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PHARMACOLOGY: Basic Pharmacology, ANS, Endocrine
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- Weak Acid
- If its pKa < pH of the environment, then the conjugate base (anion) form of the species will
predominate. Example = CH3COO-
- If its pKa > pH of the environment, then the environment is more acidic, so its acidic (neutral) form
will predominate. Example CH3COOH
- Weak acids tend to be absorbed in acidic environments, like the stomach.
- Weak Base
- 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 will give up its extra
H+ to the base, and the base will exist in its cation form. Example = NH4+
- Weak bases tend to be absorbed in basic environments, like the duodenum.
- 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.
- 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
- Endothelial cells in the brain contain enzymes that metabolize, neutralize, many drugs before they
access the CSF.
- MAO and COMT are found in brain endothelial cells. They metabolize Dopamine before
it reaches the CSF, thus we must give L-DOPA in order to get dopamine to the CSF.
- 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 to treat meningitis,
despite the fact that it doesn't normally cross the BBB.
- Penicillin-G is also actively pumped back out of the brain once it has crossed the BBB.
Routes of Administration:
- 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:
- Gastric Emptying: Generally, anything that slows gastric emptying will slow the absorption of 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.
- 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
- FAT: Drug concentrates in fat ------> lower concentration of drug in the plasma ------> high Vd
- BONE: Drug concentrates in bone ------> lower concentration of drug in the plasma ------> high Vd
- TISSUE: Drug concentrates in tissue ------> lower concentration of drug in the plasma ------> high
- PLASMA PROTEINS: Drug binds to plasma protein ------> higher concentration of drug in the plasma
------> low Vd.
- The Vd is based on the total amount of drug in the plasma -- not just the amount of free drug!
- TRANSCELLULAR: Drug concentrates in non-plasma locations ------> lower concentration of drug
in the plasma ------> high Vd
(L / kg)
||Plasma-Protein-bound drugs, and large
drugs that stay in plasma. Concentrates in
blood and thus has a small Vd.
Example = Heparin
||Large water soluble drugs.
Example = Mannitol
||Small water soluble drugs; rapid equil-ibration between body compartments.
Example = Ethanol
||Drugs that bind to tissue
Example = chloroquine, which intercalates with DNA intracellularly.
Vd may be greater than TBW volume,
hence some drug must be bound to plasma.
This is very common and occurs with
- Enterohepatic Circulation: Drugs that are recycled through the enterohepatic circulation will have a lower
concentration of drug in the plasma, and therefore a higher Vd.
PLASMA PROTEIN BINDING: Two main plasma proteins carry drugs in the blood.
|Negatively Charged, hence it binds primarily to weak
||Positively Charged, hence it binds primarily to weak
|Negative acute-phase protein: its synthesis decreases
during time of body insult.
||Positive acute-phase protein: its synthesis increases
during times of body insult.|
|Examples: Phenytoin, Salicylates
||Examples: Quinidine, Propanolol|
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 by microsomes made out of Smooth-ER folded over on itself.
- Cytochrome-P450 Enzyme Complex: Has four required components in order to work.
- Cytochrome-P450 Enzyme
- Cytochrome-P450 Reductase
- NADPH: NADPH is the only energy source. No ATP is required!
- 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 to glucuronides, making the drug more soluble.
- There are multiple isotypes.
- CYT-P450-2 and CYT-P450-3A are responsible for the metabolism of most drugs.
- CYT-P450-3A4 metabolizes many drugs in the GI-Tract, where it decreases the bioavailability of many
orally absorbed drugs.
- INDUCERS of CYT-P450 COMPLEX: Drugs that increase the production of Cytochrome-P450 enzymes.
- ANTI-CONVULSANTS: Phenobarbitol, Phenytoin, Carbamazepine induce CYT-P450-3A4
- Phenobarbitol, Phenytoin also induce CYT-P450-2B1
- Polycyclic Aromatics (PAH): Induce CYT-P450-1A1
- Glucocorticoids induce CYT-P450-3A4
- 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.
- Acute Alcohol suppresses many of the CYT-P450 enzymes, explaining some of the drug-interactions of
acute alcohol use.
- Erythromycin, Ketanazole inhibit CYT-P450-3A4.
- Terfenadine (Seldane) is metabolized by CYT-P450-3A4, so the toxic unmetabolized form builds
up in the presence of Erythromycin. The unmetabolized form is toxic and causes lethal arrhythmias.
This is why Seldane was taken off the market.
- Chloramphenicol, Cimetidine, Disulfiram also inhibit CYT-P450's.
- GLOMERULAR FILTRATION: Clearance of the apparent volume of distribution by passive filtration.
- Drug with MW < 5000 ------> it is completely filtered.
- Inulin is completely filtered, and its clearance can be measured to estimate Glomerular Filtration
- 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. Probenecid can be given to block this secretion.
- Anionic System: The anionic secretory system generally secretes weak ACIDS:
- Penicillins, Cephalosporins
- Thiazide Diuretics
- Glucuronide conjugates
- Cationic System: The cationic secretory system generally secretes BASES, or things that are
- Ion-Trapping: Drugs can be "trapped" in the urine, and their rate of elimination can be increased,
by adjusting the pH of the urine to accommodate the drug. This is useful to make the body get rid
of poisons more quickly.
- To increase excretion of acidic drugs, make the urine more basic (give HCO3-)
- 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.
- 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, Bilirubin Glucuronides,
Glucuronide conjugates, Sulfobromophthalein, Penicillins
- Neutral Transporter: Transports lipophilic agents, such as:
- Cationic Transporter: Transports positively charged agents, such as n-Methylnicotinamide,
- Charcoal can be given to increase the fecal excretion of these drugs and prevent enterohepatic reabsorption.
- Cholestyramine can be given to increase the rate of biliary excretion of some drugs.
- ORDERS of EXCRETION:
- 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.
- The half-life of the drug becomes continually shorter as the drug is excreted.
- 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 Salicylates follow zero-order kinetic at high concentration.
- FIRST-ORDER EXCRETION: The rate of excretion of a drug is directly proportional to its concentration.
- 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
- HALF-LIFE: The half-life is inversely proportional to the Kel, constant of elimination. The higher the elimination
constant, the shorter the half-life.
- One-Compartment Kinetics: Kinetics are calculated based on the assumption that the drug is distributed
to one uniform compartment.
- One compartment kinetics implies that the drug has a rapid equilibrium between tissues and the
blood, and that the release of the drug from any tissues is not rate-limiting in its excretion.
- One-compartment kinetics also assumes that the drug is distributed instantaneously throughout the
body. This is only true for IV infusion.
- Multi-Compartment Kinetics: Most drugs follow multi-compartment kinetics to an extent.
- 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 blood from which a drug is cleared per unit of time.
- CLEARANCE OF DRUG = (Vd)x(Kel)
- The higher the volume of distribution of the drug, the more rapid is its clearance.
- The higher the elimination constant, the more rapid is its clearance.
- 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 is cleared
per unit time. The higher the Kel, the higher is that fraction of volume.
- Drug Clearance of 120 ml/min ------> drug is cleared at the same rate as GFR and is not
reabsorbed. Example = inulin
- Drug clearance of 660 ml/min ------> drug is cleared at the same rate as RPF and is actively
secreted, and not reabsorbed. Example = PAH
- BIOAVAILABILITY: The proportion of orally-administered drug that reaches the target tissue and has activity.
- AUCORAL = Area under the curve. The total amount of drug, through time, that has any activity when
- AUCIV = Area under curve. The total amount of drug, through time, that has any activity when
administered IV. This is the maximum amount of drug that will have activity.
- 100% Bioavailability = A drug administered by IV infusion.
- BIOEQUIVALENCE: In order for two drugs to be bioequivalent, they must have both the same
bioavailability and the same plasma profile, i.e. the curve must have the same shape. That means they
must have the same Cmax and Tmax.
- Cmax: The maximum plasma concentration attained by a drug-administration.
- Tmax: The time at which maximum concentration is reached.
- REPETITIVE DOSES:
- 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
- The more frequent the dosing interval, the less the fluctuations. Theoretically, if you give the drug,
say, once every 30 seconds, then it is almost like continuous IV infusion and there are no fluctuations.
- Steady-State Concentration (CSS): The plasma concentration of the drug once it has reached 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
- If a drug is dosed at the same interval as its half-life, then the CSS will be twice the C0 of the drug.
- If you have a drug of dose 50 mg and a half-life of 12 hrs, and you dose it every 12 hrs, then
the steady-state concentration you will achieve with that 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 higher the Css.
- Kel: Elimination Constant. The higher the elimination constant, the lower is 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.
- 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.
- Loading Dose = twice the regular dose, as long as we are giving the drug at the same interval as the half-life.
- INTRAVENOUS INFUSION: The CSS is equal to the input (infusion rate x volume of distribution) divided by
the output (Kel)
- 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 Constant
- Loading Dose in this case is just equal to Volume of distribution time the Css:
- 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.
- 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 only 60% of the
- If the fraction of renal clearance is less then 100%, then multiply that fraction by the percent of renal
- For example: If you have only 60% of renal function remaining, and 30% of the drug 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.
- 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 the percent 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.
METABOTROPIC RECEPTOR-COUPLING MECHANISMS:
||Stimulates adenylate cyclase (cAMP)
||Inhibits adenylate cyclase
||alpha2-Receptors have Gi ------> inhibit post-synaptic
||Stimulates Phospholipase-C (IP3/DAG)
||alpha1-Receptors have Gq ------> Ca+2 in smooth
||Inhibits Ca+2 channels
||Opens K+ channels
- cAMP PATHWAY (beta-Adrenergic)
- HORMONE RECEPTORS: beta-Adrenergic, GH, most hypothalamic and pituitary hormones.
- 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.
- Xanthines: Caffeine inhibits phosphodiesterase ------> cAMP.
- beta-Arrestin Kinase (betaARK) is activated by tonically high cAMP levels. cAMP phosphorylates
betaARK to activate it.
- betaARK phosphorylates the regulatory domain of the target receptors ------> prevent cAMP
- PHOSPHO-INOSITOL PATHWAY (alpha-Adrenergic)
- HORMONE-RECEPTORS: alpha-Adrenergic
- 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:
- HORMONES: Cortisol, sex steroids, Thyroid Hormone, Aldosterone
- 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
- The hormone-receptor complex then binds to DNA to effect transcription.
- Cortisol stimulates Lipocortin ------> inhibit Phospholipase-A2 ------> inhibit synthesis of
prostaglandins ------> anti-inflammatory properties.
- TYROSINE-KINASE RECEPTORS
- Hormones: Insulin, IGF, EGF
- Pathway: auto-phosphorylation of tyrosine ------> phosphorylate target protein.
- NITRIC OXIDE:
- Constitutive NO-Synthase: Present in most cells, and is responsible for ACh-activated smooth
- Inducible NO-Synthase: Induced by cytokines to cause acute vasodilation.
- NO Functions:
- Forms free radical intermediates in PMN's and macrophages.
IONOTROPIC RECEPTOR-COUPLING MECHANISMS:
- GABA RECEPTOR:
- RECEPTOR MECHANISM: In the CNS, it is a Cl- channel. GABA binds ------> Cl- comes into neuron
------> hyperpolarization ------> Inhibitory effects in CNS.
- Barbiturates (Phenobarbitol): It binds at an allosteric site to increase the effectiveness of GABA. It is
GABAergic, but it is not a GABA agonist, because it does not bind to the same site as GABA.
- Benzodiazepines (Diazepam, Valium): It binds at a separate site than the barbiturates, but it is still
GABAergic and binds at an allosteric site.
- Picrotoxin: GABA Antagonist, it antagonizes GABA, causing excitability in the CNS. Thus it is a
- NMDA RECEPTOR: N-Methyl-D-Aspartate
- MECH: It binds excitatory neurotransmitters, glutamate and aspartate. It lets in Ca+2 (primarily) and also
- Alzheimer's Disease: The NMDA receptor may play a role in the pathogenesis of Alzheimer's Disease.
- Leaky NMDA Channels ------> Na+ comes in the neuron ------> water follows Na+ ------>
reversible cell damage to neurons (hydropic swelling).
- Leaky NMDA Channels ------> Ca+2 builds up in neuron ------> irreversible, oxidative damage
(free radicals) to neuron ------> permanent damage and cell death.
- MK-801 is an NMDA Receptor Blocker that has been tried as experimental treatment for Alzheimer's.
But it doesn't work because it has a stimulatory effect on the hippocampus, causing hallucinations, similar
to taking phencyclidine (PCP).
- ACETYLCHOLINE NICOTINIC RECEPTOR:
- MECH: It is a Na+ channel. When 2 ACh's bind, Na+ comes in, depolarizing the membrane.
- 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-affinity state, and the ACh will stay locked onto
- RESULT: Fewer receptors are available ------> ACh's effect is therefore antagonized ------>
- This explains the way in which cholinesterase inhibitors cause paralysis.
- 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.
- Affinity: A measure of the propensity of the drug to bind with a given receptor.
- Potency: A potent drug induces the same response at a lower concentration. A potent drug has a lower
- Efficacy: The biologic response resulting from the binding of a drug to its receptor. An efficacious drug
has a higher Emax value.
- 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
- EC50 = The drug concentration at which 50% efficacy is attained. The lower the EC50, the more potent
- Emax = the maximum attained biological response out of the drug.
- 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.
- ED50: The drug-dosage at which 50% of the population attains the desired characteristic.
- LD50: Lethal-Dose-50. The drug-dose at which 50% of the population is killed from a drug.
- THERAPEUTIC INDEX = LD50 / ED50
- The ratio of median lethal dose to median effective dose.
- 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 / ED99
- The ratio of the dosage required to kill 1% of population, compared to the dosage that is effective in 99%
- The higher the margin of safety, the better.
- COMPETITIVE INHIBITORS: They bind to the same site as the endogenous molecule, preventing the endogenous
molecule from binding.
- The DOSE-RESPONSE CURVE SHIFTS TO THE RIGHT in the presence of a competitive inhibitor.
- 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.
- The effect of a competitive inhibitor is REVERSIBLE and can be overcome by a higher dose of the
- The intrinsic activity of a competitive inhibitor is 0. It has no activity in itself, but only prevents the
endogenous substance from having activity.
- Partial Agonist: A substance that binds to a receptor and shows less activity than the full agonist.
- At low concentrations, it increases the overall biological response from the receptor.
- At high concentrations, as all receptors are occupied, it acts as a competitive inhibitor and decreases
the overall biological response from the receptor.
- NON-COMPETITIVE INHIBITORS: They either (1) bind to a different (allosteric) site, or (2) they bind
irreversibly to the primary site.
- The 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.
- 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.
- Drug Toxicity: Dose-dependent adverse response to a drug.
- 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.
- 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.
- TERATOGENS: Drugs that adversely affect the development of the fetus
- 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.
- TYPE-I: Immediate IgE-mediated anaphylaxis.
- Example: Penicillin anaphylaxis.
- TYPE-II: Antibody-Dependent Cellular Cytotoxicity (ADCC). IgG or IgM mediated attack against 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.
- 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.
- TYPE-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 for unexplained reasons.
- 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 yrs old) is the most important determinant
- Alcohol can lead to facial flushing, or Tolbutamide can lead to cardiotoxicity, in people with an oxidation
- Succinylcholine can produce apnea in people with abnormal serum cholinesterase. Their cholinesterase
is incapable of degrading the succinylcholine, thus it builds up and depolarization blockade results.
- 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 processes that require
NADPH are impaired.
- Note that this is Acute Hemolytic Anemia, yet it is not classified as an allergic reaction -- it is an
idiosyncrasy when caused by sulfonamides or primaquine. Other anemias are Type-II hypersensitivity
- G6PD deficiency is most prevalent in blacks and semitics. It is rare in caucasians and asians.
- Barbiturates induce porphyria (urine turns dark red on standing) in people with abnormal heme
- Psychosis, peripheral neuritis, and abdominal pain may be found.
- Pharmacokinetic Tolerance: Increase in the enzymes responsible for metabolizing the drug.
- Warfarin doses must be increased in patients taking barbiturates or phenytoin, because these drugs induce
the enzymes responsible for metabolizing warfarin.
- Pharmacodynamic Tolerance: Cellular tolerance, due to down-regulation of receptors, or down-regulation of
the intracellular response to a drug.
- Tachyphylaxis: When using indirect agonists, which stimulate the endogenous substance, this occurs when you
run out of the endogenous substance and therefore see the opposite effect, or no effect at all.
- Tyramine can cause depletion of all NE stores if you use it long enough, 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.
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AUTONOMIC NERVOUS SYSTEM
- Tyrosine ------> DOPA (Tyrosine Hydroxylase)
- This is the rate-limiting step in synthesis.
- 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)
- 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.
CATECHOLAMINE RELEASE: Other neurotransmitters are released along with NE.
- Neuropeptide-Y (NPY)
CATECHOLAMINE BREAKDOWN: The primary way to get rid of NE is reuptake back into the pre-synaptic neuron.
- UPTAKE I: Reuptake of NE back into the presynaptic neuron.
- Monoamine Oxidase (MAO): Breaks down Norepinephrine in the pre-synaptic neuron. Before it can
work, NE must be reuptaken into the presynaptic neuron.
- 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 their way back to neurons,
where they are further broken down MAO. So, MAO is required in either case.
- Catecholamine Metabolites: Two metabolites are found in urine and can be measured to estimate Catecholamine
- NE ------> Vanillyl Mandelic Acid (VMA)
- Epi ------> Vanillyl Mandelic Acid (VMA)
- Dopamine ------> Homovanillic Acid (HVA)
AUTONOMIC RECEPTORS: Brief summary
|Nicotinic Ganglionic (NG)
||Activation of parasympathetic and sympathetic post-synaptic neurons.|
||Activation of skeletal muscle|
IP3 / DAG
||Inhibit sympathetic NE release. This is the way in which
ACh causes relaxation of vascular smooth muscle: ACh
------> inhibit NE ------> vasodilation.|
Inhibitory: cAMP, K+
||Lower rate (on SA node) and force (on myocardium)|
||Pupillary constriction (contract iris muscle); accommodation|
|GI / UG
||Contraction of GI smooth muscle and relaxation of
||Bronchoconstriction and increased secretions|
||Erection (via NO), vasodilation|
IP3 / DAG
||Vasodilation: Strong indirect vasodilatory effect due to
inhibition of sympathetics. At low doses, this leads to a
Some direct vasodilatory effect (especially when exogenous ACh is given)
||Increased sweating in non-adrenergic sweating areas
(regular eccrine sweat glands). Under sympathetic control, but they are M3 muscarinic receptors.|
IP3 / DAG ------> Ca+2
||Vasoconstriction (via IP3 / DAG, increased Ca+2)|
|GI / UG
||Smooth muscle relaxation and contraction of sphincters|
||Pupillary dilation (contract radial muscle)|
Gi ------> cAMP
||Inhibitory on sympathetic and parasympathetic post-ganglionic neurons. For sympathetics, this is auto-regulatory
Gi ------> inhibit cAMP
||NE Inhibits the release of insulin ------> hyperglycemia|
Adenyl Cyclase / cAMP
||Increase rate (SA node) and inotropic state (myocardium)|
||NE stimulatory CNS effects.|
||Increased Renin release ------> higher b.p. ultimately|
Adenyl Cyclase / cAMP
||Relaxation of vascular smooth muscle in skeletal muscle
||Stimulate release of insulin in Pancreatic beta-Cells.
Thus beta-Blockers can lead to hyperglycemia as side-effect.|
||Vasodilation, especially in Kidney ------> higher Renal
||Inhibit Prolactin Release|
||Various stimulatory effects.|
VASCULATURE: There are little or no parasympathetics innervating the vasculature.
- alpha1-Receptors: Vasoconstrictive. They predominate in the splanchnic beds and kidneys, which do not need
a lot of blood flow during sympathetic stimulation.
- The vasculature is primarily under sympathetic control, via alpha1 receptors.
- 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 as ACh) in the blood, then you will see a
pharmacologic effect of direct vasodilation on vascular smooth muscle.
- Coronary Arteries: An exception to the rule. Dilation of coronary arteries occurs by parasympathetic
stimulation ------> vasodilation.
- beta2-Receptors: Vasodilatory. They predominate in skeletal muscle and brain, which get all the blood flow
during sympathetic stimulation.
- Cholinergic Sweat Glands: Thermoregulatory sweat glands throughout the body are under sympathetic control,
but they release ACh and synapse with muscarinic receptors.
- Adrenergic Sweat Glands: Nervous sweating on palms, soles, and armpits is also under sympathetic control,
but it releases NorE and synapses with adrenergic receptors.
- LOW DOSES: Primary effect is vasodilation due to inhibition of sympathetics. In response you see a reflex
- HIGH DOSES: You see a direct bradycardia.
- 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:
- SLUD: Sweating, Lacrimation, Urination, Defecation
- Profuse diarrhea, vomiting, nausea.
- Flushed skin.
- Direct Muscarinic Agonists:
- Indirect Muscarinic Agonists
- Carbamates: Reversible inhibitors of cholinesterase.
- Organophosphates: Irreversible inhibitors of cholinesterase.
- DEATH by Respiratory Suppression in the CNS is the most common cause. This is not an effect on the
diaphragm, but rather is a suppression of the respiratory drive (muscarinic receptors) in the CNS.
- 2-PAM (Pralidoxime): Only effective within the first five minutes of exposure.
- Acetylcholinesterase is a Serine-Protease. It binds to Acetylcholine by latching onto the NH3 group with
a His residue, and hydrolyzing the ester group with a Ser residue.
- Organophosphates phosphorylate the cholinesterase, rendering it inactive. Within the first few minutes,
this phosphorylation is reversible.
- 2-PAM is a strong nucleophile, and binds with the organophosphates to reverse the phosphorylation.
- 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.
- SIDE-EFFECTS of Anti-Muscarinics: Inhibit all muscarinic activities
- 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
- Central: Impairment of all things that ACh mediates in the CNS
- Memory impairment
- Hallucinations, delusions
GANGLIONIC BLOCKERS: Trimethaphan and Hexamethonium.
- They block all autonomic responses.
- Orthostatic Hypotension: block sympathetic reflex control of vasculature.
- Tachycardia: Block parasympathetic reflex control of the heart.
- GI / UG: Decreased motility, urinary retention, constipation (lost parasympathetic reflexes)
- Mouth: Xerostomia
ADRENERGIC AGONISTS: Catecholamine, catecholamine-like compounds.
- PHARMACOKINETICS: Never administered orally, due to high first-pass effect.
- ADVERSE EFFECTS:
- Increased cardiac excitability and arrhythmias ------> ventricular fibrillation.
- CONTRAINDICATIONS: MAO Inhibitors, Cocaine, Tri-cyclics. These all potentiate NE, thus don't give
- SHORT-LIVED: Endogenous catecholamines, or catechol-like compounds, have very short half-lives, due to
abundance of MAO and COMT.
- beta2-AGONISTS: They are primarily used as bronchodilators, but in severe heart failure, there is down-regulation of beta1-receptors. Thus in CHF, beta2 may have a significant effect on the inotropic 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.
- PRINCIPAL EFFECTS:
- Decreased TPR, decreased blood pressure (primary effect)
- Tachycardia (reflex)
- Increased release of renin (reflex)
- SIDE EFFECTS:
- Decreased adrenergic sweating
- Stuffy nose
- Increased insulin release
- Impaired ejaculation
- PRINCIPLE EFFECTS:
- They decrease the inotropic state of the heart ------> decrease oxygen demand of the myocardium. Useful
in treating angina pectoris.
- They decrease blood pressure:
- They increase TPR and decrease cardiac output, but the net effect is to decrease blood pressure.
- They decrease renin secretion in the kidney, which also helps to decrease blood pressure.
- They decrease AV conduction in the heart, and are useful in treating arrhythmias.
- Rebound Tachycardia can result if the drug is withdrawn quickly, due to denervation supersensitivity
(i.e. up-regulation of beta1-receptors after using the drug for a while).
- Insulin release is blocked in pancreas ------> possible hyperglycemia, which can be a problem with
- Can also lead to hypercholesterolemia.
- Local Anesthesia: Membrane-stabilizing effect occurs as the drugs block Na+-channels in heart muscle
and in neurons. This is not of clinical consequence, except when using as eye drops.
- CONTRAINDICATIONS: ASTHMA is an absolute contraindication, for non-selective beta-blockers. You don't
want to block the bronchodilatory effects of beta2-receptors!
- You can possibly use beta1-selective (cardioselective) antagonists with asthmatics, but even these drugs
still have some beta2-activity (even if minimal).
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GROWTH HORMONE (GH):
- ANABOLIC EFFECTS:
- Increases amino acid uptake into tissues.
- Enhances protein synthesis.
- CATABOLIC EFFECTS:
- Antagonizes insulin after it's been around for some time: impairs glucose uptake and promotes lipolysis.
- GH can thus be Diabetogenic for people with Diabetes.
- Synthesis of Thyroid Hormone: Thyroglobulin is synthesized in the Thyroid follicular cells and secreted into the
lumen of the follicles.
- Iodide is taken into the thyroid follicular cells from the general circulation, and it is transcytosed to the
- This transport occurs by active Na+-Cotransport
- ORGANIFICATION: The process of iodinating the thyroxines, forming MIT and DIT, and then forming
T3 and T4.
- On the outside of the membrane, in the lumen, peroxidase catalyzes the oxidation of 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 the Thionamides
- Biological Effect:
- Tri-iodothyronine (T3): Formed by joining MIT + DIT
- It is far more potent and has the principal biological effects: increase transcription at target cell, and
exhibit negative feedback at pituitary.
- Very little of it (5µg / day) is released from the Thyroid. The rest is made by converting T4 ------>
T3 in the peripheral blood.
- T3 is carried, in part, by TBG in the blood. However, T4 binds more tightly to TBG than does T3.
- 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.
- PRIMARY HYPOTHYROIDISM: Deficiency of Thyroxine itself. Goiter is present, due to
- 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 response before it finally kicks in and
- Cretinism: Childhood hypothyroidism, which leads to retarded growth and mental retardation if not treated.
- Hashimoto's Thyroiditis
- Treatment of Hyperthyroidism with radio-iodine, 131I.
- SYMPTOMS: Weakness, shallow respiration, puffy face, frowsy hair.
- HYPERTHYROIDISM: Thyrotoxicosis.
- SYMPTOMS: Hypertension, tachycardia, hypermetabolism, irritability
- Thyroid Storm: Acute hyperthyroid crisis, which can be deadly.
- Grave's Disease: Auto-immune stimulation of TSH receptors. You do see exophthalmos.
- Toxic Nodular Goiter: There is no exophthalmos.
- Thionamides: Inhibit organification of iodine.
- Has a delayed effect, because thyroglobulin stores must first be used up before the effect is
- Ionic Inhibitors: Inhibit uptake of iodine.
- Radio-iodine, 131I: Diffusely kills thyroid cells. Resulting in eventual and inevitable hypothyroidism.
- Iodide: Temporarily (early on) inhibits proteolysis of thyroglobulin, preventing freeing of thyroxine.
Effect wears off. Used to treat Thyroid Storm.
- Often given in preparation for an operation, as it makes the thyroid gland firm and shrink up.
- MINERALOCORTICOID SYNTHESIS: 21beta-Hydroxylase is required for synthesis.
- Cholesterol ------> Pregnenolone ------> Progesterone
- Progesterone ------> 11-Deoxycorticosterone (21beta-Dehydroxylase)
- 11-Deoxycorticosterone ------> Corticosterone ------> Aldosterone
- CORTICOSTEROID SYNTHESIS: 21beta-Hydroxylase, 17alpha-Hydroxylase and 11beta-Hydroxylase are
required for synthesis.
- Cholesterol ------> Pregnenolone
- Pregnenolone ------> Progesterone ------> 17alpha-Hydroxyprogesterone (21beta-Hydroxylase,
- 17alpha-Hydroxyprogesterone ------> 11-Deoxycortisol
- 11-Deoxycortisol ------> Cortisol (11beta-Hydroxylase)
- SEX HORMONE PATHWAY:
- Cholesterol ------> Pregnenolone ------> Dehydroepiandrostenedione (DHEA) ------>
Androstenedione ------> Testosterone
- Testosterone ------> Estradiol (Aromatase)
- Estrogen <====> Estriol <====> Estradiol <====> Estrone
- 21beta-Hydroxylase Deficiency: You see reduced Cortisol ------> excess ACTH ------> adrenal hyperplasia.
- You also see a buildup of the metabolic precursors.
- Buildup of progesterone and 17alpha-hydroxyprogesterone
- Buildup of Androstenedione ------> lots of androgens hanging around ------> feminine
- 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 is some residual aldosterone
- METABOLITES: 17-hydroxycorticosteroids are the metabolic byproducts of Cortisol. They can be measured
in the urine, in order to monitor Cortisol levels in the blood.
- REGULATION: Cortisol, ACTH, CRH, negative feedback, etc. etc.
- CRH: There is a diurnal rhythm of release of CRH, which results elevated levels of Cortisol in the early
- 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!
- Adrenal insufficiency (Addison's Disease)
- Inflammatory, non-infectious processes of all sorts: Arthritis (all types), auto-immune diseases, Asthma,
diseases of the eye.
- CONTRAINDICATIONS / ADVERSE EFFECTS:
- 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.
- Don't use with infections.
- Because of their side-effects (see Effects below), use with caution in case of Diabetes, CV disease, HTN,
psychoses, glaucoma, and osteoporosis.
- 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 ------> inhibit leukotrienes and prostaglandins.
- Cortisol inhibits the protein-translation of Inducible 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 cells normally have a stimulatory
effect on the hypothalamus (CRH) and pituitary (ACTH). When these cells are then
inhibited by Cortisol, 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.
- PERMISSIVE EFFECTS: The presence of glucocorticoids is required for certain events to take place:
- The actions of catecholamines on smooth muscle (contraction) and on fat cells (lipolysis).
- 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 ------> increased PTH ------> Ca+2
is 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.
- METABOLIC EFFECTS: Basically, hyperglycemia, plus any other effects that would increase the amount
of glucose delivered to the brain.
- Insulin release and glycogen deposition. Glucose use is diverted from the periphery and used
- Protein catabolism
- Uptake of fat by fat cells. Deposition of fat occurs in other places (Buffalo hump)
- CUSHING'S DISEASE: Cushing's disease is Secondary Hypercorticism. ACTH is high in Cushing's Disease.
- Cushing's Syndrome, on the other hand, describes the general cluster of symptoms attributable to adrenal
- If ACTH is low and Cortisol is high, then there is probably a steroid producing tumor somewhere, 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.
- SYMPTOMS / CHARACTERISTICS:
- Moon Facies.
- Redistribution of fat away from extremities toward the center.
- Buffalo Hump
- Bruising, poor wound healing, osteoporosis.
- Increased susceptibility to infection.
- ADRENAL INSUFFICIENCY (ADDISON'S DISEASE):
- Weakness, fatigue
- Weight loss, anorexia
- Hyperpigmentation: ACTH is derived from pre-opiomelanocortin, the same precursor that
Melanocyte Stimulating Hormone (MSH).
- High ACTH can show some cross-reactivity with melanocytes, resulting in hyperpigmentation.
- ACTH Test: Give ACTH and measure Cortisol levels, to distinguish between primary and secondary
- PRIMARY INSUFFICIENCY: Give ACTH ------> Cortisol levels remain low. Also, you should
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 should result 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.
- Pulsatile release of GnRH ------> pulsatile release of LH ------> stimulates follicular growth,
the luteal surge (via positive feedback effect of estrogen at mid-cycle), and ovulation.
- Continuous release of GnRH can actually supress the gonadotropins.
- 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+2 second messenger system.
- FSH + LH: They are large molecules and there is no synthetic analogue. They can only be obtained from natural
- PHARMACOKINETICS: Estrogen is lipophilic, metabolized in the liver, and is recycled through the
- 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.
- Natural Estrogens: The natural estrogen are not used in oral contraceptives, because they are metabolized
- Estradiol: Most potent. Formed primarily in ovary.
- Estriol: Less potent. Formed in the liver from estrogen, or in peripheral fat from androstenedione.
- Estrone: Less potent. Formed in the liver from estrogen, or in peripheral fat from androstenedione.
- POST-MENOPAUSAL THERAPY: Equine natural estrogens are used for post-menopausal therapy.
- BENEFICIAL EFFECTS:
- Antagonizes the effect of PTH on bone ------> prevent bone loss after menopause.
- Estrogen does not appreciably add bone mass, but it can prevent bone loss.
- Increases plasma levels of HDL, and decreases LDL, thus it is effective in preventing heart disease.
- Even in low doses, it prevents hot flashes associated with Menopause.
- ADVERSE EFFECTS:
- Post-menopausal bleeding.
- Breast tenderness
- Migraine headaches.
- Can promote estrogen-dependent cancers, particularly uterine cancer but also breast cancer.
- If you use progestins along with estrogen, then this risk is completely eliminated.
- Give estrogen during first 25 days of month, and add progestin during last 10-15 days.
Bleeding will result.
- 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 much higher. Today's doses are much lower, and the
adverse effects are not as pronounced.
- Increased synthesis of clotting factors ------> Thromboembolism, stroke, especially in women
- Increased production of liver hormone-binding proteins (CBG, TBG, SHBG) ------> increased
circulating levels of Thyroxine, Cortisol, sex hormones.
- Minor effects: weight gain, breast tenderness, nausea
- POST-COITAL CONTRACEPTION: Take extremely high doses of estrogens alone after intercourse. Any of
the estrogen would work.
- Mechanism unclear, but they think it disturbs the environment in the uterus, making it unfavorable for
PROGESTINS: They generally modulate the effects of estrogens (and lessen their side-effects) when used in oral
- 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.
- PHARMACOKINETICS: Natural Progesterone is rapidly degraded in liver, thus it cannot be given PO. Synthetic
(oral contraceptive) progestins can be given PO.
- 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 oral contraceptives (99%).
- There is no menstruation at all when using progestins alone.
- Depo-Provera and Norplant are both pure-progestin mixtures.
||Diabetes Type I (IDDM)
||Diabetes Type II (NIDDM)|
||Insulin is defective or is never formed.
Antibodies against pancreatic beta-cells.
||Insulin resistance; down-regulation of insulin receptors; failure of pancreas to release insulin even though it being formed.|
||Insulin is absolutely required for survival.
||Patient will survive without insulin|
||Sudden, often discovered by ketoacidosis.
Childhood polydipsia, polyphagia,
||Gradual, insidious. Often discovered incidentally, or when chronic complications
||Often thin. Failure of action of insulin.
||Seldom or never|
||Insulin always required
Never oral hypoglycemics
|Diet and exercise
- KETOACIDOSIS: Lack of insulin (i.e. high Glucagon:Insulin ratio) promotes lipolysis, breakdown of proteins,
- Coma: In hyperglycemia, high sorbitol in plasma ------> dehydration ------> coma.
- Coma is more often seen with hypoglycemia than with hyperglycemia.
- Crystalline Zinc Insulin is the most immediate-acting insulin, which is the treatment of choice for
- Ketoacidosis is treated with both HCO3- (to relieve the acidosis) and K+ (to replace lost K+ in cells).
- In Ketoacidosis, there is plenty of K+ in the blood, but the cells are starving for K+ because
the patient is dehydrated.
- When you give the IV insulin, glucose goes into cells, and K+ 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 promotes Gluconeogenesis ------> Oxaloacetate is diverted to work on making glucose
and is therefore unavailable for the TCA cycle.
- Excess Acetyl-CoA cannot be used in TCA cycle and is hence diverted to Ketone Body production.
- SYMPTOMS: Palpitations, sweating, tachycardia, fainting, coma.
- TREATMENT: IV-Glucose.
- COMA: Hypoglycemic coma is more common in Diabetic than ketoacidosis coma, due to over treatment
- Give a comatose diabetic IV glucose, until their blood sugar is known for sure. If you give insulin
to a hypoglycemic patient, you'll probably kill them!
- ALCOHOL inhibits gluconeogenesis and thus can lead to hypoglycemia in Diabetics. Alcohol combined
with insulin can lead to hypoglycemia.
- 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.
- 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 can lead to Type-II Diabetes.
- GLUCOSE-TRANSPORTERS: Insulin up-regulates the transport of GLUT4 transporters into the
membranes of target cells.
- 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 from circulating lipoproteins.
- Glucose transport and glycolysis generate glycerophosphate, 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 hurt anything. 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 in preparation.
- Human Insulin: Created by DNA recombination technology. More expensive, and more pure. Use
with folks who are allergic to other types.
- Lipodystrophy: Adverse reaction of hypertrophy or atrophy in the adipose site where injection was given.
To prevent lipodystrophy, switch injection sites.
- SULFONYLUREAS: Oral hypoglycemics used to treat Type II Diabetes.
- They promote insulin secretion in beta-cells. They block K+ channels on pancreatic beta-cells
------> K+ remain closed ------> beta-cells remain depolarized ------> promote insulin
- They antagonize the effects of glucagon.
- They potentiate the action of insulin in target tissues.
- 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.
- Corticosteroids: Leads to "adrenal Diabetes."
- Drugs that potentiate the action of Sulfonylureas, and thus must be used with care to avoid
- Sulfonamides: They displace sulfonylureas from plasma proteins
- Salicylates: Interferes with urinary secretion.
- Phenylbutazone: Competition for liver enzymes, plus interfere with urinary excretion
- Chloramphenicol: Competes for liver enzymes
- Probenecid: Interferes with urinary secretion.
- COMPLICATIONS of DIABETES:
- GLYCOSYLATION of blood proteins
- Examples of glycosylated proteins: hemoglobin, components of the lens, collagens, myelin.
- Advanced glycosylation products are formed through time. The initial glycosylations are
- POLYOL PATHWAY: The way to get rid of excess glucose in non-insulin-dependent tissues, such
as the brain.
- Glucose + NADH + N+ ------> Sorbitol + NAD+ (Aldolase Reductase).
- Accumulation of Sorbitol is believed to play a role in Diabetic retinopathy, nephropathy,
neuropathy, and microangiopathy.
- Major Complications:
- Loss of sensation can lead to foot ulcers.
PARATHYROID HORMONE (PTH): It increases serum Ca+2 and promotes resorption of Ca+2 in 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
- 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.
- Increased serum Ca+2 inhibits PTH secretion.
- Increased serum PO4-3 ------> decreased free serum Ca+2 ------> increased PTH secretion.
- GUT: Increased Ca+2 and PO4-3 absorption in gut.
- 1,25-(OH)2-Vit-D increases resorption of Ca+2 ------> increase plasma Ca+2.
- 24,25-(OH)2-Bit-D may increase deposition of Ca+2 into bones (i.e. osteoblastic activity)
- Increases reabsorption of Ca+2 ------> higher blood Ca+2
- Increases reabsorption of PO4-3 ------> higher blood PO4-3.
- SYNTHESIS: It is promoted by PTH.
- SKIN: Cholesterol ------> Cholecalciferol is a non-enzymatic cleavage catalyzed by UV-Light.
- LIVER: Form Calcifediol. 25-Hydroxylase puts a hydroxyl group on the side chain.
- KIDNEY: Form Calcitriol. 1alpha-Hydroxylase puts a hydroxyl at the 1alpha position.
- ADVERSE EFFECTS:
- Hypervitaminosis D = Vitamin D toxicity, characterized by hypercalcemia and nephrocalcinosis.
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Copyright 1999, Scott Goodman, all rights reserved