Ganglion blocking drugs

block the action of Ach at nicotinic receptors in the autonomic ganglions Can prevent later cholinergic and adrenergic functions Tetaethyl ammonium Hexamehonium Mecamylamine Trymethaphan

Cycloplegia

blurred vision Weakening of the contraction of ciliary muscles

All steroid hormones are derived from

cholesterol

Choline > acetylcholine

choline acetyltransferase uses acetyl CoA to attach an acetyl group to choline to form acetylcholine

Sympathetic nervous system

fight or flight Adrenergic receptors are involved Sweat glands here use choline Increase NE, HR, energy, sugar in blood, blood supply to muscles Decreased GI movement

Role of estrogen in breast cancer

i. Growth of breast tumor depends on estrogen. ii. Estrogen promotes cell replication by binding to the nuclear estrogen receptor which then binds to nuclear elements in the target genes and promotes gene transcription. iii. Estrogen induced cell proliferation leads to the manifestation of breast cancer. iv. Early menarche, late menopause, and estrogen replacement therapy are risk factors for breast cancer,

Conventional therapies for breast cancer

i. Selective estrogen receptor modulators (tamoxifen and raloxifen) are current treatments of choice for estrogen receptor positive breast cancers. ii. These are not the best drugs to treat the disease due to being less sensitive in ER negative breast cancers, some of the ER positive breast cancers can develop resistance to these medications, and include side effects such as development of uterine cancer, development of deep vein thrombosis, and pulmonary embolism in patients. iii. Anti-Her2 monoclonal antibodies 1. Herceptin and Trastuzumab 2. Widely accepted therapy for breast cancer 3. Herceptin cannot be used for HER2 negative breast cancers iv. Systemic chemotherapy can also be used to treat metastatic breast cancers. Unfortunately there ate many undesirable side effects with this option and new treatments need to be explored.

Formoterol

long acting B2 agonist Less lipophilic than salmeterol DOA is 12 hours Highly potent compared to salmeterol Unstable to heat and moisture so used as inhaled dry powder *R isomer has 1000x more affinity for the b2 receptor than s isomer* Due to high potency and low dose there is no clinical advantage for using r enantiomer as a bronchodilator compared to race mate *higher potency and faster onset of action compared to salmetrol*

Spironolactone

mineralocorticoid antagonist Reversed manifestations of aldosteronism Also a diuretic (*keep more salt and water in kidney tubule*) Has benefits in HF as well as an androgen blocker ADR: hyperkalemia, metabolic acidosis, and cardiac arrythmia

Tocolysis

repression of uterine contractions Cutting contractions

Terazosin

selective alpha 1 antagonist DOA >18 h HTN, BPH

Prazosin

selective alpha 1 antagonist Quinazoline ring, piperazine and a unique acyl moiety Modifications at the acyl moiety affect DOA Antihypertensive agent DOA 4-6 hours Does not increase HR and CO, only vasodilates

Alfuzosin

selective alpha 1 blocker Quinazoline derivative with a rotatable propylenediamine group Selective for alpha-1a in prostate BPH Not used for HTN

Terbutaline

short acting B2 agonist Avaliable as inhalation and injection Injection used offlabel for management of preterm labor Relaxes the uterus and maintains pregnancy for 24-48 hours in the majority of cases

Albuterol Difference between isomer

short acting B2 agonist Non catechol derivative Sold as racemic mixture -*S > bronchial muscle contraction,* slow metabolism -*R > bronchodilation*, fast metabolism

Levalbuterol

short acting beta 2 agonist Non catechol derivatives R-enantiomer Reduced side effect 1/4 dose of albuterol to attain same bronchodilation effect of albuterol Bronchodilation, fast metabolism