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Study Sheet for Exam #1

/Users/michaelthompson/Desktop/outline_of_testable_facts-for exam 1 .docx

Here is an outline of important things to know for exam #1. Unfortunately I have not had a chance to add the adrenergics material. Please also make sure to review the drug lists.

Topic #1: Principles of Drug Action

a) Potency: how much drug does it take to produce an effect

b) Efficacy: how much of an effect can the drug produce

c) Compare 2 drugs in terms of their dose response curves in terms of potency and efficacy

d) ED50 as individual measure (used as a measure of potency) vs. as a population measure (in the calculation of therapeutic index)

e) Therapeutic index (population measure of safety, TI= LD50/ED50) vs. therapeutic window (therapeutic dose range for an individual, defined by the range between the minimum therapeutic concentration and the minimum toxic concentration )

f) Physiological antagonism: examples – histamine/epinephrine, NSAIDS/diuretics

a. When one agonist drug antagonizes or reduces the effect of a second drug by acting at different receptor sites to produce opposite effects to that of the 2nd agonist drug

g) Competitive antagonism: when an antagonist drug binds competitively to the same receptor as the agonist drug, shifting the dose response curve of the agonist to the right (decreased potency/increase in ED50), no change efficacy since the antagonism can be overcome by increasing the dose of the agonist

h) Full agonist vs. partial agonist vs. antagonist vs. inverse agonist

a. Agonists have potency and efficacy

b. Partial agonists have potency but reduced efficacy compared to a full agonist, due to their inability to fully activate the receptor

c. Inverse agonists produce the opposite response to an agonist

d. Antagonists have potency, no efficacy – they can bind to the receptor but can’t activate it. Their effect is seen when they prevent the binding of an agonist

i) Shifts in dose response curve of one drug in the presence of another drug that might be an antagonist : (competitive antagonist: ED50 increases (meaning potency decreases), efficacy stays the same)

Topic #2: Kinetics

a) Types of drug response:



a. adverse (drug working on other systems – dose related),

b. toxic (dose related extensions of therapeutic effect),

c. idiosyncratic (unexpected response, genetically determined, but magnitude of response is dose related),

d. paradoxical (reverse reaction seen in elderly and children – magnitude of response is dose related),

e. allergic (not dose related)

b) Advantages/disadvantages or routes of administration

a. Oral: cheap, easy, but slow, erratic absorption and subject to 1st pass effect

b. IV: can titrate dose, no 1st pass, rapid onset, but expensive and requires trained staff, also easy to give too much drug too fast

c. Sublingual: rapid onset, no 1st pass, but not all drugs suitable for this route

d. Rectal: bypasses 50% of 1st pass effect, good for unruly patients

e. Inhalational: rapid onset & offset, titrateable, localized delivery to airways

c) Factors affecting drug response

a. Absorption – factors that alter absorption of a drug (form of drug administered, pH of environment, presence of food in stomach) – process least altered by aging

b. Distribution – factors that alter distribution

i. Plasma protein binding:

1. drugs bound to plasma proteins are incapable of reaching active site – only free, unbound drug can reach receptor.

2. Can be source of DDIs due to one drug displacing another drug from protein binding sites, thus increasing amount of “free” drug. Example: warfarin and aspirin

ii. Ionization: ionized forms of drugs cannot cross membranes. Example: local anesthetics

iii. Lipid solubility:

iv. Rate of blood flow to organ. Example: lipid soluble drugs go to brain first, since brain has the highest rate of blood delivery



c. Redistribution: action of drug is terminated not by elimination but by drug redistributing away from active site to inactive sites. Example: thiopental is short acting sedative induction agent – sedative action is terminated due to rapid redistribution out of brain to other tissues

d. Metabolism: 1st pass effect, bioavailability

i. 1st pass effect: defined as the portion of the dose of the drug administered that is eliminated by metabolism in the liver before reaching the systemic circulation

ii. Bioavailability: the proportion of the drug dose administered that can be measured in the circulation after non IV route of administration compared to the measurable after IV administration – usually a % amount. IV administration is defined as giving 100% bioavailability Bioavailability = conc. after non-‐IV administration/conc. after IV administration

e. Renal function: can be measured directly by creatinine clearance

f. Patient compliance

g. Effects of aging: increased fat to lean tissue, increased CNS sensitivity to sedatives and analgesics, decreased renal and hepatic function (phase I type of reactions), decreased plasma proteins, more potential for DDIs due to taking more drugs (polypharmacy). Example: BDZ dose needs to be reduced by ½. Aging does not alter drug absorption.

d) Volume of distribution: high Vd indicates drug is lipophilic and undergoes hepatic metabolism. low Vd indicates drug is hydrophilic and undergoes renal elimination

e) 1st order/zero order processes of elimination

a. 1st order: constant % of drug amount in body removed per unit time. Most drugs are eliminated following 1st order kinetics

b. Zero order: constant amount removed per unit time. Seen in overdose. Capacity of enzymes to metabolize the drugs or the capacity of the kidney to excrete the drug is exceeded by the excessive amount of drug. As plasma concentrations fall via zero-‐order kinetics, eventually the process falls within the capacity of clearing organs so that 1st order elimination can happen.. Examples: aspirin, alcohol

f) Steady state concentration (Css): the plasma concentration achieved when the rate of drug intake equals the rate of drug elimination. Dependent upon the rate and dose administered – ideally we dose a drug such that the Css achieved falls within the therapeutic window. Takes 4 half-‐lives to reach Css.



g) Half-‐life: 4 half-‐lives to achieve Css after we initiate drug administration, 4 half-‐lives to remove more than 90% of drug once administration is stopped

a. Calculation problems: if we have administered a drug that has a t1/2 of 5 hrs and achieved a Css of 10 mg/L, once we stop giving the drug, how much will be left in the body after two half-‐lives? Answer: 2.5 mg/L. During the 1st half-‐life of 5 hrs the concentration falls from 10 to 5 mg/L, during the second half-‐life the concentration falls from 5 mg/L to 2.5 mg/L. This question might also be asked differently: how long would it take for the concentration to fall from 10 mg/L to 2.5 mg/L once we stop giving the drug? Answer: two half-‐lives, or 10 hrs.

h) Loading dose: given to produce a rapid therapeutic effect when you can’t wait for four t½ lives to achieve steady state concentration

Topic #3: Drug Metabolism

a. Results of metabolism on drug activity – to change drug into a more excretable form

a. Active form to inactive form (most drugs)

b. Active form to active metabolite (Example: diazepam vs. lorazepam: difference in half-‐life due to formation of active metabolites from diazepam)

c. Inactive form (“prodrug”) to active metabolite (Codeine to morphine)

d. Active form to toxic form (acetaminophen to hepatotoxic form)

b. Phase I vs. Phase II reactions: examples of each type, what each accomplishes in terms of inactivation and making drug excretable

a. Phase I: removes something from compound usually via oxidation, hydroxylation, reduction. Point is to create a space to add something via Phase II reaction that makes compound more polar and thus more excretable. Metabolites may retain parent drug activity or have completely different activity, or may be inactive.

b. Phase II: addition of conjugate group (i.e., glucuronide) to increase solubility and thus excretability. Typically phase II metabolites are inactive

c. Induction (primarily effects Phase I type reactions)

a. Examples of inducers: Phenobarbital, alcohol, cigarette smoke

i. Alcohol and acetaminophen: alcohol induces liver enzymes, some of which also metabolize acetaminophen. The enzyme 2E1 is induced by alcohol – this enzyme converts acetaminophen into a hepatotoxic form. Normally this is a



very minor pathway of acetaminophen metabolism, but when 2E1 is induced, much more of this metabolite is made, causing liver damage.

ii. Cigarette smoke and theophylline: smokers require up to 4 X normal dose of theophylline due to cigarette smoke inducing enzymes (P450 1A2) that metabolize theophylline

d. Inhibition

a. Examples of inhibitors

i. Macrolide antibiotics like erythromycin, antifungals inhibit 3A4. Example: see slide of erythromycin and seldane interaction in metabolism slides. Seldane is a prodrug that needs to be metabolized by 3A4 into a form that is an H1 antihistamine. Erythromycin blocks this conversion, leaving Seldane in the parent (prodrug) form, which is toxic and causes life threatening cardiac arrthymias

ii. SSRIs and codeine: SSRIs inhibit conversion of codeine to morphine by 2D6. Patient gets little to no pain relief.

e. Genetic differences

a. 2D6: extensive metabolizers (lots of 2D6) and poor metabolizers (not enough 2D6)

i. Example: death of baby due to mother taking codeine during breastfeeding, mother was an extensive metabolizer and converted too much codeine to morphine

b. Atypical pseudocholinesterase. Example: succinylcholine toxicity due to prolonged paralysis since patient lacks normal form of pseudocholinesterase

Topic #4: Cholinergics

a) Events at the synapse – differences between adrenergic (S) and cholinergic (C) branches of autonomic nervous system

i) Neurotransmitter released

(1) Preganglionic: ACh for both (S) and (C)

(2) Postganglionic: NE (S), ACh (C)

ii) Inactivation of neurotransmitter



(1) Reuptake into presynaptic terminal (S), enzymatic breakdown in synaptic cleft(C)

b) Results of sympathetic vs parasympathetic activation

i) Sympathetic: fight vs. flight

ii) Parasympathetic: maintain homeostasis

iii) Organ specific responses

(1) Eye: miosis (papillary constriction) (C), mydriasis (papillary dilation) (S)

(2) CV: speed up (S), slow down (C)

(3) GI tract: slow down (S), speed up (C)

(4) Blood vessels: constrict (S), dilate (C)

(5) Respiratory: open airways (S), constrict airways (C)

c) Cholinergic drugs: direct-‐acting vs. indirect-‐acting

i) Direct acting mimetic (stimulates receptor directly as agonist)

(1) Pilocarpine, evoxac, bethanechol

ii) Indirect acting mimetic (does not act on receptor, but prolongs ACh action in synapse)

(1) Cholinesterase inhibitors: neostigmine, physostigmine, ambenonium, echothiophate, edrophonium, Aricept

(2) Spider venom: causes excessive Ach release

iii) Direct acting lytic (competitive receptor antagonists)

(1) Muscarinic receptors: Atropine, scopolamine

(2) Nicotinic receptors: NMJ – blockers: curare type (non-‐depolarizing), SUX (depolarizing), snake venom

iv) Indirect acting lytic

(1) Botox: blocks Ach release



v) Clinical uses of cholinergic acting drugs

(1) Agonists

(a) stimulate salivation: pilocarpine, cevemilene (Evoxac)

(b) reduce intraocular pressure in glaucoma: pilocarpine, reversible cholinesterase inhibitors like physostigmine, neostigmine

(c) myasthenia gravis: reversible cholinesterase inhibitors like physostigmine, neostigmine

(d) nerve gas (Sarin), insecticides (Malathion): both are nonreversible cholinesterase inhibitors

(e) Alzheimer’s Disease: Aricept, Rivastigmine – used to prolong action of Ach to enhance cognitive functioning in Alzheimer’s – only works as long as there are functioning cholinergic neurons

(2) Antagonists

(a) Muscarinic:

(i) Eye exams: atropine analogues used to dilate pupils (mydriasis)

(ii) Block vagal reflex: atropine

(iii) Motion sickness: scopolamine transdermal patch behind ear

(iv) Reduce salivation: atropine analogues like Pro-‐Banthine

(v) Overactive bladder: oxybutynin (Ditropan)

(b) Nicotinic

(i) Induce general skeletal muscle paralysis: d-‐tubocurarine (non-‐depolarizing competitive receptor block), succinylcholine (SUX) – depolarizing NMJ blocker

(ii) Localized paralysis to treat wrinkles, TMD pain: BOTOX (prevents ACh release from presynaptic terminal by blocking Ca++ influx in presynaptic terminal, causing localized muscle paralysis at site of injection))

(3) Adverse side effects

(a) Signs/symptoms of cholinergic overstimulation



(i) Muscarinic – “SLUDE”: excessive salivation, lacrimation, urination, diarrhea, emesis

(ii) Nicotinic-‐ paralysis

(b) Symptoms of cholinergic (muscarinic)blockade

(i) “Mad as a hatter, hot as hell, dry as a bone, blind as a bat”

(4) Drug:Drug interactions:

(a) Muscarinic antagonists: additive CNS depression, xerostomia with drugs that have anticholinergic side effects: TCAs, H1-‐antihistamines

vi) Direct Acting Neuromuscular Junction Blocking Agents:

(1) Action:

(a) interruption of the nervous impulse at the skeletal neuromuscular junction by direct antagonist action on the nicotinic post-‐synaptic receptor, resulting in muscular paralysis

(2) Medical Use:

(a) as adjuncts to general anesthesia to relax the abdominal skeletal wall muscular during abdominal surgery, allowing less general anesthesia to be used

(3) In Dentistry:

(a) to aid endotracheal intubation during general anesthesia, in trismus to permit opening of the jaw for diagnosis and treatment, in mandibular fractures to relax muscles so that bone fragments can be manipulated

(4) Non-‐depolarizing: Curare-‐type

(a) Agents: d-‐tubocurarine, pancuronium, vecuronium, rocuronium

(b) Action: competitive receptor block prevents ACh from binding to nicotinic end-‐plate receptor. Action is reversible by increasing the concentration of ACh at the receptor by giving an anticholinesterase such as physostigmine or neostigmine

(5) Depolarizing: Succinylcholine type

(a) Agents: Succinylcholine, Decamethonium



(b) Action: these agents do not act by receptor block, but by prolonged receptor stimulation that leads to depolarization of the neuron and an inability to repolarize and fire again. Thus there is a brief period of muscle stimulation or fasiculatiion prior to paralysis. This action can’t be reversed by an anticholinesterase; the blocking drug itself must be removed

(c) Remember that some patients have atypical pseudocholinesterase, and thus the usually brief action of succinylcholine will be prolonged

(6) Indirect-‐Acting NMJ-‐Blocking Agents:

(a) Botulinum Toxin (Botox)

(i) Action: blocks ACh release by interfering with extracellular Ca++ ion influx into the presynaptic nerve terminal, which is needed for ACh to be released, so no stimulation of nicotinic receptors, thus causing muscle relaxation, reducing muscle contraction, wrinkles.

(ii) Dental Use:

1. Oromandibular Dystonia:

2. Jaw closure dystonia including bruxism, related dental problems, and associated pain can be controlled with BTX injections into the masseter and temporalis muscles bilaterally. In more severe forms weakening the internal pterygoids will also be required.

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