basic pharmacology[1]

7/31/2019 Basic Pharmacology[1]

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HENDERSON-HESSELBACH EQUATION:

Weak Acido pKa:

If its pKa < pH of the environment, then the conjugate base (anion) form of thespecies will predominate. Example =CH3COO

-

If its pKa > pH of the environment, then the environment is more acidic, so itsacidic (neutral) form will predominate. ExampleCH3COOH

o Weak acids tend to be absorbed in acidic environments, like the stomach. Weak Base

o pKa If its pKa < pH of the environment, then the environment is more basic, so the

species will remain in the neutral form. Example = NH3

If its pKa > pH of the environment, then the environment is more acidic, so it willgive up its extra H

+to the base, and the base will exist in its cation form. Example

=NH4+

o Weak bases tend to be absorbed in basic environments, like the duodenum.

DRUG PERMEATION: Partition Coefficient: The ratio of lipid solubility to aqueous solubility. The higher the partition

coefficient, the more membrane soluble is the substance.

Kidney Glomeruli have the largest pores through which drugs can pass ------> drug filtration. Blood Brain Barrier (BBB):Only lipid-soluble compounds get through the BBB.

o Four components to the blood-brain barrier: Tight Junctions in brain capillaries Glial cell foot processes wrap around the capillaries Low CSF protein concentration ------> no oncotic pressure for reabsorbing protein

out of the plasma.

Endothelial cells in the brain contain enzymes that metabolize, neutralize, manydrugs before they access the CSF.

MAO and COMT are found in brain endothelial cells. TheymetabolizeDopamine before it reaches the CSF, thus we must give L-DOPA in order to get dopamine to the CSF.

o Exceptions to the BBB. Certain parts of the brain are not protected by the BBB: Pituitary, Median Eminence Supraventricular areas Parts of hypothalamus

Meningitis: It opens up the blood brain barrier, due to edema. Thus Penicillin-G can be used totreat meningitis, despite the fact that it doesn't normally cross the BBB.

o Penicillin-G is also actively pumped back out of the brain once it has crossed the BBB.

Routes of Administration:


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ORALo FIRST-PASS EFFECT: Alteration of drugs in liver via protal circulation. Some drugs have a

high first-pass effect and thus a lower bioavailability. Know these:

Morphine Imipramine Propanolol

o Gastric Emptying: Generally, anything that slows gastric emptying will slow the absorptionof drugs.

Things that slow gastric emptying: Fats, acidic pH, bulk, anticholinergics,hypothyroidism, Al(OH)3

Faster gastric emptying is beneficial for the absorption of most drugs Tetracycline chelates calcium and should therefore not be given with milk.

TOPICAL: Lipophilic drugs absorbed through skin.o Examples: Nicotine patch, nitroglycerine,scopolamine = anti-histamine given for motion-

sickness.

VOLUME OF DISTRIBUTION: The apparent amount of volume that a drug seems to distribute to.

Sites of Concentration: They can affect the Volume of Distribution

o FAT: Drug concentrates in fat ------> lower concentration of drug in the plasma ------> high Vd

o BONE: Drug concentrates in bone ------> lower concentration of drug in the plasma ------> high Vd

o TISSUE: Drug concentrates in tissue ------> lower concentration of drug in the plasma ------> high Vd

o PLASMA PROTEINS: Drug binds to plasma protein ------> higher concentration of drug inthe plasma ------> low Vd.

The Vd is based on the total amount of drugin the plasma -- not just the amount offree drug!

o TRANSCELLULAR: Drug concentrates in non-plasma locations ------> lower concentration ofdrug in the plasma ------> high Vd

Apparent Vd ApparentVd

(L/kg)

#Litersin70kgman

%TotalBodyWeight

Example,Explanation

Plasma Water 0.045L/kg

3 L 4.5% Plasma-Protein-bounddrugs, andlarge drugsthat stay in

plasma.Concentratesin blood andthus has asmall Vd.

Example

=Heparin

ExtracellularWater

0.2 L/kg 14 L 20% Large watersoluble drugs.


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Example=Mannitol

Total BodyWater

0.6 L/kg 42 L 60% Small watersoluble

drugs;rapid

equil-ibrationbetween bodycompartments.

Example=Ethanol

Tissue

Concentration

>0.7 L/kg >42 L ----- Drugs thatbind to tissue

Example

=chloroquine,whichintercalates

with DNAintracellularly.

Vd may begreater thanTBW volume,hence some

drug must bebound toplasma.

This is verycommon andoccurs with

many drugs.

Enterohepatic Circulation: Drugs that are recycled through the enterohepatic circulation will havea lower concentration of drug in the plasma, and therefore a higher Vd.

PLASMA PROTEIN BINDING: Two main plasma proteins carry drugs in the blood.

ALBUMIN

alpha1-Acid Glycoprotein

OROSOMUCOID

Negatively Charged, hence it bindsprimarily to weak acids.

Positively Charged, hence it bindsprimarily to weak bases.

Negative acute-phase protein: itssynthesis decreases during time of bodyinsult.

Positive acute-phase protein: itssynthesis increases during times of bodyinsult.

Examples:Phenytoin, Salicylates Examples: Quinidine, Propanolol


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Basic Pharmacology

BIOTRANSFORMATION:

Alteration of drugs by the liver. Drugs can be metabolized from active to inactive, or from inactive to active.Generally drugs are made more hydrophilic by the process.

PHASE I: Mixed-Function Oxidases, formed bymicrosomes made out of Smooth-ER folded overon itself.

o Cytochrome-P450 Enzyme Complex: Has four required components in order to work. Cytochrome-P450 Enzyme Cytochrome-P450 Reductase O2 NADPH: NADPH is the only energy source. No ATP is required!

o Phase I enzymes perform multiple types of reactions: OXIDATIVE REACTIONS: on drugs, such as: Aromatic hydroxylation, aliphatic

hydroxylation, N-dealkylation, O-dealkylation, S-dealkylation, N-Oxidation, S-Oxidation, Desulfuration.

REDUCTIVE REACTIONS: Azo, Nitrile, Carbamyl HYDROLYTIC REACTIONS: Ester hydrolysis, Amide hydrolysis.

PHASE II: Drug Conjugation. usually toglucuronides, making the drug more soluble.

CYTOCHROME-P450 COMPLEX:

There are multiple isotypes.o CYT-P450-2 and CYT-P450-3A are responsible for the metabolism of most drugs.o CYT-P450-3A4 metabolizes many drugs in the GI-Tract, where it decreases the

bioavailabilityof many orally absorbed drugs.

INDUCERS of CYT-P450 COMPLEX: Drugs that increase the production of Cytochrome-P450enzymes.

o ANTI-CONVULSANTS: Phenobarbitol, Phenytoin, Carbamazepine induce CYT-P450-3A4

o Phenobarbitol, Phenytoin also induce CYT-P450-2B1o Polycyclic Aromatics (PAH): Induce CYT-P450-1A1o Glucocorticoids induce CYT-P450-3A4o Chronic Alcohol, Isoniazid induce CYT-P450-2E1. This is important as this drug

activates some carcinogens such as Nitrosamines.

Chronic alcoholics have up-regulated many of their CYT-P450 enzymes. INHIBITORS of CYT-P450 COMPLEX: Drugs that inhibit the production of Cytochrome-P450

enzymes.o Acute Alcohol suppresses many of the CYT-P450 enzymes, explaining some of the drug-

interactions of acute alcohol use.o Erythromycin, Ketanazole inhibit CYT-P450-3A4.

Terfenadine (Seldane) is metabolized by CYT-P450-3A4, so the toxicunmetabolized form builds up in the presence of Erythromycin. The unmetabolized

form is toxic and causes lethal arrhythmias. This is why Seldane was taken off themarket.

o Chloramphenicol, Cimetidine, Disulfiramalso inhibit CYT-P450's.


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EXCRETION:

KIDNEY

o GLOMERULAR FILTRATION: Clearance of the apparent volume of distribution by passivefiltration.

Drug with MW < 5000 ------> it is completely filtered. Inulin is completely filtered, and its clearance can be measured to estimate

Glomerular Filtration Rate (GFR).o TUBULAR SECRETION: Active secretion.

Specific Compounds that are secreted: para-Amino Hippurate (PAH)is completely secreted, so its clearance can

be measured to estimate Renal Blood Flow (RBF).

Penicillin-G is excreted by active secretion. Probenecidcan be given toblock this secretion.

Anionic System: The anionic secretory system generally secretes weak ACIDS: Penicillins, Cephalosporins Salicylates Thiazide Diuretics Glucuronide conjugates

Cationic System: The cationic secretory system generally secretes BASES, orthings that are positively charged.

Ion-Trapping: Drugs can be "trapped" in the urine, and their rate of eliminationcan be increased, by adjusting the pH of the urine to accommodate the drug. Thisis useful to make the body get rid of poisons more quickly.

To increase excretion of acidic drugs, make the urine more basic (giveHCO3

-)

To increase excretion of basic drugs, make the urine more acidic. BILIARY EXCRETION: Some drugs are actively secreted in the biliary tract and excreted in the feces.

Some of the drug may be reabsorbed via the enterohepatic circulation.o Transporters: The liver actively transporters generally large compounds (MW > 300), or

positive, negative, or neutral charge.

Anionic Transporter: Transports some acids, such as Bile Acids, BilirubinGlucuronides, Glucuronide conjugates, Sulfobromophthalein, Penicillins Neutral Transporter: Transports lipophilic agents, such as:

Steroids Ouabain

Cationic Transporter: Transports positively charged agents, such as n-Methylnicotinamide, tubocurarine.

o Charcoal can be given to increase the fecal excretion of these drugs and prevententerohepatic reabsorption.

o Cholestyramine can be given to increase the rate of biliary excretion of some drugs.

ORDERS of EXCRETION:o ZERO-ORDER EXCRETION:The rate of excretion of a drug is independent of its

concentration.

General properties: dC/dt = -K A plot of the drug-concentration -vs- time is linear.


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The half-life of the drug becomes continually shorter as the drug isexcreted.

Examples: Ethanol is zero-order in moderate quantities, because the metabolism

system is saturated. The rate of metabolism remains the same no matter

what the concentration.

Phenytoin and Salicylatesfollow zero-order kinetic at high concentration. FIRST-ORDER EXCRETION: The rate of excretion of a drug is directly proportional to itsconcentration.

o General properties: dC/dt = -K[C] A plot of the log[conc] -vs- time is linear. slope of the line = -Kel / 2.303 The half-life of the drug remains constant throughout its excretion

o Equation:

HALF-LIFE: The half-life is inversely proportional to the Kel,constant of elimination. The higher the

elimination constant, the shorter the half-life.

COMPARTMENTS:

One-Compartment Kinetics: Kinetics are calculated based on the assumption that the drug isdistributed to one uniform compartment.

o One compartment kinetics implies that the drug has a rapid equilibrium between tissuesand the blood, and that the release of the drug from any tissues is not rate-limiting in itsexcretion.

o One-compartment kinetics also assumes that the drug is distributed instantaneouslythroughout the body. This is only true for IV infusion.

Multi-Compartment Kinetics: Most drugs follow multi-compartment kinetics to an extent.o Biphasic Elimination Curve: Many drugs follow a biphasic elimination curve -- first a

steep slope then a shallow slope.

STEEP (initial) part of curve ------> initial distribution of the drug in the body. SHALLOW part of curve ------> ultimate renal excretion of drug, which is

dependent on the release of the drug from tissue compartments into the blood.

CLEARANCE: The apparent volume of bloodfrom which a drug is cleared per unit of time. CLEARANCE OF DRUG = (Vd)x(Kel)

o The higher the volume of distribution of the drug, the more rapid is its clearance.o The higher the elimination constant, the more rapid is its clearance.

o This is based on the Dilution Principle:

(Conc)(Volume) = (Conc)(Volume) Total Amount = Total Amount

MEANING: In first-order kinetics, drug is cleared at a constant rate. A constant fraction of the Vd iscleared per unit time. The higher the Kel, the higher is that fraction of volume.

o Drug Clearance of 120 ml/min ------> drug is cleared at the same rate as GFR and is notreabsorbed. Example = inulin


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o Drug clearance of 660 ml/min ------> drug is cleared at the same rate as RPF and isactively secreted, and not reabsorbed. Example = PAH

BIOAVAILABILITY: The proportion of orally-administered drug that reaches the target tissue andhas activity.

o AUCORAL = Area under the curve. The total amount of drug, through time, that has

any activity when administered orally.

AUCIV = Area under curve. The total amount of drug, through time, that has anyactivity when administered IV. This is the maximum amount of drug that will haveactivity.

o 100% Bioavailability = A drug administered by IV infusion.o BIOEQUIVALENCE: In order for two drugs to be bioequivalent, they must have both the

same bioavailability andthe same plasma profile, i.e. the curve must have the same shape.That means they must have the same Cmax and Tmax.

o Cmax: The maximum plasma concentration attained by a drug-administration.o Tmax: The time at which maximum concentration is reached.

REPETITIVE DOSES:o FLUCTUATIONS: Drug levels fluctuate as you give each dose. Several factors determine the

degree to which drug levels fluctuate.

There are no fluctuations with continuous IV infusion. Slow (more gradual) absorption also reduces fluctuations, making it seem more

like it were continuous infusion.

The more frequent the dosing interval, the less the fluctuations. Theoretically, ifyou give the drug, say, once every 30 seconds, then it is almost like continuous IVinfusion and there are no fluctuations.

o Steady-State Concentration (CSS): The plasma concentration of the drug once it hasreached steady state.

It takes 4 to 5 half-lives for a drug to reach the steady state, regardless of dosage. After one half-life, you have attained 50% of CSS. After two half-lives, you

have attained 75%, etc. Thus, after 4 or 5 half-lives, you have attained~98% of CSS, which is close enough for practical purposes.

If a drug is dosed at the same interval as its half-life, then the CSS will be twice theC0 of the drug.

If you have a drug of dose 50 mg and a half-life of 12 hrs, and you dose itevery 12 hrs, then the steady-state concentration you will achieve withthat drug will be 100 mg/L.

D: Dose-amount. The higher the dose amount, the higher the Css.

: Dosage interval. The shorter the dosage interval, the higher the Css

F: Availability Fraction. The higher the availability fraction, the higherthe Css.

Kel: Elimination Constant. The higher the elimination constant, the loweris the Css.

Vd: Volume of Distribution. A high volume of distribution means we're putting the drug into a large

vessel, which means we should expect a low Css.

Cl: Clearance. The higher the drug-clearance, the lower the Css.


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If you know the desired steady-state concentration and the availability

fraction, then you can calculate the dosing rate.

LOADING DOSE: When a drug has a long half-life, this is a way to get to CSS much faster.o Loading Dose = twice the regular dose, as long as we are giving the drug at the sameinterval as the half-life.

o INTRAVENOUS INFUSION: The CSS is equal to theinput(infusion rate x volume of distribution)

divided by the output(Kel)

o R0 = the rate of infusion. Vd = the volume of distribution, which should be equal to plasma volume, or 3.15L,

or 4.5% of TBW.

Kel = Elimination Constanto Loading Dose in this case is just equal to Volume of distribution time the C ss:

RENAL DISEASE: Renal disease means the drug is not cleared as quickly ------> the drug will have

a higher Css ------> we should adjust the dose downward to accommodate for the slower clearance.o If the fraction of renal clearance is 100% (i.e. the drug is cleared only by the kidneys), then

you decrease the dosage by the same amount the clearance is decreased.

For example: If you have only 60% of renal function remaining, then you give only60% of the original dose.

o If the fraction of renal clearance is less then 100%, then multiply that fraction by thepercent of renal function remaining.

For example: If you have only 60% of renal function remaining, and 30% of thedrug is cleared by the kidney, then the dose adjustment = (60%)(30%) = 20%.The dose should be adjusted 20%, or you should give 80% of the original dose.

o G = The percentage of the original dose that we should give the patient.

If G = 60%, then we should give the patient 60% of the original dose.

f= The fraction of the drug that is cleared by the kidney.If f is 100%, then the drug is cleared only by the kidney.

ClCr = Creatinine clearance of patient, and normal clearance. The ratio is thepercent of normal kidney function remaining.

Renal disease increases the time to reach steady-state concentration. Renal Disease ------>longer half-life ------> longer time to reach steady-state.


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METABOTROPIC RECEPTOR-COUPLING MECHANISMS:

SPECIFIC G-RECEPTORSGs Stimulates adenylate cyclase (cAMP)

Gi Inhibits adenylate cyclase alpha2-Receptors have Gi ------> inhibit post-synapticadrenergic neurons

Gq Stimulates Phospholipase-C (IP3/DAG) alpha1-Receptors have Gq ------> Ca+2

in smoothmuscle

Go Inhibits Ca+2

channels

Gi Opens K+

channels

cAMP PATHWAY (beta-Adrenergic)o HORMONE RECEPTORS: beta-Adrenergic, GH, most hypothalamic and pituitary hormones.o Signal Transduction Pathway:

Adenylyl Cyclase ------> cAMP ------> PKA ------> phosphorylate target protein. Phosphodiesterase then cleaves cAMP ------> 3',5'-AMP The GTP on the G-Protein spontaneously cleaves back to GDP, to inactive the G-

Protein.o Xanthines: Caffeine inhibits phosphodiesterase ------> cAMP.o Desensitization:

beta-Arrestin Kinase (betaARK) is activated by tonically high cAMP levels. cAMPphosphorylates betaARK to activate it.

betaARK phosphorylates the regulatory domain of the target receptors ------>prevent cAMP activation.

PHOSPHO-INOSITOL PATHWAY (alpha-Adrenergic)o HORMONE-RECEPTORS: alpha-Adrenergico Signal Transduction Pathway:

Phospholipase-A2 cuts apart PIP2 ------> IP3 + DAG IP3 goes to Rough-ER where it opens calcium channels ------> Ca+2 DAG phosphorylates PKC, a calmodulin-kinase, which then phosphorylates the

target protein, whenever Ca+2

(from IP3) is available.

Ca+2 is then sequestered back into the Rough-ER by active transport. STEROID RECEPTORS:

o HORMONES: Cortisol, sex steroids, Thyroid Hormone, Aldosteroneo Signal Transduction:

Heat-shock proteins normally bind to the nuclear receptor to hold it inactive. The hormone (Cortisol, Sex Steroids, Tyrosine) bind to the nuclear receptor,

releasing the heat shock protein.

The hormone-receptor complex then binds to DNA to effect transcription.o Cortisol stimulates Lipocortin ------> inhibit Phospholipase-A2 ------> inhibit synthesis of

prostaglandins ------> anti-inflammatory properties.

TYROSINE-KINASE RECEPTORS

o Hormones: Insulin, IGF, EGFo Pathway: auto-phosphorylation of tyrosine ------> phosphorylate target protein.

NITRIC OXIDE:o NO-Synthases:

Constitutive NO-Synthase: Present in most cells, and is responsible for ACh-activated smooth muscle relaxation.

Inducible NO-Synthase: Induced by cytokines to cause acute vasodilation.o NO Functions:


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Forms free radical intermediates in PMN's and macrophages.

IONOTROPIC RECEPTOR-COUPLING MECHANISMS:

GABA RECEPTOR:

o RECEPTOR MECHANISM: In the CNS, it is a Cl-channel. GABA binds ------> Cl- comes intoneuron ------> hyperpolarization ------> Inhibitory effects in CNS.

o Barbiturates (Phenobarbitol): It binds at an allosteric site to increase the effectivenessof GABA. It is GABAergic, but it is nota GABA agonist, because it does not bind to the samesite as GABA.

o Benzodiazepines (Diazepam, Valium): It binds at a separate site than the barbiturates,but it is still GABAergic and binds at an allosteric site.

o Picrotoxin: GABA Antagonist, it antagonizes GABA, causing excitability in the CNS. Thus itis a convulsive agent.

NMDA RECEPTOR: N-Methyl-D-Aspartateo MECH: It binds excitatory neurotransmitters, glutamate and aspartate. It lets in

Ca+2

(primarily) and also Na+.

o Alzheimer's Disease: The NMDA receptor may play a role in the pathogenesis ofAlzheimer's Disease.

Leaky NMDA Channels ------> Na+comes in the neuron ------> water follows Na+ ------> reversible cell damage to neurons (hydropic swelling). Leaky NMDA Channels ------> Ca+2builds up in neuron ------> irreversible,

oxidative damage (free radicals) to neuron ------> permanent damage and celldeath.

o MK-801 is an NMDA Receptor Blocker that has been tried as experimental treatment forAlzheimer's. But it doesn't work because it has a stimulatory effect on the hippocampus,causing hallucinations, similar to takingphencyclidine (PCP).

ACETYLCHOLINE NICOTINIC RECEPTOR:o MECH: It is a Na+ channel. When 2 ACh's bind, Na+ comes in, depolarizing the membrane.o Desensitization: If you let ACh hang around long enough (such in the presence of

cholinesterase inhibitors), then some of the ACh-receptors will convert to a high-affinitystate, and the ACh will stay locked onto the receptors.

RESULT: Fewer receptors are available ------> ACh's effect is thereforeantagonized ------> depolarization blockade.

This explains the way in which cholinesterase inhibitors cause paralysis.o Succinylcholine binds to the ACh with a higher affinity than ACh.

Early on, you will see fasciculations, as it has its stimulatory effect on ACh. After that you see paralysis. Succinylcholine becomes an ACh antagonist, as all the

receptors convert to the high-affinity state, and the molecule locks on.

Definitions:o Affinity: A measure of the propensity of the drug to bind with a given receptor.o Potency: A potent drug induces the same response at a lower concentration. A potent drug

has a lower EC50 value.

o Efficacy: The biologic response resulting from the binding of a drug to its receptor. Anefficacious drug has a higher Emax value.o Partial Agonist: A compound whose maximal response (Emax) is somewhat less than the full

agonist.

GRADED-RESPONSE CURVE: A plot of efficacy (some measured value, such as blood pressure) -vs-drug concentration.

o EC50 = The drug concentration at which 50% efficacy is attained. The lower the EC50, themore potent the drug.

o Emax = the maximum attained biological response out of the drug.


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o QUANTAL DOSE-RESPONSE CURVE: A graph of discrete (yes-or-no) values, plotting the number of

subjects attaining the condition (such as death, or cure from disease) -vs- drug concentration.o ED50: The drug-dosage at which 50% of the population attains the desired characteristic.o LD50: Lethal-Dose-50. The drug-dose at which 50% of the population is killed from a drug.

THERAPEUTIC INDEX = LD50 / ED50o The ratio of median lethal dose to median effective dose.o The higher the therapeutic index, the better. That means that a higher dose is required for

lethality, compared to the dose required to be effective.

MARGIN OF SAFETY = LD1 / ED99o The ratio of the dosage required to kill 1% of population, compared to the dosage that is

effective in 99% of population.o The higher the margin of safety, the better.

COMPETITIVE INHIBITORS: They bind to the same site as the endogenous molecule, preventing theendogenous molecule from binding.

o The DOSE-RESPONSE CURVE SHIFTS TO THE RIGHT in the presence of a competitiveinhibitor.

The EC50 is increased: more of a drug would be required to achieve same effect. The Emax does not change: maximum efficacy is the same, as long as you have

enough of the endogenous molecules around.

o The effect of a competitive inhibitor is REVERSIBLE and can be overcome by a higher doseof the endogenous substance.

o The intrinsic activity of a competitive inhibitor is 0. It has no activity in itself, but onlyprevents the endogenous substance from having activity.

o Partial Agonist: A substance that binds to a receptor and shows less activity than the fullagonist.

At low concentrations, it increases the overall biological response from thereceptor.

At high concentrations, as all receptors are occupied, it acts as a competitiveinhibitor and decreases the overall biological response from the receptor.

NON-COMPETITIVE INHIBITORS: They either (1) bind to a different (allosteric) site, or (2) they bindirreversibly to the primary site.

oThe DOSE RESPONSE CURVE SHIFTS DOWN in the presence of a non-competitive inhibitor.

The EC50 is increased: more of a drug would be required for same effect. The Emax decreases: The non-competitive inhibitor permanently occupies some of

the receptors. The maximal attainable response is therefore less.o The intrinsic activity of the non-competitive inhibitor is actually a negative number, as the

number of functional receptors, and therefore the maximum attainable biological response,is decreased.

ADVERSE EFFECTS:

Drug Toxicity:Dose-dependentadverse response to a drug.o Organ-Directed Toxicity:

Aspirin induced GI toxicity (due to prostaglandin blockade) Epinephrine induced arrhythmias (due to beta-agonist) Propanolol induced heart-block (due to beta-antagonist) Aminoglycoside-induced renal toxicity Chloramphenicol-induced aplastic anemia.

o Neonatal Toxicity: Drugs that are toxic to the fetus or newborn. Sulfonamide-induced kernicterus. Chloramphenicol-induced Grey-Baby Syndrome Tetracycline-induced teeth discoloration and retardation of bone growth.

o TERATOGENS: Drugs that adversely affect the development of the fetus


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Thalidomide: Antifolates such as Methotrexate. Phenytoin: Malformation of fingers, cleft palate. Warfarin: Hypoplastic nasal structures. Diethylstilbestrol: Oral contraceptive is no longer used because it causes

reproductive cancers in daughters born to mothers taking the drug.

Aminoglycosides, Chloroquine:Deafness Drug Allergy: An exaggerated, immune-mediated response to a drug.

o TYPE-I: Immediate IgE-mediated anaphylaxis. Example: Penicillin anaphylaxis.

o TYPE-II: Antibody-Dependent Cellular Cytotoxicity (ADCC). IgG or IgM mediated attackagainst a specific cell type, usually blood cells (anemia, thrombocytopenia, leukopenia).

Hemolytic anemia: induced by Penicillin or Methyldopa Thrombocytopenia: induced by Quinidine SLE: Drug-induced SLE caused by Hydralazine or Procainamide.

o TYPE-III: Immune-complex drug reaction Serum Sickness: Urticaria, arthralgia, lymphadenopathy, fever. Steven-Johnson Syndrome: Form of immune vasculitis induced by sulfonamides.

May be fatal.

Symptoms: Erythema multiforme, arthritis, nephritis, CNS abnormalities,myocarditis.

oTYPE-IV: Contact dermatitis caused by topically-applied drugs or by poison ivy.

Drug Idiosyncrasies: An unusual response to a drug due to genetic polymorphisms, or forunexplained reasons.

o Isoniazid:N-Acetylation affects the metabolism of isoniazid Slow N-Acetylation: Isoniazid is more likely to cause peripheral neuritis. Fast N-Acetylation: Some evidence says that Isoniazid is more likely to cause

hepatotoxicity in this group. However, other evidence says that age(above 35 yrsold) is the most important determinant of hepatotoxicity.

o Alcohol can lead to facial flushing, orTolbutamide can lead to cardiotoxicity, in peoplewith an oxidation polymorphism.

o Succinylcholine can produce apnea in people with abnormal serum cholinesterase. Theircholinesterase is incapable of degrading the succinylcholine, thus it builds up anddepolarization blockade results.

o Primaquine, Sulfonamides induce acute hemolytic anemia in patients with Glucose-6-Phosphate Dehydrogenase deficiency.

They have an inability to regenerate NADPH in RBC's ------> all reductive processesthat require NADPH are impaired.

Note that this is Acute Hemolytic Anemia, yet it is not classified as an allergicreaction -- it is an idiosyncrasy when caused by sulfonamides or primaquine. Otheranemias are Type-II hypersensitivity reactions.

G6PD deficiency is most prevalent in blacks and semitics. It is rare in caucasiansand asians.

o Barbiturates induce porphyria (urine turns dark red on standing) in people with abnormalheme biosynthesis.

Psychosis, peripheral neuritis, and abdominal pain may be found.

TOLERANCE

Pharmacokinetic Tolerance: Increase in the enzymes responsible formetabolizing the drug.

Warfarin doses must be increased in patients taking barbituratesor phenytoin, because these drugs induce the enzymes responsiblefor metabolizing warfarin.

Pharmacodynamic Tolerance: Cellular tolerance, due to down-regulation of receptors, or down-regulation of the intracellular response toa drug.


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Tachyphylaxis: When using indirect agonists, which stimulate theendogenous substance, this occurs when you run out of the endogenoussubstance and therefore see the opposite effect, or no effect at all.

Tyramine can cause depletion of all NE stores if you use it longenough, resulting in tachyphylaxis.

Physiologic Tolerance: Two agents yield opposite physiology effects. Competitixve Tolerance: Occurs when an agonist is administered with

an antagonist. Example: Naloxone and Morphine are chemical antagonists, and

one induces tolerance to the other.

CATECHOLAMINE SYNTHESIS: Tyrosine ------> DOPA (Tyrosine Hydroxylase)

o This is the rate-limiting step in synthesis.o alpha-Methyltyrosine is a false substrate for this step and inhibits the enzyme.

DOPA ------> Dopamine (DOPA Decarboxylase) Dopamine ------> Norepinephrine (Dopamine beta-Hydroxylase) Norepinephrine ------> Epinephrine (Phenylethanolamine N-Methyltransferase, PNMT)

o The methyl group is obtained from S-Adenosyl-Methionine (SAM)

SYNTHESIS OF ACETYLCHOLINE: Choline + Acetyl-CoA ------> Acetylcholine (Choline Acetyltransferase)

ACETYLCHOLINE RELEASE: Other neurotransmitters are released along with ACh.

ATP VIP Prostaglandins

l>

CATECHOLAMINE RELEASE: Other neurotransmitters are released along with NE.

o Neuropeptide-Y (NPY)o Dopamineo Metenkephalino CGRP

CATECHOLAMINE BREAKDOWN: The primary way to get rid of NE is reuptake back into the pre-synaptic neuron.

o UPTAKE I: Reuptake of NE back into the presynaptic neuron.


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Monoamine Oxidase (MAO): Breaks down Norepinephrine in the pre-synapticneuron. Before it can work, NE must be reuptaken into the presynaptic neuron.

o UPTAKE II: Reuptake of NE back into non-neuronal cells -- glial and smooth muscle cells. Catechol-O-Methyltransferase (COMT): Breaks down NE in glial cells and other

non-neuronal cells.

The methylated products of COMT then diffuse out of the glial cells and make theirway back to neurons, where they are further broken down MAO. So, MAO is

required in either case.o Catecholamine Metabolites: Two metabolites are found in urine and can be measured to

estimate Catecholamine turnover.

NE ------> Vanillyl Mandelic Acid (VMA) Epi ------> Vanillyl Mandelic Acid (VMA) Dopamine ------> Homovanillic Acid (HVA)

AUTONOMIC RECEPTORS: Brief summary

Receptor Location Effect

Nicotinic Ganglionic (NG) ANS Ganglions Activation of parasympathetic and sympathetic post-synaptic neurons.

Nicotinic NeuromuscularJunction (NMJ)

NeuromuscularJunction

Activation of skeletal muscle

Muscarinic (M1)

IP3 / DAG

Sympathetic post-ganglionics

Inhibit sympathetic NE release. This is the way in whichACh causes relaxation of vascular smooth muscle: ACh ------> inhibit NE ------> vasodilation.

Muscarinic (M2)

Inhibitory: cAMP, K+influx

Heart Lower rate (on SA node) and force (on myocardium)

Eye Pupillary constriction (contract iris muscle);accommodation

GI / UG Contraction of GI smooth muscle and relaxation ofsphincters.

Respiratory Bronchoconstriction and increased secretions

Penis Erection (via NO), vasodilation

Muscarinic (M3)

IP3 / DAG

Vascular Vasodilation: Strong indirect vasodilatory effect due toinhibition of sympathetics. At low doses, this leads toa reflex tachycardia.

Some direct vasodilatory effect (especially when

exogenous ACh is given)

Exocrine glands Increased sweating in non-adrenergic sweating areas(regular eccrine sweat glands).Under sympatheticcontrol, but they are M3 muscarinicreceptors.

Adrenergic (alpha1)

IP3 / DAG ------> Ca+2

Vascular smooth

muscle

Vasoconstriction (via IP3 / DAG, increased Ca+2

)

GI / UG Smooth muscle relaxation and contraction of sphincters


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Eye Pupillary dilation (contract radial muscle)

Adrenergic (alpha2)

Gi ------> cAMP

Post-ganglionics Inhibitory on sympathetic and parasympathetic post-ganglionic neurons. For sympathetics, this is auto-regulatory feedback.

Gi ------> inhibit cAMP

Pancreatic beta-

Cells

NE Inhibits the release of insulin ------> hyperglycemia

Adrenergic (beta1)

Adenyl Cyclase / cAMP

Heart Increase rate (SA node) and inotropic state

(myocardium)

Lipocytes Increase lipolysis

Brain NE stimulatory CNS effects.

Kidney Increased Renin release ------> higher b.p. ultimately

Adrenergic (beta2)

Adenyl Cyclase / cAMP

Vascular Relaxation of vascular smooth muscle in skeletal muscle

and brain.

Pancreatic beta-

Cells

Stimulate release of insulin in Pancreatic beta-Cells.

Thus beta-Blockers can lead to hyperglycemia as side-effect.

Dopamine (D1)

G-Protein, cAMP

Vasculature Vasodilation, especially in Kidney ------> higher Renal

Blood Flow.

Dopamine (D2)

G-Protein, cAMP

Anterior Pituitary Inhibit Prolactin Release

CNS Various stimulatory effects.

VASCULATURE: There are little or no parasympathetics innervating the vasculature.

o alpha1-Receptors: Vasoconstrictive. They predominate in the splanchnic beds andkidneys, which do not need a lot of blood flow during sympathetic stimulation.

The vasculature is primarily under sympathetic control, via alpha1 receptors.o Muscarinic Receptors: There are, however, muscarinic receptors on vascular smooth

muscle, and they do cause vasodilation. Thus, if there is ever a muscarinic agonist (such asACh) in the blood, then you will see a pharmacologic effectof direct vasodilation onvascular smooth muscle.

Coronary Arteries: An exception to the rule. Dilation of coronary arteries occursby parasympathetic stimulation ------> vasodilation.

o beta2-Receptors: Vasodilatory. They predominate in skeletal muscle and brain, which getall the blood flow during sympathetic stimulation.

SWEAT GLANDS:

o Cholinergic Sweat Glands: Thermoregulatory sweat glands throughout the body areunder sympathetic control, but they release ACh and synapse with muscarinic receptors.


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o Adrenergic Sweat Glands: Nervous sweating on palms, soles, and armpits is also undersympathetic control, but it releases NorE and synapses with adrenergic receptors.

LOW DOSES: Primary effect is vasodilation due to inhibition of sympathetics. In response you seeareflex tachycardia.

HIGH DOSES: You see a direct bradycardia.o You can see Atrial Fibrillation as a side effect, as the Ventricular refractory period is

prolonged and the atrial refractory period is shortened.

EFFECTS: Cholinergic outflow shows the following symptoms:o SLUD: Sweating, Lacrimation, Urination, Defecationo Profuse diarrhea, vomiting, nausea.o Flushed skin.

Direct Muscarinic Agonists:o Choline Esterso Alkaloids

Indirect Muscarinic Agonistso Carbamates: Reversible inhibitors of cholinesterase.o Organophosphates: Irreversible inhibitors of cholinesterase.

ORGANOPHOSPHATE POISONING:

DEATH by Respiratory Suppression in the CNS is the most common cause. This is notan effecton the diaphragm, but rather is a suppression of the respiratory drive (muscarinic receptors) in theCNS.

2-PAM (Pralidoxime): Only effective within the first five minutes of exposure.o Acetylcholinesterase is a Serine-Protease. It binds to Acetylcholine by latching onto the

NH3group with a His residue, and hydrolyzing the ester group with a Ser residue.o Organophosphates phosphorylate the cholinesterase, rendering it inactive. Within the first

few minutes, this phosphorylation is reversible.o 2-PAM is a strong nucleophile, and binds with the organophosphates to reverse the

phosphorylation.o After the first 5 or 10 minutes, aging occurs and the phosphorylation becomes irreversible.

After that, 2-PAM no longer works.

ATROPINE is the treatment of choice after that.

ANTI-MUSCARINIC AGENTS:

SIDE-EFFECTS of Anti-Muscarinics: Inhibit all muscarinic activitieso Peripheral:

Dry mouth (no salivation) Constipation (no anal sphincter relaxation, lost GI motility) Blurred Vision (no accommodation) Urinary retention (lost UG motility, no sphincter relaxation) Increased intraocular pressure (sympathetics increase intraocular pressure and

parasympathetics decrease it).o Central: Impairment of all things that ACh mediates in the CNS

Confusion Memory impairment


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Hallucinations, delusions

GANGLIONIC BLOCKERS: Trimethaphan and Hexamethonium.

They block all autonomic responses.

RESULTS:o Orthostatic Hypotension: block sympathetic reflex control of vasculature.o Tachycardia: Block parasympathetic reflex control of the heart.o GI / UG: Decreased motility, urinary retention, constipation (lost parasympathetic reflexes)o Mouth: Xerostomia

ADRENERGIC AGONISTS: Catecholamine, catecholamine-like compounds.

PHARMACOKINETICS: Never administered orally, due to high first-pass effect. ADVERSE EFFECTS:

o Increased cardiac excitability and arrhythmias ------> ventricular fibrillation. CONTRAINDICATIONS: MAO Inhibitors, Cocaine, Tri-cyclics. These all potentiate NE, thus don't give

catecholamines!

SHORT-LIVED: Endogenous catecholamines, or catechol-like compounds, have very short half-lives,due to abundance of MAO and COMT.

beta-AGONISTS:

beta2-AGONISTS: They are primarily used as bronchodilators, but in severe heart failure, there isdown-regulation of beta1-receptors. Thus in CHF, beta2 may have a significant effect on theinotropic state of the heart.

MAO-INHIBITORS: Mono-Amine Oxidase Inhibitors. MAO has two isozymes.

MAO-A: More effective in degrading NE and serotonin. MAO-B: Less selective for individual amines. Older MAO-Inhibitors are non-selective. Newer ones are isozyme-selective.

alpha-ANTAGONISTS:

PRINCIPAL EFFECTS:o Decreased TPR, decreased blood pressure (primary effect)o Tachycardia (reflex)o Increased release of renin (reflex)

SIDE EFFECTS:o Miosiso Decreased adrenergic sweatingo Stuffy noseo Increased insulin release


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o Impaired ejaculation

beta-ANTAGONISTS:

PRINCIPLE EFFECTS:o They decrease the inotropic state of the heart ------> decrease oxygen demand of the

myocardium. Useful in treating angina pectoris.o They decrease blood pressure:

They increase TPR and decrease cardiac output, but the net effect is to decreaseblood pressure.

They decrease renin secretion in the kidney, which also helps to decrease bloodpressure.

o They decrease AV conduction in the heart, and are useful in treating arrhythmias. SIDE-EFFECTS:

o Rebound Tachycardia can result if the drug is withdrawn quickly, due to denervationsupersensitivity (i.e. up-regulation of beta1-receptors after using the drug for a while).

o Insulin release is blocked in pancreas ------> possible hyperglycemia, which can be aproblem with Diabetics.

oCan also lead to hypercholesterolemia.

o Local Anesthesia: Membrane-stabilizing effect occurs as the drugs block Na+-channels inheart muscle and in neurons. This is not of clinical consequence, except when using as eyedrops.

CONTRAINDICATIONS: ASTHMA is an absolute contraindication, for non-selective beta-blockers.You don't want to block the bronchodilatory effects of beta2-receptors!

o You can possibly use beta1-selective (cardioselective) antagonists with asthmatics, but eventhese drugs still have some beta2-activity (even if minimal).

Basic Pharmacology

GROWTH HORMONE (GH)

ANABOLIC EFFECTS:o Increases amino acid uptake into tissues.o Enhances protein synthesis.

CATABOLIC EFFECTS:o Antagonizes insulin after it's been around for some time: impairs glucose uptake and

promotes lipolysis.o GH can thus be Diabetogenic for people with Diabetes.

THYROID HORMONE

Synthesis of Thyroid Hormone: Thyroglobulin is synthesized in the Thyroid foll icular cells andsecreted into the lumen of the follicles.

o Iodide is taken into the thyroid follicular cells from the general circulation, and it istranscytosed to the apical membrane.

This transport occurs by active Na+-Cotransport


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o ORGANIFICATION: The process of iodinating the thyroxines, forming MIT and DIT, andthen forming T3 and T4.

On the outside of the membrane, in the lumen, peroxidase catalyzes the oxidationof iodide and its attachment to Thyroglobulin, forming Mono-iodothyronine(MIT) and di-iodothyronine (DIT).

MIT and DIT then join to form T3 and T4 This process is blocked by theThionamides

Biological Effect:o Tri-iodothyronine (T3): Formed by joining MIT + DIT

It is far more potent and has the principal biological effects: increase transcriptionat target cell, and exhibit negative feedback at pituitary.

Very little of it (5g / day) is released from the Thyroid. The rest is made byconverting T4 ------> T3 in the peripheral blood.

T3 is carried, in part, by TBG in the blood. However, T4 binds more tightly to TBGthan does T3.

o Thyroxine (T4): Formed by joining DIT + DIT It is far less potent than T3. It has little biological effect in itself and is more of a

"pro-hormone."

It is released, in quantity, by the Thyroid, where it then binds to TBG in the blood.It is slowly converted to T3 in the periphery.

It binds more tightly to TBG then does T3. It has a longer half-life, so it sticks around longer than T3.

HYPOTHYROIDISM: Myxedema.o TYPES:

PRIMARY HYPOTHYROIDISM: Deficiency of Thyroxine itself. Goiter is present,due to increased TSH.

TSH will be high and T4 will be low. TRH Test: Give TRH, and TSH will show a hypersensitive response and

shoot way up.

SECONDARY HYPOTHYROIDISM: No goiter is present. TSH will be low and T4 will be low. TRH Test: Give TRH, and TSH will remain low and show little or no

response.

TERTIARY HYPOTHYROIDISM: TSH is low, initially, and T3 is low. TRH Test: Give TRH, and TSH will show a delayed responsebefore it

finally kicks in and increases somewhat.o Cretinism: Childhood hypothyroidism, which leads to retarded growth and mental

retardation if not treated.o CAUSES:

Idiopathic Hashimoto's Thyroiditis Treatment of Hyperthyroidism with radio-iodine, 131I.

o SYMPTOMS: Weakness, shallow respiration, puffy face, frowsy hair. HYPERTHYROIDISM: Thyrotoxicosis.

o SYMPTOMS: Hypertension, tachycardia, hypermetabolism, irritabilityo Thyroid Storm: Acute hyperthyroid crisis, which can be deadly.o CAUSES:

Grave's Disease: Auto-immune stimulation of TSH receptors. You do seeexophthalmos.

Toxic Nodular Goiter: There is no exophthalmos.o TREATMENT:

Thionamides: Inhibit organification of iodine. Has a delayed effect, because thyroglobulin stores must first be used up

before the effect is seen.

Ionic Inhibitors: Inhibit uptake of iodine. Surgery Radio-iodine, 131I: Diffusely kills thyroid cells. Resulting in eventual and inevitable

hypothyroidism.


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Iodide: Temporarily (early on) inhibits proteolysis of thyroglobulin, preventingfreeing of thyroxine. Effect wears off. Used to treat Thyroid Storm.

Often given in preparation for an operation, as it makes the thyroid glandfirm and shrink up.

ADRENAL HORMONES:

MINERALOCORTICOID SYNTHESIS: 21beta-Hydroxylase is required for synthesis.o Cholesterol ------> Pregnenolone ------> Progesteroneo Progesterone ------> 11-Deoxycorticosterone(21beta-Dehydroxylase)o 11-Deoxycorticosterone ------> Corticosterone ------> Aldosterone

CORTICOSTEROID SYNTHESIS: 21beta-Hydroxylase, 17alpha-Hydroxylase and 11beta-Hydroxylase are required for synthesis.

o Cholesterol ------> Pregnenoloneo Pregnenolone ------> Progesterone ------> 17alpha-Hydroxyprogesterone (21beta-

Hydroxylase, 17alpha-Hydroxylase)o 17alpha-Hydroxyprogesterone ------> 11-Deoxycortisolo

11-Deoxycortisol ------> Cortisol (11beta-Hydroxylase) SEX HORMONE PATHWAY:

o Cholesterol ------> Pregnenolone ------> Dehydroepiandrostenedione (DHEA) ------>Androstenedione ------> Testosterone

o Testosterone ------> Estradiol (Aromatase)o Estrogen Estriol Estradiol Estrone

21beta-Hydroxylase Deficiency: You see reduced Cortisol ------> excess ACTH ------> adrenalhyperplasia.

o You also see a buildup of the metabolic precursors. Buildup of progesterone and 17alpha-hydroxyprogesterone Buildup of Androstenedione ------> lots of androgens hanging around ------>

feminine virilization.o TREATMENT: Cortisol will relieve the ACTH and the adrenal hyperplasia, and will replace

deficient Cortisol. Sometimes you also have to give mineralocorticoid, but usually there issome residual aldosterone activity.

CORTISOL

METABOLITES: 17-hydroxycorticosteroids are the metabolic byproducts of Cortisol. They can bemeasured in the urine, in order to monitor Cortisol levels in the blood.

REGULATION: Cortisol, ACTH, CRH, negative feedback, etc. etc.o CRH: There is a diurnal rhythm of release of CRH, which results elevated levels of Cortisol

in the early morning hour.o None of the steroids are stored in the adrenals. They are synthesized on demand and

released immediately. Lipophilic substances don't easily fit into vesicles!

INDICATIONS:o Adrenal insufficiency (Addison's Disease)o Inflammatory, non-infectious processes of all sorts: Arthritis (all types), auto-immune

diseases, Asthma, diseases of the eye.

CONTRAINDICATIONS / ADVERSE EFFECTS:o You must taper off the dose of Cortisol slowly, to allow the patient to adjust. If you

withdraw the drug quickly, you will see adrenal insufficiency.

ADRENAL ATROPHY: Giving exogenous corticosteroids ------> suppressed ACTH ------> adrenal gland atrophy.

o Don't use with infections.


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o Because of their side-effects (see Effects below), use with caution in case of Diabetes, CVdisease, HTN, psychoses, glaucoma, and osteoporosis.

EFFECTS:o ANTI-INFLAMMATORY: Corticosteroids are the most potent anti- inflammatories available.

Effects on Protein Synthesis: Cortisol promotes synthesis of proteins called Lipocortins ------> inhibit

Phospholipase-A2 ------> inhibit production of arachidonic ------> inhibitleukotrienes and prostaglandins.

Cortisol inhibits the protein-translation ofInducible Cyclooxygenase II(COX-II) ------> inhibit prostaglandins and thromboxanes.

Physiologic Effects: Cortisol has a negative effect on lymphocytes, monocytes, and

macrophages. It inhibits release of cytokines, IL-1, IL-2, and IL-6, and TNF-alpha.

There is feedback inhibition here, too, because these cellsnormally have a stimulatory effect on the hypothalamus (CRH)and pituitary (ACTH). When these cells are then inhibited byCortisol, then the extra stimulus is gone.

Reduced migration of inflammatory cells to site of injury. Increased susceptibility to infection. Decreased lymphocyte production. Impairment of DTH (Delayed-Type Hypersensitivity) reactions.

o PERMISSIVE EFFECTS: The presence of glucocorticoids is required for certain events to takeplace:

The actions of catecholamines on smooth muscle (contraction) and on fat cells(lipolysis).

o TISSUE EFFECTS: Inhibit fibroblasts ------> connective tissue loss and thinning of skin. Negative Ca+2 balance ------> osteoporosis.

Ca+2 and Vit. D absorption in the intestine is decreased ------> increasedPTH ------> Ca

+2is lost from bones.

Negative nitrogen balance Cardiovascular effects: Increased blood pressure, heart-rate, and TPR. Cross-

reactivity with Aldosterone leads to increased Na+

retention.

CNS: Euphoria, psychosis, behavioral changes, lost cognitive function. GI: Increase stomach acid and pepsin production, which can lead to peptic ulcer. Electrolyte balance: Aldosterone cross-reactivity causes higher Na+ and lower K+.

This can lead to hypokalemia, salt retention, and metabolic alkalosis.o METABOLIC EFFECTS: Basically, hyperglycemia, plus any other effects that would increase

the amount of glucose delivered to the brain.

Gluconeogenesis. Insulin release and glycogen deposition. Glucose use is diverted from the periphery

and used centrally.

Protein catabolism Uptake of fat by fat cells. Deposition of fat occurs in other places (Buffalo hump)

CUSHING'S DISEASE: Cushing's disease isSecondary Hypercorticism.ACTH is high in Cushing'sDisease.

o Cushing's Syndrome, on the other hand, describes the general cluster of symptomsattributable to adrenal hyperfunction.

oIf ACTH is low and Cortisol is high, then there is probably a steroid producing tumorsomewhere, such as in the adrenal gland, or ectopically, in another location. On the other

hand, if ACTH levels are high, then it is Cushing's Disease.o SYMPTOMS / CHARACTERISTICS:

Moon Facies. Redistribution of fat away from extremities toward the center. Buffalo Hump Bruising, poor wound healing, osteoporosis. Increased susceptibility to infection. Hyperglycemia


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ADRENAL INSUFFICIENCY (ADDISON'S DISEASE):o SYMPTOMS:

Weakness, fatigue Weight loss, anorexia Hypotension Hypoglycemia Hyperpigmentation: ACTH is derived from pre-opiomelanocortin, the sameprecursor that Melanocyte Stimulating Hormone (MSH).

High ACTH can show some cross-reactivity with melanocytes, resulting inhyperpigmentation.

o ACTH Test: Give ACTH and measure Cortisol levels, to distinguish between primary andsecondary adrenal insufficiency.

PRIMARY INSUFFICIENCY: Give ACTH ------> Cortisol levels remain low. Also, youshould see normal or high ACTH levels to start with.

SECONDARY INSUFFICIENCY: Give ACTH ------> Cortisol levels shoot up. Metyrapone Test: Confirmatory test for secondary adrenal insufficiency.

Give Metyrapone to inhibit 11beta-Hydroxylase and therefore inhibit

Cortisol synthesis. Normally, this blocking of Cortisol synthesis shouldresult in high ACTH levels. If Metyrapone does not yield high ACTH levels,then we know the problem is secondary.

GnRH: Stimulates release of FSH and LH.o EFFECTS:

Pulsatile release of GnRH ------> pulsatile release of LH ------> stimulates folliculargrowth, the luteal surge (via positive feedback effect of estrogen at mid-cycle), andovulation.

Continuous release of GnRH can actually supress the gonadotropins.o STRUCTURE: GnRH is a decapeptide. Two analogues have replaced one amino acid (Lys-6)

in order to give the structure a longer half-life.

Leuprolide: Replace Lys-6 with d-Leucine Nafarelin: Replace Lys-6 by a naphthalene-derived Alanine. SECOND MESSENGER: GnRH-Receptors are coupled to the IP3/DAG/Ca+2second

messenger system.o FSH + LH: They are large molecules and there is no synthetic analogue. They can only be

obtained from natural products.

ESTROGEN:

o PHARMACOKINETICS: Estrogen is lipophilic, metabolized in the liver, and is recycledthrough the enterohepatic circulation. It has a high concentration of effects on the liver compared to the periphery. Antibiotics can destroy normal GI flora ------> interfere with enterohepatic

recycling of estrogen ------> reduce estrogen levels. This is why oral contraceptives

can fail when taken with antibiotics.o Natural Estrogens: The natural estrogen are not used in oral contraceptives, because they

are metabolized

Estradiol: Most potent. Formed primarily in ovary.


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Estriol: Less potent. Formed in the liver from estrogen, or in peripheral fat fromandrostenedione.

Estrone: Less potent. Formed in the liver from estrogen, or in peripheral fat fromandrostenedione.

o POST-MENOPAUSAL THERAPY: Equine natural estrogens are used for post-menopausaltherapy.

BENEFICIAL EFFECTS: Antagonizes the effect of PTH on bone ------> prevent bone loss aftermenopause.

Estrogen does not appreciably add bone mass, but it can preventbone loss.

Increases plasma levels of HDL, and decreases LDL, thus it is effective inpreventing heart disease.

Even in low doses, it prevents hot flashes associated with Menopause. ADVERSE EFFECTS:

Post-menopausal bleeding. Nausea Breast tenderness Migraine headaches. Can promote estrogen-dependent cancers, particularlyuterine cancer but

also breast cancer.

If you use progestins along with estrogen, then this risk iscompletely eliminated.

Give estrogen during first 25 days of month, and add progestinduring last 10-15 days. Bleeding will result.

o ORAL CONTRACEPTION: ESTROGEN ADVERSE EFFECTS: The adverse effects of estrogen are dose-related.

They were a bigger deal in the past, because estrogen doses used to be muchhigher. Today's doses are much lower, and the adverse effects are not aspronounced.

Increased synthesis of clotting factors ------>Thromboembolism,stroke,especially in women who smoke.

Increased production of liver hormone-binding proteins (CBG, TBG, SHBG)------> increased circulating levels of Thyroxine, Cortisol, sex hormones.

Cholelithiasis Depression Minor effects: weight gain, breast tenderness, nausea

o POST-COITAL CONTRACEPTION: Take extremely high doses of estrogens alone afterintercourse. Any of the estrogen would work.

Mechanism unclear, but they think it disturbs the environment in the uterus,making it unfavorable for implantation.

PROGESTINS: They generally modulate the effects of estrogens (and lessen their side-effects)when used in oral contraceptives.

o EFFECTS: Makes cervical mucous thicker. This is an important effect in contraception, as the

thick mucous inhibits movement of sperm and can even be spermicidal. Decreases the endometrial proliferation caused by Estrogen.

o PHARMACOKINETICS: Natural Progesterone is rapidly degraded in liver, thus it cannot begiven PO. Synthetic (oral contraceptive) progestins can be given PO.

o ORAL CONTRACEPTIVES: Combined Oral Contraceptives: The main reason progestins are added to oral

contraceptives is to ensure prompt withdrawal bleeding.

Progestins used alone are not as effective (96.5-97%) as combined oralcontraceptives (99%).


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There is no menstruation at all when using progestins alone. Depo-Provera and Norplant are both pure-progestin mixtures.

DIABETES:

Diabetes Type I (IDDM)

Mechanism Insulin is defective or is never formed.

Survival Insulin is absolutely required for surviv

Synonyms Ketosis-Prone Diabetes

Juvenile-Onset Diabetes

Onset Sudden, often discovered by ketoacido

Nutrition Often thin. Failure of action of insulin.

Ketoacidosis Frequent

Treatment (order of importance) Insulin always required

Diet

Never oral hypoglycemics

o KETOACIDOSIS: Lack of insulin (i.e. high Glucagon:Insulin ratio) promotes lipolysis,breakdown of proteins, and glycogenolysis.

Coma: In hyperglycemia, high sorbitolin plasma ------> dehydration ------>coma.

Coma is more often seen with hypoglycemia than with hyperglycemia. TREATMENT:

Crystalline Zinc Insulin is the most immediate-acting insulin, which isthe treatment of choice for acute ketoacidosis.

Ketoacidosis is treated with bothHCO3- (to relieve the acidosis) and K+ (toreplace lost K

+in cells).

In Ketoacidosis, there is plenty of K+ in the blood, but the cells arestarving for K

+because the patient is dehydrated.

When you give the IV insulin, glucose goes into cells, andK

+follows it. We therefore must replace this K

+to avoid

hypokalemia.

BIOCHEMICAL CAUSE:

Glucagon promotes Lipolysis ------> lots of Acetyl-CoA in the blood. Acetyl-CoA builds up in liver.

Glucagon promotesGluconeogenesis ------>Oxaloacetate is diverted towork on making glucose and istherefore unavailable for the TCA cycle.

Excess Acetyl-CoA cannot be used in TCA cycle and is hence diverted toKetone Body production.

o HYPOGLYCEMIA: SYMPTOMS: Palpitations, sweating, tachycardia, fainting, coma.


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TREATMENT: IV-Glucose. COMA: Hypoglycemic coma is more common in Diabetic than ketoacidosis coma,

due to over treatment with insulin.

Give a comatose diabetic IV glucose, until their blood sugar is known forsure. If you give insulin to a hypoglycemic patient, you'll probably killthem!

ALCOHOL inhibits gluconeogenesis and thus can lead to hypoglycemia in Diabetics.Alcohol combined with insulin can lead to hypoglycemia.o EXERCISE: The cornerstone of treatment of Type-II Diabetes.

It leads to lower blood-sugar and the up-regulation of insulin receptors. It allows for greater penetrance of insulin into muscle tissue, improving the

utilization of insulin.o INSULIN:

SYNTHESIS: Proinsulin is hydrolyzed to Insulin + C-Peptide SECRETION: Stimulated by Glucose, Vagal stimulation, and some amino acids.

Mechanism involves a K+

channel and Ca+2

channel on the pancreatic beta-cell.

Fasting State: No glucose is around. ATP is depleted. K+ channels are open. The cell is in the resting, hyperpolarized state.

Resting State: Plenty of glucose is around (or vagal stimulation). ATP is plentiful. The K+ channel closes. The cell depolarizes. Ca+2-channels open, Ca+2 flows in, and insulin is secreted.

Sulfonylureas:They promote insulin release by blocking the K+-channel,such that it is always closed. Hence the cell is depolarized and insulin is

released.

INSULIN RECEPTOR: It's a Tyrosine Kinase. Down-Regulation: Binding of insulin causes aggregation of receptor-

subunits, and repeated binding can cause internalization and destruction o-f the receptor. This is one way in which continual insulin stimulation canlead to Type-II Diabetes.

ACTION: GLUCOSE-TRANSPORTERS: Insulin up-regulates the transport

ofGLUT4 transporters into the membranes of target cells. LIVER:

Insulin promotes glycogenesis Insulin antagonizes glucagonic effects of glycogenolysis,

ketogenesis, and gluconeogenesis.

MUSCLE: Insulin promotes protein synthesis and glycogenesis. FAT: Insulin promotes fat uptake and storage in adipocytes.

It stimulates lipoprotein lipase ------> free fatty acids fromcirculating lipoproteins.

Glucose transport and glycolysis generateglycerophosphate,which is needed as the glycerol backbone in triglyceride synthesis.

It inhibits intracellular lipase, preventing lipolysis in adipose tissue. TYPES of Therapeutic Insulin:

Porcine Insulin: Has a better allergy profile than the bovine insulin. Bovine Insulin: Insulin antibodies are formed, but they usually don't hurtanything. They can decrease the effectiveness of the insulin, at which point

a different insulin prep can be used.

Allergic reaction is possible, usually due to impurities inpreparation.

Human Insulin: Created by DNA recombination technology. Moreexpensive, and more pure. Use with folks who are allergic to other types.

Lipodystrophy: Adverse reaction of hypertrophy or atrophy in the adipose sitewhere injection was given. To prevent lipodystrophy, switch injection sites.


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o SULFONYLUREAS: Oral hypoglycemics used to treat Type II Diabetes. MECHANISMS:

They promote insulin secretion in beta-cells. They block K+channels onpancreatic beta-cells ------> K

+remain closed ------> beta-cells remain

depolarized ------> promote insulin secretion.

They antagonize the effects of glucagon. They potentiate the action of insulin in target tissues. CONTRAINDICATIONS: Do not use in pregnancy. They cross the placental border. Never use with

gestational diabetes.

DRUG INTERACTIONS: Drugs that neutralize the action of Sulfonylureas:

Diazoxide: Inhibits release of insulin. Phenytoin Propanolol Corticosteroids: Leads to "adrenal Diabetes."

Drugs that potentiate the action of Sulfonylureas, and thus must be usedwith care to avoid hypoglycemia:

Sulfonamides: They displace sulfonylureas from plasma proteins Salicylates: Interferes with urinary secretion.

Phenylbutazone: Competition for liver enzymes, plus interferewith urinary excretion

Chloramphenicol: Competes for liver enzymes Probenecid: Interferes with urinary secretion.

o COMPLICATIONS of DIABETES: MECHANISMS:

GLYCOSYLATION of blood proteins Examples of glycosylated proteins: hemoglobin, components of the

lens, collagens, myelin.

Advanced glycosylation productsare formed through time. Theinitial glycosylations are usually reversible.

POLYOL PATHWAY: The way to get rid of excess glucose in non-insulin-dependent tissues, such as the brain.

Glucose + NADH + N+ ------> Sorbitol + NAD+(AldolaseReductase).

Accumulation of Sorbitol is believed to play a role in Diabeticretinopathy, nephropathy, neuropathy, and microangiopathy.

Major Complications: Atherosclerosis Neuropathy

Loss of sensation can lead to foot ulcers. Retinopathy Nephropathy Microangiopathy

PARATHYROID HORMONE (PTH): It increases serum Ca+2

and promotesresorption of Ca

+2in bone.

EFFECTS: It increases serum Ca+2 and decreases serum phosphate. BONE: It increases resorption of Ca+2 from bone. It increases

osteoclastic activity by promoting the action of osteoblasts.

KIDNEY: It increase resorption of Ca+2, Na+, Cl-, and some amino

acids.

It promotes synthesis of 1,25-(OH)2-Vit-D It increases excretion of PO4-3.

REGULATION: Increased serum Ca+2inhibits PTH secretion.


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basic pharmacology[1]

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