Transcript NPLEX Combination Review Introductory Chapter – Concepts

NPLEX Combination Review
Concepts 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
Pharmacodynamics
and
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
Hepatic Detoxification Pathways:
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…
This process NATURALLY creates peroxide and superoxide free radicals!
PHASE-2 (Conjugation) Pathways:
Take intermediary (more-polar) P450 metabolites and
conjugate them with Amino Acids.
EXCRETION:
BILE
SERUM  URINE
LIVER DETOXIFICATION PATHWAYS
Fat –
Soluble
Compounds
Phase-1
CYP450
(-OH added)
Phase-2
Water –
Soluble
compounds
Enzymatic
Conjugation
Excreted
derivatives
Glycine  Hippurates
Glutathione  Mercapturates
Glucuronic Acid  Glucuronides
Natural creation of Hydroxyl and
Superoxide Radicals leading to Lipid
Peroxidation.
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 GFR
GFR 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.
Half Life and Elimination
• 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.
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
Increase plasma drug level
Decrease plasma drug levels
Increase plasma drug levels
Increase plasma drug levels
DRUG INTERACTIONS / SIDE EFFECTS - 2
DRUG INTERACTIONS / SIDE EFFECTS - 3
Gent., Tobra., and Streptomycin
Antidepressants should not be combined due to possible
additive effects, but often are now prescribed in combination.
DRUG INTERACTIONS / SIDE EFFECTS - 4
DRUG INTERACTIONS / SIDE EFFECTS - 5
•
Physiologic
Actions
Prefix recognition:
– Cholinergic:
• Muscarinic
• Nicotinic
jct.
– Adren___
• Beta 1&2
• Alpha 1&2
Acetylcholine receptor.
Found at postsynaptic parasympathetic locations
Autonomic ganglia. Adrenal medulla. Neuromuscular
“Adrenal acting” (Epi. N.E.) acting receptor:
Cardio-pulmonary postsynaptic sympathetic
GI, Vascular, CNS presynaptic sympathetic
• Suffix recognition:
– __mimetic:
Mimics / acts like the physiologic substance.
• I.e. Sympathomimetic substances
– __lytic
substance.
Blocks the action of the physiologic
• I.e. Parasympatholytic substances
• Receptor activity:
– Agonist:
– Antagonist:
Stimulates that receptor to action.
Blocks that receptor from action.
Autonomic Nervous System Activity:
• Sympathetic N.S.
• Parasympathetic 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.
– 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
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.
ICF
ECF
[Na]
[K]
[K]
[Na]
[Mg]
[Ca]
[Mg]
[Ca]
Cl(Cl- influx hyperpolarizes
the cell, inactivating it.)
CHEMICAL COMPOSITION OF ECF –vs- ICF
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
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
Phosphatidylethanolamine
SAMe
Betaine
[Folate / B3 / B6]
SAMh
Phosphatidylcholine
Acetate
[B2 / B5 / B6]
Acetyl-CoA
Choline
[Choline Acetylase]
Acetylcholine (ACh)
Diet
[Acetylcholine esterase]
Choline
Acetate
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
H2O2
2 GSH (Red)
Glut. Peroxidase [Se]
GSSG (Ox)
2 H2O
NADP+
[B2-FAD] Glut. Reductase
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-2
VITAMIN
FUNCTION
DEFICIENCY
A
D
E
K
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
B-1
B-2
B-3
B-5
B-6
B-12
ALDEHYDE transfer / DECARBOXYLATION
H+ Transfer / FMN – FAD (Flavins)
H+ Transfer / NAD – NADP
ACYL Group Transfer / Co-A
AMINO Group transfer / De-& Trans “aminations”
BERIBERI
CHEILOSIS / GLOSSITIS
VIT-C
BIOTIN
H+ Transfer / Hydroxylation of
Lysine
CARBOXYLATION
FOLATE
METHYL Transfer
METHYL Transfer / Methionine Synth.
Proline&
PELLEGRA (Dementia/Diarrhea/Dermatitis)
Burning Feet / HA / Nausea
Microcytosis / Neuropathy
Macrocytosis / Pernicious
Anemia / Neuropathy
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
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:
CH3
N-5-METHYL-THF
THF
METHIONINE
HOMOCYSTIENE
CH3
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
Ascorbyl Radical
Ascorbate
[ASC*]
[ASC]
Dehydroascorbic Acid
[DHA]
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
RBC
Plasma
LDL
Reduced Glutathione
ASC
Toco R
Oxidized
Glutathione
ASC R
DHA
LDL + R = “oxidized LDL”
Toco
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
H2O2
2 GSH (Red)
Glut. Peroxidase [Se]
GSSG (Ox)
2 H2O
NADP+
[B2-FAD] Glut. Reductase
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.
Normally synthesized by bacteria in the gut. Newborns are deficient.
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
VITAMIN - E
Vitamin E
a-Tocopherol
Vitamin E is a mixture of several related compounds known as tocopherols.
The a-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 a-tocopherol can be regenerated by interaction with vitamin C following scavenge of a peroxy
free radical.
Alternatively, a-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
MACROMINERALS
• Magnesium Mg++
MACROMINERALS
MACROMINERALS
MICROMINERALS
MICROMINERALS
MICROMINERALS
MICROMINERALS
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.