Phosphodiesterase Inhibitor 

 - such that CAMP does not get degraded 

Phosphodiesterase Inhibitor

- prevents CAMP from being degraded to 5' AMP

Phosphodiesterase Inhibitor

- which prevents CAMP from degradation to 5' AMP

Tx Impotence 

Phosphodiesterase Inhibitors 

- which prevents CGMP from degradation to 5' GMP which can lead to severe vasodilation 

TX Impotence 

Carbonic Anhydrase Inhibitor 

Make Urine Basic

Increases the excretion of weak acids by making urine alkaline

 Salicylic Acid hyrdrolyzed from apsirin is a weak acid

TX of Glaucoma

Decrease the production of aqueous humor 

S/E: headache, dec libido, kidney stones, etc 

say no to p.o.

Makes Urine Acidic

Increase the excretion of weak bases

Ex. Amphetamine

SLOW acetylators 

hepatic damage and blood dyscrasias

SLOW acetylators

Relaxes Vascular Smooth Muscle to Lower BP

Increase HR via the arterial baroreflexes 

INDIRECT 

lupus-like syndrome

SLOW acetylators 

lupus-like syndrome 

Cholinergic agonist

Cardiac: (i.v.) causes a rapide and transient decrease in BP (via NO in endothelial cells) and baroreflexly-mediated tachycardia 

After TX with Atropine the i.v. injection increase BP and heart rate by stimulating N1 cholinergic receptors at symp ganglia

Eye: cause rapid and complete MIOSIS

Tertiary Amine

Degraded by hepatic enzymes not AChase or pseudocholinesterase

TX: Dry mouth and Dry eyes (Sjogren's syndrome)

TX of Glaucoma

MOA: Contracts the meridional fibers of the ciliary muscle increasing the IC angle or tone of the trabeculae allowing better flow of aq humor

Can cause fixation of the lens for near vision

Persistent miosis causes poor night vision (headache)

Contraindicated: asthma & COPD, peptic ulcer, atrial flutter

B-adrenoreceptor antagonists, selective for beta 1 

TX Glaucoma and IOP, w/ no effect on visual accomodation or pupillary size , by reducing aqueous humor production. 

MOA: Decreases prodcution of aq. humor

Can cause bradycardia

B adrenoreceptor antagonist (b1 & b2)

TX Glaucoma and IOP

MOA: decrease aqueus humor 

Side Effects: Can cause bronchoconstriction 

Stable analog of PGF (2alpha)

TX Glaucoma and IOP

Increase uveoscleral outflow 

more efficacious than unoprostone 

alpha Adrenergic Agonist

Increase normal outflow

Cause MYDRIASIS w/ dipivefrin bound to it due to alpha 1 stimulation of radial muscle

TX Glaucoma and IOP

MOA: alpha 1 - enhances outflow of aqueous humor via the normal pathway

MOA: Lower IOP by increasing the amount of ACh available to contract meridional fibers of the ciliary muscle 

Carbamate ACHase inhibitors

Tertiary amine - freely enters CNS

MOA: 1. noncompetitive, slowly reversible inhibition of AChase

2. Cause carbamoylation of AChase active site

3. No direct affect at ACh receptors

TX. Alzheimers (improves behavior and cognition)

many side effects 

excacerbates Parkinson's

too much = cholinergic crisis

too little = myasthenic crisis 

Organophosphate AChase inhibitors

insecticide for lawns and gardens

insecticide 

1. converted to active metabolite by p450

2. causes many accidental deaths

Insecticide

1. used to kill lice

2. safer than parathion

3. used to kill mosquitos

TX of Organophosphate Poisoning

quarternary

NOT USE for carbamate insecticides 

Muscarinic receptor antagonists 

block peripheral and central muscarinics 

* exhibits differential sensitivity to atropine sulfate 

* not expressed when the drug is given in normal therapeutic doses

* decrease production of saliva or pulmonary secretions

* counteract bradycardia

* blocks SE of neostigmine and pyridostigmine

TX motion sickness

GI Disease

TX overactive bladder

Direct Antispasmodic effect on detrusor

May cause drowsiness, somnolence, dizziness

* DO NOT USE IN ELDERLY

TX Overactive bladder 

S/e somnolence, dry mouth, blurred vision, and constipation

no CNS or CV effects

less dry mouth compared to oxybutynin, tolteridine and trospium

Muscarinic receptor antagonists (quaternary)

quartenary cmpd

Muscarinic receptor antagonists (quaternary)

* used to decrease the production of saliva/pulmonary secretions

* counteracts bradycardia caused by ocular pressure

Muscarinic receptor antagonists (quaternary)

nicotinic receptor agonists

1. Adverse effect on plasma lipid profile

2. endothelial cell dysfunction

3. increased platelet aggregation 

4. neutrophil activation and aggregation

5. increased transcapillary escape of albumin

6. insulin resistance and hyperinsulinemia

7. cardiac dysrhymias via carbon monoxide

IV injection causes an initial, single contraction of skeletal muscle followed by a flaccid paralysis 

Flaccid paralysis is caused by the constant depolarization of the motor endplate = noncompetitive block 

degraded by plasma cholinesterase 

N-1 receptor antagonis = ganglionic blocking drugs 

used to produce controlled hypotension during head and neck injury 

can also cause further dilation 

Adrenergic agonists 

(selective for alpha 1)

Decrease HR 

INDIRECT via baroreflexes

Increase TPR, Increase DBP 

SV NOT CHANGED b/c Starling 

Vasoconstrictive with local anesthetic or CO and tissue perfusion are normal

Dopamine

(including receptor preference)

Dobutamine

A1 > A2

Alpha-adrenoceptor antagonist

* non-competitive receptor blockade due to alkylation of receptors

S/E: Fainting 

used to reverse ischemia and tissue necrosis caused by extravasated dopamine from veins during iv

relieve urinary obstruction 

prazosin ( treatment of peripheral vascular disease ie frostbite, vasospasm) 

beta-adrenoceptor antagonists

alpha -adrenoceptor antagonists 

alpha 2 > alpha 1

causes tachycardia, tremor, and slight increase BP

lowers BP in hypertensive pts (not helpful in pheochromocytoma pts)

highly lipid soluble 

Alpha 2 > Alpha 1

constricts cerebral blood vessels by acting as a partial alpha agonist 

TX - migraine headache -- many s/e

Sympatholytic drugs

Decrease release of NE from sympathetic neurons --> Reducing TPR --> reducing BP

HR decreased, TPR decreased, DBP decreased

balanced vasodilation

TX hypertension in pregnant women and children because its not teratogenic 

Sympatholytic Drugs

MAO: 1. destorys storage vesicles for neurotransmitter in central and peripheral neurons

2. NE release is not inhibited 

Effects: Balanced Vasodilation

Decreased HR, CO is unchanged 

S/E: teratogenic, orthostatic hypotension, sexual dysfunction

Chronic decrease in the neuronal release of NE results in up-regulation of a and B receptors -- supersensitivity

Alters NE Metabolism

MOA: 1. local anesthesia (blocks Na channels)

2. noncompetitive blockade of uptake 1 (NE accumlates in nerve junction = vasoconstriction)

3. acts centrally to increase peripheral sympathetic flow

4. euphoria and addiction from DA stimulation in nucleus accumbens

Increase BP and HR

Sodium

What happens when ion conductance is increased?

Decreased ion conductance? 

Increase = rapid depolarization

Decrease = no depolarization 

Potassium 

What happens when ion conductance is increased?

Decreased ion conductance? 

Increase = rapid hyperpolarization

Decrease = decreased membrane potential membrane

Chloride 

What happens when ion conductance is increased?

Decreased ion conductance? 

Increase = rapid depolarization

Decrease = decreased membrane potential difference

Calcium

What happens when ion conductance is increased?

Decreased ion conductance? 

Increase = slow depolarization

Decrease = no depolarization

A patient with increase ACh release. 

How is ion conductance related?

Where type of receptors are involved and where are they located?

Sodium ion conductance increases. 

Coupled to N1-cholinergic receptors located in sympathetic and parasympathetic ganglia and N2 cholinergic receptors at the neuromuscular junction. 

A patient given inhibitory amino acids would be expected to exhibit ______?

Name 2 inhibitory amino acids

Increased Chloride Conductance

1. GABA

2. Glycine

Properties of lipid-solube compounds on transmembrane travel.

Name 3 important ones:

They freely cross the cell memrbane and bind to cytoplasmic receptors. 

Corticosteroids, Aldosterone, Vitamin D

Barbiturates

Volatile Anesthetic gases

propofol

ETHANOL

Role of excitatory amino acids on ion conductance.

Name two important ones.

Increase in Sodium and Calcium conductance

1. Glutamate [kainate, AMPA, NMDA receptors]

2. Aspartate

Activates adenyl cyclase -> cAMP -> degraded by PDEases to 5'-AMP

PDEases inhibited by theophylline, caffeine and papaverine

Cannot say. It may have no effect on free intracellular Calcium 

Ex. Beta2 adrenoceptors causes relaxation of vascular smooth muscle 

Vascular endothelial cells - constitutive

Marcophages, neutrophils, smooth muscle cells - induced by cytokines

Vasodilation

Decrease BP

inhibits platelet adhesion and aggregation

inhibts neutrophil adhesion to vascular endo

neurotransmitter in CNS

Erection 

 = 1/Kd = 1/ (k2/k1)

ability of drug to form a stable complex with receptor

Biological effectiveness of a drug receptor complex 

- quantal response when one drug molecules occupies one receptor 

Competitive = reversible

Non-competitive = irrversible

for non competive -- tissue must synthesize new receptors before the reponse to the agonist can be restored completely

the tissue response to the drug dimishes 

a. decrease in receptor number

b. decrease in efficiency of signal transduction

example: ethanol

If intercept of x-axis moves right = increase receptor

If interecept of x-axis moves left = decrease receptor

Steeper slope = greater the affinitu

Efficacy - max clinical effect (which one does the most)

Potency - the dose of drug required to achieve a particular affect 

LD (50)/ ED (50)

Death / Anesthesia of 50% of subjects

PDynamics -What the drug does to your body

PKinetics - What your body does to the drug

Buccal - rapid, high FIRST PASS

Per os - absorption is low

Rectal - decreased FIRST PASS

IV - rapid

IM - rapid, good for depot

SQ - rapid for aqueous preps

Intrathecal - high local concentration

Oil/Water coefficient

10 is very soluble and will easily pass through membranes 

0.1 indicates that the drug is poorly lipid-soluble

Phase 1 - changes the chemical structure of the drug by oxidation, hydroxylation, deamination and dealkylation 

Phase 2 - involve the conjugation of drugs to endogenous compounds

By manipulating the urinary PH we can keep ions in the urine

- acidic things are trapped in the urine by an acidic pH

- basic things are trapped/excreted in urine by alkaline pH

Free drug travels easily through capillaries to interstitial fluid

Free drug has difficulty passing through cell membranes unless it is very lipid or actively transported 

Location of 

N1 receptors

Symp and Parasymp ganglia

Adrenal Medulla 

Location of 

N2 receptors 

Cholinergic 

Motor end plate of skeletal muscle 

Smooth muscle (bladder, intestine, lungs, heart)

Sweat glands

Prejunctional sites of on symp & parasymp neurons

Surface of endothelial cells 

Iris

Radial Muscle

ALPHA-1 Adrenergic: 

Contraction = mydriasis

Iris

Sphincter Muscle 

Cholinergic (muscarinic)

Contraction = MIOSIS (decrease in size)

Cholinergic (muscarinic)

Contraction = near vision 

hemicholinium

ACh - on its own M2 receptors

NE - Alpha 2 on heteroreceptors

Opiates - inhibts in GI tract

MOA: binds to surface protein and transported into cholinergic neurons; protease hydrolyzes protein involved in synaptic storage and exocytotic release of ACh

3. Cholinergic neurotransmission ceases in the nerves which supply the NMJ

Causes: spastic paralysis

* acts within the spinal cord preventing release of inhibitory neurotransmitter 

enzyme that chews up acetylcholine

localized: neuronal membranes, NMJ, RBC's

Recovery time: 2-3 months

preferred substrates: succinylcholine 

procaine

localization: plasma, liver, brain, GI smooth muscle

Recovery: 2 weeks

Pressure Pathway = flow through anterior part of lens --> anterior chamber --> exit Canal of Schlemm (IC angle) --> trabeculae 

Uveoscleral = flow into spaces within the ciliary muscle and tissue surrouding sclera (5-25% of normal outflow)

Intraocular Pressure

(define & utility as indicator)

Pressure measured on the anterior chamber of the eye

clinical indicator for glaucoma 

narrowing of the IC angle inhibiting outflow

Cause: MYDRIASIS (which can be drug induced by cyclopentolate)

Symptoms: blurred vision, pain, redness, sweating, nausea, vomiting 

(95% of patients) 

flow of aqueous humor through Canal of Schlemm is impeded due to poor tone or alignment of trabeculae 

Drugs classes necessary to treat IOP

(name the drugs in each class)

3 drugs that do the following:

1. Decreases Outflow normal path

* Beta adrenoreceptor antagonist

* Carbonic anhydrase inhibitors

* alpha adrenoceptor agonists 

2. Increase Outflow normal path

* PGF (2 alpha) analogs

3. Increase Outflow the Uveoscleral path

* alpha adrenoceptor agonists

* pilocarpin, isofluophate

Selective alpha 2 adrenoceptor agonists

Decrease the rate of production of aq. humor

Stable analog of PGF (2alpha)

increase uveoscleral outflow

not as good a latanoprost 

msk - weakness, cramping

symp ganglia - tachycardia, hypertension

Atropine sulfate (tertiary) - block peripheral and central muscarinics

Praidoxime (quartenary) - regenerates enzyme in periphery

Atropine sulfate

Metabolic effects of IV infusion of EPI and NE during excercise or hypoGlycemia

Glucose (plasma)

Insulin release

FFA (plasma)

Lactic A (plasma)

Oxygen consump

K (plasma) 

                                    EPI                   NE

Glucose (plasma)   B2     ++                   0/+

Insulin release       A2     -                      - 

FFA (plasma)         B1     ++                   0/+

Lactic A (plasma)    B2    ++                   0/+

Oxygen consump            ++                   0/+

K (plasma)            B2     ++                   0/+

CNS effects of EPI and NE during excercise

Anxiety

Respiration

Tremor

                            EPI                       NE

Anxiety                 ++                        0/+

Respiration            +                          +

Tremor                  +                          +/0

EPI = Beta 2 (arterial msk)> Beta 1 > alpha

NE = alpha (arterial GI & kid.) > beta1 > beta 2

small iv dose:

Increase vasodilation (Beta 2)

Decrease in TPR and DBP

Increase in SV, SBP, contractility

Large iv dose:

Vasoconstriction (alpha)

Increase TPR and DBP

Increase in SV, SBP, contractility

* blood decreases in kidney, GI tract and skin

alpha and beta 

bronchodilator in astma and COPD patients

Vasoconstrictive w/ local anesthetic 

DOC for TX anaphylactice reactions (reverse bronchoconstriction and laryngeal edema)

DOC for releaving priapism (alpha receptor stim)

* though may damage kidney

Stroke Volume:

Normal vs. Myocardial Infarction

(increased preload, contractility, afterload)

                                 normal heart               MI

increase preload           inc                          dec 

increased contractility    inc                         inc

increased afterload       n.c.                         DEC

releases nitric oxide which dilates both arterioles and venules 

can be given by iv infusion during MI along with dobutamine

1. does not increase DBP (afterload)

is less likely to cause tachycardia

causes venodilation which decreases venous return (preload), so cardiac filling pressure is decreased 

Epinephrine causes increase in BP with alpha and b2 receptor stimulation

if alpha antagonist is used (phenoxy, phentolmine, prazosin, tamsulosin, labetalol, yohimbine) then it depresses the BP even more than the antagonist

However if you use a non-selective beta antagonist then give epi -- the spike in BP is greater 

Hypertensive patient, normal cardiac function, alph receptor blocker PRAZOSIN

Effect on TPR, BP, Venous Capacitance, HR, dp/dt, CO

decrease TPR

decrease BP

Increase VC

balanced dilation so no change in the following:

HR, Contractility, CO

Doxazosin

Terazosin

Tamsulosin

Phentolamine

Papaverine

Alprostadil

Sildenafil

hypotension

angina

failure to ejaculate

miosis

nasal congestion

abdominal cramps

retention of water and salt 

Name the Beta-blockers for the heart 

& selectivity

BAM

Betaxolol

Atenolo

Metoprolol

B1 selective

Propranolol

Timolol

non-selective 

Esmolol - short half life

HR decrease

Prevent Tachycardia caused by excercise, stress

also decrease conduction, AV, Ventricles, dp/dt, CO, Coronary Blood flow

BP is decreased

initial reduction in CO

Plasma renin and angiotenin II fall

decline in BP

Salt and Water retention

Increased Airway resistance decrease FEV1

BAM has the least decrease in FEV while propranolol and timolol have the greatest decrease 

Reduce blood flow

pts. compain of cold hands

blocks the increase FFA (plasma) cause by smp stimulation of B1 in fat

Blocks B2 glycogenolysis in liver and skeletal muslce 

Cardiac dysrhytmias (especially catecholamine induced) especially in MI pts (decrease chance of death)

Heart failure (diastolic dysfunction - tx with carvedilol or metoprolol)

Hyperthyroidism (block trmor, tachycardia)

Pheochromocytoma, Glaucoma, essential tremor, mirgraines, portal hypertension (propranolol)

Depressed mycoardial contractility

Bradycardia

Up-regulation of B-adrenoceptors due to withdrawl of propranolo

Asthma

Diabetes (mask warning signs except sweating)

Digital Blood Flow decrease

Excercise Intolerance 

1. Cardia dysrhythmias

2. MI

3. Chest pain

4. Pulmonary Edema

5. CVA - subarachnoid hemorrhage

6. Necrosis of nasal septum

7. Seizure

8. Resp. Disease

9. Sudden death

Scopolamine, atropine, or cyclopentolate

MYDRIASIS and cycloplegia

Diphenoxylate (opiate) inhibits GI motility

+

Atropine

STOp the Darn Tinkling 

Oxybutynin

Tolterodine

Trospium

Solifenacin

Darifenacin

BBATS in the belfry

Benxtropine

Biperiden

Atropine

Trihexyphenidyl

Red as a beet (cutaneous dilation)

Hot as a pistol (hot skin)

Mad as a hatter (delusions)

Dry as a Desert (inhibit salivation)

CNS - nervous, excitation, confusion, hypertension, etc

PNS - dry mouth, thirst, dilated pupils, tachycardia, photophobia

N1 Receptor Antagonists

describe MOA

Decrease TPR

decrease venodilation

decrease contractility

decreased cardiac output

hypotension

decreased sweating

impotence

Tachycardia

Mydriasis and cycloplegia

decreased salivation & lacrimation

decreased GI secretion, motility and tone

decreased gastric acid secretion

decrease release of pancreatic enzymes and bile

constipation and urinary retention

impotence (no erection)

Chewing gum

Transdermal

Nasal Spray

perscription antidepressant drug taken p.o. 

can cause seizure

partial agonist at central alpha and beta nicotinic receptors whose effects mimic tobacco

* causes the release of dopamine 

SLUDGE 

Salivation

Lacrimation

Urination

Diaphoresis

GI motility

Emesis 

1. Muscarinic receptor:

Pilocarpine - allow flow

Alpha agonist - Epi, Apraclonidine & Brimonidine (alpha 2 selective), Dipivefrin

Beta antagonist - betaxolol, timolol 

Carbonic Anhydrase inhibitor - acetazolamide, dorzolamide

2. Inhibitors of AChase - Isoflurophate and echothiophate

Mannitol - given iv

causes cellular deydration 

DTP

Tacrine

Donepezil

Physostigmine

Neostigmine 

Pyridostigmine

Edrophonium

organophosphate 

DIMPLE

Dimpylate

Isoflurophate

Malathion

Parathion

L

Echothiophate

N methyl PIG

N-methylatropine

N-methylhomatropine

methscopolamine

propantheline

ipratropium

glycopyrrolate

TT

Trospium

tiotropium

Muscarinic Antagonist Quartenary

(RAP)

Atro - Sco - Ho - Cy

Tropic - Benz Tri

Bi Di hyo- Oxy

To So Da Di