Quinine, Only anti malarial in the 1920's, Less potency but has re-emerged due to resistance which develops less readily. 

Mechanism: Intercalates into DNA of Parasite. This disrupts the parasites replication and transcription

Chloroquin ( Aralen), Mechanism: Sketchy - interfers with metabolism and hemoglobin utilization by the parasites. 

Resistance: Resistance is widespread through sub-saharan africa and S. America due to the decrease in accumulation in the food vavuole by decreased uptake.

Pyrimethamine ( Daraprim) 

Use: Both prophylaxis and treatment of P. Falciparum. 

Mechanism: Inhibits dihydrofolate reductase and synthesis of folic acid.

Artemether and Lumefantrine ( Coartem) 

Use: Treatment of acute , uncomplicated infections due to P. Falciparum. 

Mechanism : Exact mechanism unknown. May inhibit nucleic acid and protein syntesis

Isoniazid : Highly specific for mycobacteria. Bactericidal against actively growing bacilli. Exact mechanism unkown. Required activation by KatG or AhpC catalase-perioxidase to produce isonicotinic acyl-NADH. 

Resistance due to: Mutation in KatG.

-Rifampin inhibits the DNA-dependent RNA Polymerase. 

-Inhibits initiation of RNA synthesis but NOT THAT IS ALREADY IN PROGRESS prior to drug treatment. 

-Does not inhbit DNA-RNA polymerase complex formation but INHIBITS TRANSLOCATION. Selectively toxic because mammalian RNA plymerases are not sensitive. Effective in preventing emergence of isoniazid resistance in combination therapy, although resistance to rifampin is on the rise it has a very high sterilizing activity . Useful in the reatment of pulmonary and extrapulmonary TB.

Antitubercular agent, 

-Use: Adjunctive treatment of tuberculosis in combination with isoniaxid or rifampin. 

-Mechanism: Conversion to a drug metabolite in mycobacterium which lower pH with bacteria: exact mechanism not elucidated.

POLYENES: 

-[Amphotericin ]B - Injections, conventional ( Fungizone), 

 -Lipid complex form ( Ablecet), 

 -Colloidal suspension w/ cholesterol sulfate (Amphotec), 

 -Liposomal drug devlivery system (AmBisome), 

-Nystatin. 

Cyclic macrolide lactones 

(Amphotericins; Nystatin) - inhibit by binding to the cell mebrane. Preferentially binds to

Describe the mechanism of antifungal action of polyenes.

ERGOSTEROL in fungal cytosolic membranes. 

[Ergosterol is a major component of the fungal cell membrane. This binding forms PORES in the membrane leading to K+ LEAKAGE and subsequent death of the fungal cell. Ergosterol is unique to fungi.

BROAD SPECTRUM

Describe the mechanism of antifungal action of Flucytosine

flucytosine (Ancobon)

 ○ Interferes with RNA synthesis and protein synthesis in fungus

       • Converted to 5-flurouracil (5-FU), which competitively interferes with fungal RNA/protein synthesis

 ○ Works On: only Cryptococcus neoformans and agents of chromomycosis

Desccribe the mechanism of antifungal action of Azoles

Inhibits Synthesis of Ergosterol (inhibits lanosterol 14alpha-demethylase).

lanosterol 14alpha-demethylase. -> lanosterol -> ergosterol -> fungal cytochrome P450 complex

Inhibitor of cell wall synthesis

 -inhibits Beta-(1,3) - D- Glucan synthase.

Mammalian cells do not require B-(1,3)-D-glucan,limiting drug toxicity.

Describe how nystatin is used in dentistry

○ Treats fungal infections caused by Candida in oral cavity and mucocutaneous membranes

 ○ Applied topically 

 § When swallowed, is NOT absorbed from GI tract

 ○ Typical Dental Dose

 $400,000-600,000 liquid units, use 4x/day - swish and retain for as long as possible, then swallow

Identify names of drugs within azoles,

• Triazoles

 □ Oral

      Fluconazole - "Diflucan

      Voriconazole - "Vfend"

      Itraconazole - "Sporanox"

 □ Topical

      Terconazole - "Terazol"

• Imidazoles

 □ Oral

      Ketoconazole - "Nizoral"

 □ Topical

      Clotrimazole - "Lotrimin AF"

      Micronazole - "Oravig"

      Econazole - none

• Acetylcholine Synthesis & Release(General Overview)
• "Acid + Alcohol --> Ester"
• Acetyl CoA + Choline --> Acetylcholine (Ach)
• Note: Esters are easily destroyed/broken down… so while Acetylcholine is a good agonist, it is readily destroyed via Acetylcholine esterase

• Specific Mechanism
• 1. Choline in diet
• 2. & 3. Transporter to get Choline into neuron
• 4. Cytosol: Acetyl CoA + Choline --(Ach Transferase)--> Ach
• 5. Ach is transported into storage vesicle for

protection from breakdown

• 6. Remains in storage until AP causes release of

Ach from vesicle

• 7. AP is caused by influx of Ca2+ via voltage regulated

Channels --> causes Ach vesicle to fuse to synaptic

membrane

(Botulism Toxin blocks this step)

• 8. Ach released into synaptic space

• 9. Ach travels across synapse and binds to receptor

Serves as an agonist

Can bind to 2 types of receptors:

• G-Protein coupled receptors
• Ion channels

• 10.  Ach's action is terminated by metabolism via

Ach-esterase after it is released from receptors

• Sites of Action
• Ach primarily binds to post-synaptic sites
• Ach can also bind to pre-synaptic sites
• Help coordinate what is occurring pre-synaptically

3. Describe the pre- and postsynaptic sites and mechanisms for potential drug action to affect colinergic neurotransmission.

Cholinergic Receptors(Ach is the NT)

• Nicotinic
• Ion-Channel Receptors
• Subtypes
• Non-neuronal (skeletal muscle): Receptor present in the muscle for contraction
• Neuronal types: In immune cells, CNS and ganglia, where Ach is working
• Nicotine has high affinity for receptors located in:
• Skeletal muscle
• Autonomic Ganglia and Adrenal Medulla
• Spinal cord
• Brain
• Ligand Gated Ion Channel
• 5 subunits: α2, β, γ, δ surround a central pore
• Ach binds to α subunits --> channel opens--> Na+ passes through --> generates AP

Muscarinic

• G-Protein Coupled Receptors
• Subtypes
• M1, M3, M5 (IP3/DAG)
• M2, M4 (cAMP)
• Muscarine has high affinity for receptors located in:
• Cardiac muscle
• Salivary glands
• GI and Genitourinary smooth muscle
• Smooth muscle of arterioles and vein, and eye (pupillary sphincter & ciliary muscle)
• Brain
• Example: Muscarinic Signaling in Heart (M2)
• Ach --> G-Protein Receptor (binding site if deep within G-Protein) --> α subunit separates, β & γ subunits stay together
• α: inhibits ATP production by inhibiting adenylyl cyclase --> inhibits cAMP --> inhibits Ca2+ and Na+ channels from opening and causing the depolarization of the cell
• β & γ: opens K+ channel, K+ leaves cell (membrane potential becomes hyperpolarized
• Overall: DECREASES HR (cell is hyperpolarized, thus decreasing the firing rate)
• Keep in mind: A Muscarinic receptor in a different tissue may do something entirely different…

Acetylcholine Esterase

• Performs the enzymatic hydrolysis and terminated of Ach
• Happens in micro-seconds!!
• Mechanism
• 2 Parts to the Active Site:
• 1. Esteratic Site: binds to the ester part of Ach
• 2. Anionic Site: binds to the N (bound to 3 C's) part of Ach
• Hydrolysis occurs --> splitting Ach
• Choline can be reused
• Acetate is then further metabolized/used by other systems

CNS

• M1, M2, Nn receptors are all present in CNS
• This is why nicotine in tobacco has an effect
• Nicotine poisoning can occur (often from insecticides)
• See tremor, emesis, convulsions, coma, even death
• Study results of treatment for quitting smoking
• CHANTIX: 44% quit
• Good because it's a partial agonist (person gets satisfied only to some extent)

PNS

• Nnand Nmare sites of action for Nicotinic agonists
• Nn(autonomic ganglia): Drugs that have 6 Carbons are selective for this
• Nm(motor end plate): Drugs that have 10 Carbons are selective for this
• Nicotine has a greater affinity for nicotinic receptors at ganglia than at motor end-plate receptors
• Prolonged/high exposure to nicotine to produce depolarizing blockade of the ganglia (it shuts down…)

Overall Ganglionic Stimulation

• Cardiac -- primarily sympathetic response
• GI -- primarily parasympathetic response

Cholinergic agonist

How direct acting works

• Direct Acting
• Have high affinity for receptor and activate receptor
• Can be Alkaloids or Choline esters that are synthesized in the lab

Cholinergic agonist example:  Direct Acting

Acetylcholine

• Acetylcholine
• Acts at BOTH Nicotinic and Muscarinic receptor
• Use: Produces complete miosis in eye surgery

Cholinergic agonist example:  Direct Acting

Methacholine

• Methacholine
• Addition of methyl group
• Selective at Muscarinic receptor on effector organ
• Add Methyl group to Ach --> less susceptible to Ach-esterase
• Use: Produces complete miosis in eye surgery

Cholinergic agonist example:  Direct Acting

Carbachol

Carbachol

• Addition of amine group
• Acts at BOTH Nicotinic and Muscarinic receptor; very similar

composition to Ach

• Not metabolized by Ach-esterase
• Use: Asthma airway hyper-reactivity diagnostic

Cholinergic agonist example:  Direct Acting

Bethanechol

Bethanechol

• Addition of amine AND methyl group
• Selective at Muscarinic receptor on effector organ
• AND not metabolized by Ach-esterase
• Use: Bladder and GI

Cholinergic agonist example:  Direct Acting

Muscarine

Muscarine

• Selective at Muscarinic receptor on effector organ
• Use: NONE (not used anymore); experimental drug -- Mushrooms!!!

Cholinergic agonist example:  Direct Acting

Pilocarpine

Pilocarpine

• Selective at Muscarinic receptor on effector organ
• Use: Sjogren's Syndrome, Glucoma -- stimulates saliva/tears
• New version on market today: Clevilemine --> used strictly for Sjogren's Syndrome

Cholinergic agonist example:  Direct Acting

Oxotremorine

Oxotremorine

• Selective at Muscarinic receptor on effector organ
• Use: Experimental drug; tool to help develop anti-Parkinson's drugs

• Indirect Acting
• Have low affinity for receptor
• Inhibit activity of Ach-esterase, allowing Ach drug to buildup
• Can be "reversibly" or "irreversible"
• More on this in the section below

• Both Direct and Indirect Acting:
• Affect Muscarinic and Nicotinic receptors, increasing their effects

• Absorption, Distribution, and Metabolism
• Choline esters are poorly absorbed and poorly distributed into the central nervous system
• Are hydrolyzed in the gastrointestinal tract and are, therefore, less active when given orally
• Choline esters differ markedly in their rate of hydrolysis by cholinesterase (acetylcholinesterase and pseudocholinesterase or butyrylcholinesterase) in the body
• The duration of action of a large iv dose of acetylcholine is only a matter of 5-20 seconds
• Addition of a B-methyl group to form methacholine increases resistance to hydrolysis by 3 fold

• Mechanism of Cholinergic Agonists

• Mechanism of Cholinergic Agonists
• Agonists at Muscarinic Receptors
• (Varies in potency and efficacy)
• Activation of the IP3 and DAG cascade
• Increase in cellular concentration of cGMP (indirectly via NO generation --> causes relaxation of smooth muscle)   
• Inhibition of cAMP formation
• K channel opening   
• Agonists at Nicotinic Receptors
• Nicotinic receptor activation peripherally producesopening of sodium/potassium channels leading to postganglionic neuronal depolarization or neuromuscular end-plate depolarization
• In the CNS nicotinic receptor activation presynaptically increases Ca2+ entry and transmitter release
• NT could be Ach, dopamine, serotonin, or some other

What do Indirect Cholinegic Agonists Do?

Acetlycholinesterase Inhibitors (ACHEI's)

• Blocks hydrolytic action of the enzyme acetylcholinesterase located at the pre- and postsynaptic sites
• Leads to an intensification and prolongation of the action of acetylcholine

• Major Uses of ACHEI's(rather limited…)
• Insecticides
• Chemical warfare agents (nerve gas)
• Ophthalmic drugs
• Treatment of the autoimmune muscular weakness disorder of myasthenia gravis

• (1) Quaternary ammonium alcohols
• Used in diagnostic and special situations
• Short duration of action (minutes)

• (2) Tertiary or quaternary ammonium carbamic acid esters
• Limited access to organ systems
• Duration is few-several hours

• (3) Organic derivatives of phosphoric acid (organophosphates)
• Will attach to enzyme, and can remain their forever -- completely inhibiting it
• aging - breaking O2 / phosphorus bond making bond stronger => irreversible 

Edrophonium

• Use: Diagnostic tool for Myasthenia Gravis
• Alcohol

Neostigmine

• Use: Tx for Myasthenia Gravis
• ALSO: post GI surgery, because smooth muscle in GI sometimes 'quits' or 'shuts down' following surgery to it, so this drug stimulates movement again

Physostigmine

• Use: Tx of Glaucoma

Pyridostigmine

• Use: Tx for Myasthenia Gravis

Dysflos

• Use: Eye drops for Glaucoma

Eccothiopate

• Use: Tx for Glaucoma
• Organsophosphate

Parathion

• Use: Insecticide

• Myasthenia Gravis

Autoimmune disease affecting the skeletal muscle neuromuscular junctions (creates muscle weakness)

• An autoimmune response produces antibodies that destroy nicotinic receptors at the postsynaptic site, resulting in muscle weakness
• Gap at synapse is wider
• Pits are spread out
• Density of receptors are decreased

Treatment

• Pt needs Ach agonist!
• Want to stimulate those remaining receptors vigorously
• Direct agonist do NOT work as well on these pts
• Best Tx: Irreversible ACHEI, allowing natural Ach NT to 'do its thing'
• Neostigmine
• Pyridostigmine
• Ambenonium
• Atropine may be used to counteract the muscarinic side effect
• Often tolerance develops to side effects so that atropine is not needed

Diagnosis(No idea if this is even important, but he did talk about it)

• Edrophonium: Used in diagnosis and management of myasthenia gravis

• Administer Edrophonium Intravenously
• If A is converted to B then pt has Myasthenia Gravis
• Tx: Pyridostigmine to maintain B
• If A is present on follow-up visit
• Adm. edrophonium:
• If B occurs
• Increase Rx dose of pyridostigmine
• If A persists or gets worse
• Decrease dose of Rx pyridostigmine

• • e