NPLEX Combination Review Concepts in Pharmacology, Pharmacognosy and Nutrition Paul S. Anderson, ND...

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NPLEX Combination ReviewConcepts in Pharmacology,

Pharmacognosy and Nutrition

Paul S. Anderson, ND

Medical Board Review Services

Copyright MBRS

4-Day Review Synopsis:• *With the exception of the introductory section, each

organ system will be integrated in the manner the cases will likely come on the Board Exams:

==========================================GENERAL SCHEDULE:• Day 1

– Introduction through Pulmonology / Hematology

• Day 2– Hematology through Neurology

• Day 3– Emergency Medicine through Dermatology / Gastro

• Day 4– Gastro through GYN

Pharmacodynamicsand

Pharmacokinetics

They are reactions between the body, the drug and possibly other substances that can potentially affect the availability and usefulness of the drug administered.

Pharmacology of Interactions:• Pharmacokinetic Reactions

– Absorption– Distribution

• Additive to or Displacing from Albumen• Cellular Effects

– Distribution / Receptor Activity

– Metabolism– Elimination

• Pharmacodynamic Reactions– Antagonist– Synergist / Additive / Agonist

Interactions: Absorption• pH Alteration

– Drugs that require ionization (Antifungal, Minerals) suffer in higher pH gastric environments.

• Direct Blockade– Binding / Chelating agents

• GI Motility Alteration– Increased motility = Increased absorption– Decreased motility = Decreased absorption– (To a point).

Interactions: Distribution• Albumen Effects

– Most drugs / Hormones are transported on albumens– The “Free” portion (unbound) is the bio-available portion– Substances that increase binding DECREASE availability of

drug to tissues– Substances that decrease binding INCREASE availability of

drug to tissues

• Cellular Effects– Distribution / Receptor activity

• Actions by one substance on another substance at the receptor level.

• May include displacement from cellular binding site• May include receptor blockade• May include enzyme modification (common with poisons)

Interactions: Metabolism• Induction Errors

– Substances that INDUCE hepatic metabolism REDUCE plasma availability of the drug

• Inhibition Errors– Substances that SLOW hepatic metabolism

INCREASE plasma availability of the drug

• Substrate Errors– Some substances supply substrate for the

hepatic detoxification pathways– These substances induce metabolism,

REDUCING plasma availability

PHASE-1 (Cytochrome P450) Pathways:

Generally render Non-polar (Lipid Soluble) substances Polar

Reactions: Oxidation, Reduction, Hydrolysis, Hydration…

Co-factors / Substrates: B2,3,6,12,Folate, GSH, AA’s…

PHASE-2 (Conjugation) Pathways:

Take intermediary (more-polar) P450 metabolites and conjugate them with Amino Acids.

Hepatic Detoxification Pathways:

EXCRETION:

BILE SERUM URINE

This process NATURALLY creates peroxide and superoxide free radicals!

LIVER DETOXIFICATION PATHWAYS

Phase-1 CYP450

(-OH added)

Phase-2

Enzymatic Conjugation

Excreted derivativesFat –

Soluble Compounds

Water – Soluble compounds

Natural creation of Hydroxyl and Superoxide Radicals leading to Lipid Peroxidation.

Glycine Hippurates

Glutathione Mercapturates

Glucuronic Acid Glucuronides

Interactions: Elimination

• Kidney Clearance Issues:

– Reduced GFR can result in Increased plasma levels of RENALLY CLEARED DRUGS.

– Increased GFR will cause lower effect of chronically prescribed drugs, due to increased excretion.

Calculated GFRGFR Changes and drug elimination considerations:

• Healthy Kidneys: 60 or higher

• Stage 1 Chronic Kidney Disease (CKD):– 90 or higher with HTN, Proteinuria, AbN Ki anatomy

• Stage 2 Chronic Kidney Disease (CKD):– 60-89 with the above

• Stage 3 Chronic Kidney Disease (CKD):– 30-59

• Stage 4 Chronic Kidney Disease (CKD):– 15-29

• Stage 5– 15 or less / Dialysis

The Bottom Line:

• Use caution applying typical dosing for substances in patients with any pathologic alteration in the physiologic parameters of drug metabolism:– Kidney disease– Liver disease– GI disease– Any patient over 65

Interactions: Antagonist

• Antagonistic Pharmacologic Properties– Must have opposite actions of drugs at same

time– Different sites of action in the body– Drugs of equal strength (of action) will have

uniform antagonism– Unequal antagonism will favor the stronger

acting drug.

Interactions: Synergist / Additive / Agonist

• Additive effects of drugs

• May have: – Common receptor activity

• I.e. Alcohol and Benzodiazepines

– Synergistic receptor activity• I.e. H-1 Blockers and Skeletal Muscle Relaxants

Half Life• The biological half-life of a substance is

the time required for half of that substance to be removed from an organism by either a physical or a chemical process.

• Biological half-life is an important pharmacokinetic parameter and is usually denoted by the abbreviation t-1/2.

• First-order elimination Fast.This process is usually a first-order logarithmic process - that is, a constant proportion of the agent is eliminated per unit time.

• Michaelis – Menten (and Hill) – Saturable quality of Enzyme reactions:– Estimating the speed of enzymatic reaction based on [substrate.]– Once the enzyme system is saturated (by substrate) the kinetics (eA)

change (First order to Zero order elimination.)

• Zero-order elimination Slow.There are circumstances where the half-life varies with the concentration of the drug. – For example, Aspirin, Phenytoin and Ethanol may be consumed in

sufficient quantity to saturate the metabolic enzymes in the liver, and so is eliminated from the body at an approximately constant rate (zero-order elimination).

Half Life and Elimination

• First-order elimination Fast.This process is usually a first-order logarithmic process - that is, a constant proportion (percent) of the agent is eliminated per unit time.

Half Life and Elimination

Michaelis – Menten (and Hill) Saturable quality of Enzyme reactions:Estimating the speed of enzymatic reaction based on [substrate.]Once the enzyme system is saturated (by substrate) the kinetics (eA) change (First order to Zero order elimination.)

Shows drug in and drug out over time, initially as first order. Once the enzymatic elimination pathways are saturated the kinetics of elimination (and build-up) in the body change to zero order, often causing overdose.

Vmax Maximum elimination under MM kinetics:

Half Life and Elimination• In practice, this means that it takes just over 4.7

times the half-life for a drug's serum concentration to reach steady state after regular dosing is started, stopped, or the dose changed. – “The 5X rule”

• So, for example, digoxin has a half-life (or t½) of 24-36 hours; this means that a change in the dose will take the best part of a week to take full effect.

• For this reason, drugs with a long half-life (e.g. amiodarone, elimination t½ of about 90 days) are usually started with a loading dose to achieve their desired clinical effect more quickly.

Sample Rx – Narcotic (C-II)

Sample Rx – General

DRUG INTERACTIONS / SIDE EFFECTS

Decrease plasma drug levels

Increase plasma drug levels

Increase plasma drug level

Increase plasma drug levels

DRUG INTERACTIONS / SIDE EFFECTS - 2

Antidepressants should not be combined due to possible additive effects, but often are now prescribed in combination.

Gent., Tobra., and Streptomycin

Physiologic Actions• Prefix recognition:

– Cholinergic: Acetylcholine receptor. • Muscarinic Found at postsynaptic parasympathetic locations• Nicotinic Autonomic ganglia. Adrenal medulla.

Neuromuscular jct.

– Adren___ “Adrenal acting” (Epi. N.E.) acting receptor:• Beta 1&2 Cardio-pulmonary postsynaptic sympathetic• Alpha 1&2 GI, Vascular, CNS presynaptic sympathetic

• Suffix recognition:– __mimetic: Mimics / acts like the physiologic substance.

• I.e. Sympathomimetic substances

– __lytic Blocks the action of the physiologic substance.• I.e. Parasympatholytic substances

• Receptor activity:– Agonist: Stimulates that receptor to action.– Antagonist: Blocks that receptor from action.

Autonomic Nervous System Activity:• Sympathetic N.S.

– Generally stimulating– GI & GU Tract Depressing

• Sympathomimetic– Drug (i.e. Epinephrine) that

acts at one or more sympathetic receptor site.

– Actions of the drug mimic sympathetic activity to the extent that receptors are activated

• Sympatholytic– Drug (i.e. Reserpine) that

blocks or otherwise decreases catecholamines. Thus increasing some parasympathetic tone.

• Parasympathetic N.S.– Generally relaxing– GI & GU Tract Stimulating

• Parsympathomimetic– Drug (i.e. Pilocarpine) that acts

at one or more parasympathetic receptor site.

– Actions of the drug mimic parasympathetic activity to the extent that receptors are activated

• Parasympatholytic– Drug (i.e. Atropine) that blocks

one or more parasympathetic receptor sites.

– Actions of the drug effectively block parasympathetic activity and thus increase some sympathetic tone.

Excitable Membrane Physiology

[Na][Mg]

Cl-(Cl- influx hyperpolarizes the cell, inactivating it.)

The resting membrane potential is predicated on the ionic balance between the ICF and the ECF. Changes in those ion concentrations create AP generation and cellular activation.

E.C.F. I.C.F.

Na 142 mEq/L 10 mEq/L

K 4 “ 140 “

Ca 2.4 “ 0.0001 “

Mg 1.2 “ 68 “

Cl 103 “ 4 “

HCO3- 28 “ 1 “

pH 7.4 7.0

CHEMICAL COMPOSITION OF ECF –vs- ICF

CHOLINERGIC (ACh) RECEPTORS

THE ACETYLCHOLINE (ACh) CHANNEL(A Ligand Gated Ion Chanel)

Acetylcholine

• Multiple sites of action in the body– Acts as a neurotransmitter (PNS / CNS)– Acts as a hormone (Cornea)

• Peripherally acts at the neuromuscular junction, and elsewhere via Nicotinic and Muscarinic receptors

• Centrally seems to be involved in memory and other neurological counter regulation

Acetylcholine Metabolism

SERINE

Pyruvate[Folate / B3 / B6]

Acetate[B2 / B5 / B6]

Acetyl-CoA[Choline Acetylase]

Acetylcholine (ACh)Diet [Acetylcholine esterase]

Choline Acetate

Phosphatidylethanolamine

Phosphatidylcholine

Choline

Betaine

ADRENERGIC (Epi. / NE) RECEPTORS

Plant Medicine Prototypes - 1• Rauwolfia serpentina

– Acts by decreasing activity of neuronal storage vessicles.• CNS: Decreases Catecholamines• PNS: Decrease Norepinephrine and Serotonin

• Digitalis lanata (leaf)– Decreases aberrant SA to AV conduction

• Positive Inotrope and Dromotrope– Blockade of Na/K ATPase pump (Increases intracellular Ca.

results in elongated plateau on cardiac AP)– Improves atrial dysfunction

• Chincona (bark)– Two primary chincona alkaloids:– Mild to moderate anticholinergic effects, direct toxic effects.

• Quinine (Anti spasmodic [noctournal leg cramps], antipyretic, Ameobacide)

• Quinidine (Antiarrhythmic)

• Atropa belladonna– Acetylcholine antagonist (Parasympatholytic)

• Muscarinic receptor blocade (Post-synaptic parasympathetic)• Slows digestion, decreases secretions, dilates pupils…

Plant Medicine Prototypes - 2

• Calabar (bean)– Physostigmine

• Reversible inhibition of Acetylcholine Esterase• Increases Acetylcholine levels (Parasympathomimetic)

– Increases secretions, digestion, constricts pupils…

• Pylocarpus mycrophyllus / jaborandi– Pilocarpine

• Cholinergic (Parasympathomimetic)• Used as eye drop in glaucoma treatment

• Erythroxylon coca– Cocaine

• Dilates pupils• Anesthetic to mucous membranes• Increases Dopamine (reuptake inhibition) especially active in the

nucleus accumbuns / pleasure centers.

Plant Medicine Prototypes - 3• Eschscolizia californicum

– California poppy• Used in pain control tincture formulas etc.

• Papaver somniferum– Opium, Codeine, Morphine…

• The “Opiates”– Analgesic pain medications, centrally acting– Also block parasympathetic activity

– Papaverine• Papaver alkaloid

– Used for angina (vasodilatation)

• Claviceps purpurea (Ergot – Rye or Wheat fungus)– Primarily vasoconstrictive agents (Ergonovine, DHE …)

• Post partum / abortive hemorrhage

– Also Bromocriptine (Dopamine agonist) and LSD family.

Glutathione

The Glutathione Redox Cycle and Peroxide

2 GSH (Red) NADP+

Glut. Peroxidase [Se] [B2-FAD] Glut. Reductase

GSSG (Ox) NADPH+H HMP Shunt

LIPID METABOLISM AND CARNITINE

PROTEINS: Amine Transfer

B6 and Transaminase Reactions

VITAMINS-1

• WATER SOLUBLE– B-1, B-2, B-3, B-5, B-6, B-12– C– FOLACIN – BIOTIN

• FAT SOLUBLE– A– D– E– K

VITAMINS-2VITAMIN FUNCTION DEFICIENCY

Part of RHODOPSIN / VISION

GI (Incr. Calcium absorption)

Antioxidant

CARBOXYLATION (of glutamate) / Calcium “chelation” with glutamate.

NIGHT BLINDNESS

Rickets / Osteomalacia

Ataxia

Factor 2/7/9/10 bleeding disorders

ALDEHYDE transfer / DECARBOXYLATION

H+ Transfer / FMN – FAD (Flavins)

H+ Transfer / NAD – NADP

ACYL Group Transfer / Co-A

AMINO Group transfer / De-& Trans “aminations”

METHYL Transfer / Methionine Synth.

BERIBERI

CHEILOSIS / GLOSSITISPELLEGRA (Dementia/Diarrhea/Dermatitis)

Burning Feet / HA / Nausea

Microcytosis / Neuropathy

Macrocytosis / Pernicious Anemia / Neuropathy

BIOTIN

FOLATE

H+ Transfer / Hydroxylation of Proline& Lysine

CARBOXYLATION

METHYL Transfer

SCURVY

Seborrheic Dermatitis, Nervous disorders, Bound by Avidin (in egg white)

Macrocytosis / Glossitis / Colitis

VITAMINS-3

• B-1 (THIAMIN) Thiamin pyrophosphate - active– Beri-beri. Oxidative decarboxylation– Wheat germ, fish, meat, eggs, milk, cereals, green veggies.– Cardiac and neurological effects.

• B-2 (RIBOFLAVIN)– FMN (flavinoidmononucleotide), FAD

(flavinadeninedinucleotide)– Fish, meat, eggs, milk, greens.– Angular stomatitis, glossitis, seborrhea, anemia

• B-3 (NIACIN / NIACINAMIDE)– Pellagra. NAD / NADH formation.– Part of the GTF. Used in Dehydrogenase reactions.– Aka. Nicotinic acid / Nicotinamide.– Wheat germ, fish, liver, peanuts.

VITAMINS-4

• B-5 (Pantothenic acid)– Ubiquitous in foods. – Deficiency not common. Part of Acetyl~S~CoA. (CoA)

• B-6 (Pyridoxine) Pyridoxal-5-Phosphate (active)– Magnesium is a cofactor. Used for amino acid metabolism.– Cereals, fish, meat, eggs, greens.– Anemia, dermatitis, neurological deficits (peripheral)

• B-12 (Cyanocobolamin)– Meat, dairy, fermented foods. (Bacterial action)– Intrinsic Factor facilitates absorption.– Pernicious anemia. Macrocytic (megaloblastic) anemia.– Activates the conversion of Homocystiene to Methionine– Terminal Ileum absorption

VITAMINS-5 : B12 & FOLATE

N-5-METHYL-THF THF

HOMOCYSTIENE

METHIONINE

THF (TetraHydroFolate) is active in methyl group transfer.

The CH3 transfer helps DNA in new cell production.

B12 frees FOLATE from its bound form (N-5-CH3-THF) to its coenzyme form (THF). It does this via a CH3 release in the following reaction:

VITAMINS-6• C (ASCORBATE)

– Fruit / Vegetables– Reducing agent (antioxidant). Large amounts convert to

oxalate. Hydroxylation Reaction cofactor. (Bile, Proline, Dopamine)

– Collagen integrity, immune function.• FOLATE

– Converted to the active form (Tetrahydrofolate – THF) by B12. Required for nucleotide synthesis. Methyl donor.

– Cereals, liver, fruit, greens.– Macrocytic anemia, like B-12, without the neurologic deficits.

• BIOTIN– Many foods, produced by intestinal bacteria.– Dermatitis.– Carries CO2 in carboxylase reactions– Avidin (from raw eggs) will bind Biotin.

Oxidation of Ascorbic Acid

Dehydroascorbic Acid

Ascorbate

Ascorbyl Radical

[ASC*]

LDL Oxidation: The LDL has the potential to carry an incredible load of free radical.Anti-Oxidant effects of Vitamins E, C, GSH and the RBC - Lipid – Plasma Interaction

Reduced Glutathione

Oxidized Glutathione

Plasma

ASC RDHA

LDLRBC

TocoToco R

LDL + R = “oxidized LDL”

GLUTATHIONE• A TRIPEPTIDE (thiol glutathione [GSH])• Poor oral absorption• Cofactor for antioxidant enzymes

– Mitochondrial protection from endogenous oxygen radicals– High electron donating capacity, coupled with its high

intercellular concentration give it extreme reducing power.

• Two forms:– Reduced (the antioxidant) and Oxidized

• Production:– Step 1: {[methionine cysteine] + glutamate}GGCS enz

gamma-glutamylcysteine– Step 2 : {gamma-glutamylcysteine+glycine–GSH enz GSH– Glutathione is preserved by Ascorbate

Glutathione

The Glutathione Redox Cycle and Peroxide

2 GSH (Red) NADP+

Glut. Peroxidase [Se] [B2-FAD] Glut. Reductase

GSSG (Ox) NADPH+H HMP Shunt

VITAMIN - K

Vitamin K serves as an essential cofactor for a carboxylase that catalyzes carboxylation of glutamic acid residues on vitamin K-dependent proteins.

The key vitamin K-dependent proteins include:

1. Coagulation proteins: factors II (prothrombin), VII, IX and X

2. Anticoagulation proteins: proteins C, S and Z

3. Others: bone proteins osteocalcin and matrix-Gla protein, and certain ribosomal proteins

Normally synthesized by bacteria in the gut. Newborns are deficient.

VITAMIN - E

Vitamin E

-Tocopherol

Vitamin E is a mixture of several related compounds known as tocopherols.

The -tocopherol molecule is the most potent of the tocopherols. Vitamin E is absorbed from the intestines packaged in chylomicrons.

The liver can export vitamin E in VLDLs. Due to its lipophilic nature, vitamin E accumulates in cellular membranes, fat deposits and other circulating lipoproteins.

The major site of vitamin E storage is in adipose tissue.

The major function of vitamin E is to act as a natural antioxidant by scavenging free radicals and molecular oxygen.

In particular vitamin E is important for preventing peroxidation of polyunsaturated membrane fatty acids. The vitamins E and C are interrelated in their antioxidant capabilities.

Active -tocopherol can be regenerated by interaction with vitamin C following scavenge of a peroxy free radical.

Alternatively, -tocopherol can scavenge two peroxy free radicals and then be conjugated to glucuronate for excretion in the bile.

VITAMIN - A

Vitamin A

Use RBP

(Retinol Binding Protein)

VITAMIN - D

MACROMINERALS

MACROMINERALS• Magnesium Mg++

MACROMINERALS

MICROMINERALS

OTHER NUTRIENTS - FLAVINOIDS

• Phenols are universal in plant material

• Flavinoids are polyphenolic compounds– Act as antioxidant to foods in storage– Protect Ascorbate and Tocopherol from oxidative

decomposition during digestion– Have various levels of activity after absorption,

based on the form taken in the plasma.

• Some forms stabilize mast cells – (anti histaminic)– Hesperidin, Quercetin, Rutin…

OTHER NUTRIENTS – Co-Q-10

• Aka. Ubiquinone– Dose for Cardio Effect 75 mg +– Absorption is better with fat intake (either in the

supplement or taken with dietary fats)

• Powerful antioxidant– Helps in the preservation of Vitamin E– Found in Fish and other Meats (low quantity)

• Body ability to synthesize drops after 30

• Formed in the Cholesterol / HMG pathway– Decreased by the “statin” class of drugs

OTHER NUTRIENTS – ALPHA-Lipoic-acid

• Cofactor for mitochondrial energy reactions• Substrate production for Krebs cycle

– Catalyses the metabolism of the branch chain AA’s• Leucine, Isoleucine, Valine

– Supports glycine cleavage which supports 5-10-Methyl Tetrahydrofolate production

• Used in nucleic acid synthesis

• Antioxidant capabilities– Complexes with arsenic as an antioxidant– Regenerates other antioxidants (C,E,Q10, GSH)– Repairs oxidative damage

• Inhibits the enzyme elastase which degrades pulmonary elastin in COPD

• Metal ion chelation ?? (in vitro only?)

Some charts and figures come from the Case Files series, Particularly Case Files in Emergency Medicine and Case files in Internal Medicine.

Lang Publishing.

NPLEX Combination Review Concepts in Pharmacology, Pharmacognosy and Nutrition Paul S. Anderson, ND...

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