Synaptic transmission relies on the synthesis, storage, release, and diffusion through the synaptic cleft of transmitters. We see acetylcholine synthesized from acetyl CoA, then the storage and release of Ach, and also the degradation. Once we have the transmitter in the cleft, depending on how long its there, the effect is greater or lesser. Norepinephrine is the same. We see DOPA forming to dopamine, stored, then release and chemical degradation (not shown) by MAO, also the norepinephrine can be picked up again. Also shown is GABA, formed from glutamine. GABA is especially in the CNS. Also we have peptides as neurotransmitters. This is where the pharmacology of the CNS plays. This is a difficult field because there is such a lack of specificity.


Sometimes when you go on the street you see people who are homeless, here in SF it is very common to see. You might think that person is a bum or something. From a pharmacological perspective though, most of those people are treated and the reason that they act like zombies is because of the lack of specificity of those drugs. Dr. Levy comes in and makes the drugs sound very good, but in fact its very bad. This is a field of pharmacology where specificity is lower than anywhere else.



Once you have a transmitter going through the synaptic cleft, it will have to bind to the receptor. Depending on what receptor we have, we have a specific mechanism. Here we have an example of a nicotinic receptor in the ganglia, which is mostly just a channel that can bind ACh. When this is bound the channel opens to give electrical activity. On the other hand, if you go to the post ganglionic nerve fiber terminal and find a muscarenic receptor, it still binds ACh but the mechanism is totally different. It relies on the interactions of several proteins, G proteins mediate it, then after you get this complex response, it opens different pathways. In this example they give the example of a K+ channel, if the potassium channel opens it will have an opposite effect from the Na channel. Sodium channel opening results in depolarization, resulting in firing of nerve fibers. But if the potassium channel is opened, it causes the nerve fiber to relax. This is an opposite effect! So how do we get one or the other? The body knows how to specifically stimulate certain nerves for a specific response, but if you inject or ingest some drug, the effects will be throughout the body and we can’t really target specific receptors.



This is a pharmacologist’s view of the CNS. The pharmacologist sees the nerve that conducts an impulse, the synthesis and storage of transmitters, the release of the transmitter and reuptake, then the signal transduction and pharmacological response. So when you see a drug, either now or later in your career, remember this figure and try to figure out where the drug fits in the outline of mechanisms. We will try to do that with regard to the drugs that are anti-psychotic.

The most common example of psychosis is schizophrenia. This is not somebody who has a little anxiety or is not quite right, this is totally crazy. There are positive symptoms and negative symptoms. You know, the psychiatrists are the least concrete of the medical specialties because its very difficult to measure these sort of things. A positive symptom is when somebody thinks that they’re Napoleon or something, or has terrific manic symptoms. Negative symptoms are people who don’t do anything, they might sit in the corner or sleep all of the time. In the old days, if these pts were too difficult to manage they were put in a straight jacket, which was a big shirt with very long sleeves and you tie up the sleeves so that the person can’t move. It was a terrible situation.


These anti-psychotic drugs are able to control psychotic behavior, especially the positive symptoms, but are not able to cure the cause of the disease.

Synthetic chemistry improved the specificity and power of these drugs by making different substitutions. Drugs such as Compazine, Thorazine, and Mellaril are synthetic variations of the phenothiazine class. Depending on the different ions that are attached, for instance adding Cl- or F- to R2, we can increase antipsychotic potency. The classic phenothiazine is Chlorpromazine (Thorazine). The basic pharmacologic effect of these drugs is a general interference with transmission in different receptors.



This is a very complicated figure that looks so complex that you may just give up and say “to hell with it.” What this figure shows are different psychoactive drugs and the concentrations that they are effective at. These different colored areas represent the different receptors such as dopamine, 5-HT2, muscarine, etc. How can we know what drugs interact with what receptors? The author doesn’t know himself, he just copied from another author… what they do to figure this out is mash out brain (of a rat, hopefully) and measure radioactively how drugs bind to particular receptors. When I look at this figure, I see that these drugs act on all receptors! They are not specific. But maybe some are specific depending on the dose, for specific receptors. All of the drugs more or less specifically affect the dopamine receptors. But they very often affect the other receptors also, so we must expect some secondary effects. Also there is a more subtle thing, the dopamine D2 receptor is more commonly associated with these things. But in one case (we’ll see later) the D4 is more involved… so maybe D4 is the real one.


So you can walk away and say “He told me a lot of confusion.” But I told you the reality. So take this with you: these drugs do have some lack of specificity, but nevertheless the dopaminergic receptors are most commonly affected, and the D2 is usually more affected.


Generally speaking, another thing that the anti-psychotics do is interfere with mental activity; for instance the ability to perform conditioned reflexes is interfered with. We know this by testing rats; when given some of these drugs they will not be able to learn conditioned responses like associating a light with a shock, whereas normal rats will learn to associate the two and behave accordingly.



So focusing on the dopamine business, it is an analog of norepinephrine. So you still have the chemical reactions for the transformation of tyrosine into DOPA and then Dopamine, then you have storage of dopamine and release. The antipsychotic activities are mostly focused on D2, therefore they prevent signaling coming after D2 and you have an interference with dopaminergic stimulation of the CNS.



There is one further indication that the control on psychosis is dependent on anti-dopaminergic activity, due to the fact that if you measure the concentration of these drugs in the CSF and compare to the effects in blocking the psychosis, you get a linear relationship. So it seems that D2 is involved except for Clozapine… but in this case it is the D4 receptor, which is also a little more specific than D2.


So if we take an animal and give it these drugs, we see a paradoxical response of increased activity. But after 2-3 weeks of treatment, you get a paralysis, or block of lower activity. So that’s where the therapeutic effects show up. The therapeutic effect of positive control of schizophrenia is due to lowering the activity of dopaminergic bundles coming from the midbrain. So we have certainly made a case for the dopamine blocking activity of the psychotic drugs.


What we find in addition is a cholinergic block, because of the fact that other receptors (in addition to the dopamine receptors) are involved. So people who are taking these drugs will have xerostomia, and other anti-cholinergic symptoms such as difficulty urinating (in men) or constipation. These drugs also block central vomiting receptors. At one time, pregnant women were treated with anti-psychotics to counter the effects of morning sickness—anti-psychotics have effects on the medullary receptors associated with vomiting. Dopaminergic transmission is instrumental in the working of the extra-pyramidal system. The extra-pyramidal system controls involuntary movement; very often people on anti-psychotics develop strange movements.

-Calming psychotic patients without excessive CNS depression; as contrasted to giving a barbiturate to a pt, which will calm the pt but also put him to sleep because of the CNS depression associated with that drug.

-Anti-emetic effects (anti-vomiting).

-Reduce pruritis (itching). The cause of pruritis is not eliminated, but the excessive itching is controlled.

-Extra-pyramidal secondary effects, or Parkinson’s-like effects.

-Good thing: The anti-psychotics are not addictive.


INDICATIONS:

-Schizophrenia -Pruritis

-To reduce agitation -Nausea

KINETICS:

-Given by mouth (P.O.). The ½ life is 8-9 hours, so they must be given 2-3 times/day.


ADVERSE EFFECTS:

Extrapyramidal disturbances such as Tardive Dyskinesia (uncontrolled movement of the tongue), Parkinsonian rigidity, and motor restlessness.

Liver toxicity, jaundice, skin-rash, aggravation of alcohol-induced depression, and endocrine effects can also occur.


Haloperidol (Butyrophenone) is stronger than phenothiazine, and is used if phenothiazine is ineffective. It still has the problem of extra-pyramidal effects.



Another drug that seems more promising and is an atypical antipsychotic, is Clozapine.

The advantage of Clozapine and other atypical antipsychotics is that the extrapyramidal effects are decreased. So if the psychiatrist is careful with the dosing of these drugs, he can control the psychosis without extrapyramidal effects. Remember, you are not curing schizophrenia, you are only controlling it; you can think of it like a straightjacket.

LITHIUM is a monovalent cation that is given by mouth, for 1-2 weeks, to alleviate manic phases of manic-depressive syndromes. Mechanism attributed to competition with socium in channel activity, and in turnover of CNS transmitters.


“Sometimes if I look at myself, it seems to me that I get this manic behavior. Like the other day I was at an airport in Milan, there were these carts all lined up in an engaging mechanism and there was one Euro on the side and I picked it up, you know I don’t want to pay the tab, and I put it in the slot to get the cart. When I put the cart back, I took thirty steps and then the idea came that the reason I found the Euro there is that they give it back to you, the Euro is to make sure that you bring back the cart! So I ran back and grabbed that Euro! My wife says ‘This is manic behavior!’ And I say ‘You must have Euros growing out of trees, I’d rather have it.’ So all of us have some manic behavior, but if you indulge too much, the physician may give you Lithium.”


Lithium is hardly a drug, because you have to take grams; very large amounts. It is said to compete with Sodium and therefore decrease the nerve excitation. “So I’ll see you next time.”

Rheumatoid arthritis: is basically a severe form of chronic synovitis that can lead to destruction and ankylosis of affected joints.

[Blood vessels, skin, heart, lungs, nerves and eyes may also be affected.]

Rheumatoid arthritis is thought to be initiated by an arthritogenic microbial agent in an immunogenetically susceptible host (associated with HLA-DR4). After initial injury, a continuing autoimmune reaction ensues, in which T cells (CD4+) release cytokines and inflammatory mediators that ultimately destroy the joint.

Pathological changes of rheumatoid arthritis: laboratory and biopsy findings…

Rheumatoid synovitis:

• Neutrophils (rheumatoid arthritis cells) can be present in synovial fluid

• The synovium demonstrates chronic inflammation (intense lympho-plasmacytic and histiocytic synovial infiltrate)

• Hypertrophy and hyperplasia (swollen – villous pattern) frequently with fibrinous exudates at the surface.

• Exuberant synovium known as a pannus eventually fills the joint space
  

Articular cartilage destruction:

• Due to release of destructive enzymes (proteases and collagenase), cytokines (IL-1 & TNF-) and pannus formation across articular surfaces.

• Changes reminiscent of DJD but with fibrous and bony ankylosis (fusion of joint)

• The capsule and periarticular structures are also destroyed; this can lead to instability in the joint, with subluxation and dislocation

Focal destruction of bone:

• Osteolytic destruction of bone occurs at the edges of the joint; with little reparative activity

• Bone ‘erosions’ can be seen on radiography, and they are associated with joint deformity.

Clinical aspects:

• Typically polyarticular, bilateral and symmetric

• Any joint can be affected; most common are small joints of the hands and fee

• Presents with: general malaise, pain and stiffness in the joints (most marked in the morning)

• On examination: hot, woollen and tender joint

Other investigative findings are:

• Radiology: osteoporosis, erosion

• Serology: rheumatoid factor (70%)

• Synovial fluid analysis: milky and turbid

Pathological fractures: refers to the break (in bone) that occurs in previously diseased or abnormal bone.

Two major conditions that may present with a pathological bone fracture involving the femur are as follows:

Osteoporosis: refers to a reduction in bone mass owing to small but incremental losses incurred in the constant turnover of bone. This common condition is seen most often in the elderly of both sexes but is more pronounced in postmenopausal women.

Osteoporosis may occur as a primary disorder of obscure origin or as a secondary complication of a large variety of diseases.

Osteoporosis may present with:

• Bone pain: owing to microfractures (especially in the back because of compression of vertebral bodies); this may result in loss of height and instability of the vertebral column ( kyphosis)

• Fractures: reduced bone mass leads to predisposes to fractures (even following minimal trauma) especially of femoral necks, wrists and vertebrae
  

Morphology of osteoporosis: laboratory or biopsy findings…

Macroscopically:

• Bones are lighter in weight, less dense on radiography and show thinning of the cortex.

• Lumbar vertebral bodies are more biconcave than normal, such that the intervertebral disc space appears more spherical (so-called ‘fish vertebrae’ because similar of that in fish)

Microscopically:

• Bone trabeculae are thinner and reduced in number (haversian systems are widened)

• Decrease in the number of osteoblasts

Note: such bone as remains is of normal composition (mineralization is not affected)

Paget’s disease of the bone: (osteitis deformans) is a chronic disease of excessive uncontrolled resorption and deposition of bone particularly affects the skull, backbone, pelvis and long bones.

Paget disease can be divided into the following stages:

1. An initial osteolytic stage, followed by

2. A mixed osteolytic-osteoblastic stage, evolving ultimately into

3. A burnt-out, quiescent osteosclerotic stage

[Is thought to be caused by a slow viral infection of osteoblasts and then osteoclasts by paramyxovirus]

Because the new bone formation in active disease is disordered and poorly mineralized, it is soft and porous, lacks structural stability and is vulnerable to fracture or deformation under stress.

Patients may demonstrate pathological fractures, nerve compression symptoms, osteoarthritis and skeletal deformities (tibial bowing, skull enlargement).

Pathological changes of Paget’s disease: laboratory or biopsy findings…

The osteolytic phase is marked by resorption by numerous overly large osteoclasts (some with >100 nuclei)

The mixed phase shows, in addition, disordered neo-osteogenesis of predominantly woven bone (but some lamellar) with areas of new bone formation producing tilelike or mosaic pattern pathognomonic of Paget disease.

Eventually, after many years, there is a burnt-out phase, marked predominantly by bone formation and osteosclerosis.

Other investigative findings are:

• Serology: normal calcium and phosphate, alkaline phosphatase

• Urine: increased urinary excretion of hydroxyproline

• Abnormal isotope bone sans

• X-ray: localized bone enlargement, altered trabecular pattern and alternating areas of rarefaction and increased density

• Remember, these mimic acetylcholine and should therefore yield parasympathetic effects

• Effects include DUMBELS (defecation, urination, miosis, bronchoconstriction, electrical changes (heart), lacrimation, secretion)

Direct-Acting (Agonists)

• All activate muscarinic receptors, some also activate nicotinics (carbachol, e.g.)

• Low oral bioavailability

• Contraindicated in Parkinson’s, pregnancy, etc.

Choline Esters

• Due to quarternary state, do not cross BBB

  1. Acetylcholine – short ½ life makes it useless

  2. Methacholine – strong effect on heart (use for paroxysmal atrial tachycardia)

  3. Carbachol – use for open-angle glaucoma, least antagonized by atropine

  4. Bethanecol – give PO or SC but not IV (increased adverse effects).

Natural Alkaloids

• Cross BBB to cause arousal, excitation, headache, and tremors

• Stimulation of salivation and sweating is particularly prominent

  1. Muscarine – no therapeutic uses, found in poisonous mushrooms (mycetism)

  2. Pilocarpine – use for open-angle glaucoma, xerostomia (Sjörgen’s syndrome)

Indirect-Acting (Cholinesterase Inhibitors)

• Effects are dose dependent

Reversible (Carbamates and Quarternary Alcohols)

• Hydrolyzed by plasma esterases

  1. Edrophonium – use to diagnose myasthenia gravis; never for cholinergic crisis

  2. Physostigmine – crosses BBB, use to treat antimuscarinic toxicity by atropine, Scopolamine

  3. Neostigmine – does not cross BBB, use to treat myasthenia gravis, can directly activate N_m

  4. Tacrine – used for early Alzheimer’s

Irreversible (organophosphates)

• Bind covalently to esteratic site, bond is strengthened by loss of alkyl group (aging)

• Hydrolyzed by paraoxonases

  1. Isofluorophate – Distributed in all tissues, unlike echothiophate

  2. Echothiophate – may be used for open-angle glaucoma if carbachol and pilocarpine prove ineffectual

• Remember, these block acetylcholine receptors and should therefore yield sympathetic effects

• Effects include blind as a bat (mydriasis), red as a beet (flush), dry as a bone (xerostomia), mad as a hatter (psychosis), and hot as a hare (increased body temperature).

• All competitively block muscarinic receptors (quarternaries block nicotinics as well)

Tertiary Amines

• Cross BBB

• Do not block nicotinic receptors

  1. Atropine – (natural) behavioral effects, biphasic cardiac response (low dose = bradycardia, high = tachycardia), relax smooth muscle, decrease secretions, etc.

  2. Scopolamine – (natural) motion sickness, vestibulation, biphasic cardiac response, relax smooth muscle, decrease secretions, etc.

  3. Homatropine, Cyclopentolate, Tropicamide – [eyes] used to examine mydriasis and measure cycloplegia

  4. Pirenzepine, Telenzepine – [GI] primarily block M1 to decrease gastric secretion in peptic ulcer

  5. Dicyclomine – [GI] use for visceral hypermotility and spasms

  6. Oxybutynin, Oxyphencyclimine – used to relieve bladder spasms following urologic surgery

  7. Benztropine, Trihexyphenidyl – [CNS] use to treat Parkinson’s

Quarternary Ammonium Compounds

• Do not cross BBB

• Able to block nicotinic receptors

  1. Propantheline, Methantheline, Mepenzolate, Methscopolamine – use for visceral hypermotility and spasms, as well as duodenal ulcer treatment

  2. Glycopyrrolate – use for visceral hypermotility and spasms, duodenal ulcer treatment, and cardiovascular disorders; pre-anesthetic drug of choice to reduce salivation (due to mild effect on heart in comparison to atropine)

  3. Ipratropium – key respiratory drug, use to treat bronchial asthma and COPD

• Remember, these drugs have sympathetic effects

• Direct activation of adrenergic receptors, stimulate release/inhibition of reuptake, and reflex homeostatic mechanism (e.g. heart)

a-b Agonists

• Refer to chart below for cardiovascular effects

• Causes general vasoconstriction, relaxation of smooth muscle, i GI motility and bronchorelaxation.

  1. Epinephrine – used for glaucoma, anaphylactic shock, asthma. Hits a1 a2 b1 b2 receptors, diabetogenic effects (decreased insulin, increased lipolysis).

  2. Norepinephrine – used for hypotension and neurogenic shock. No b2, vagal reflex overrides direct effect, vasodilates cardio/pulmonary vessels.

  3. Dopamine – [renal] used as "renal drug" causing vasodilation in kidneys; also for cardiogenic and septic shock. Inotropic in low doses; chronotropic in high doses; no to CNS; tolerance.

a 1 Agonists

• Effects smooth muscle (vasculature, visceral and sphincters)

•  BP associated with sinus bradycardia

• Adverse effects: hypertension, anginal pain, headache, anxiety and rebound congestion

• Not degraded by COMT therefore longer lasting

  1. Methoxamine, phenylephrine – use for orthostatic hypotension, nasal decongestant and mydriatics (p).

a 2 Agonists

• Effects presynaptic terminals and pancreatic beta cells; hits a 2 and/or imidazoline receptors

• Cause a decrease in central adrenergic tone

• Adverse effects: sedation, xerostomia, drowsiness, dizziness, impotence, (hypertension)

  1. Clonidine and apraclonidine – used for withdrawal from tobacco, alcohol and opiods; second drug of choice for hypertension; glaucoma, preoperative sedative, ADD; modulates release of norepinephrine hits a 2 and imidazoline receptors.

  2. Guanabenz, guanafacine, tizanidine – use for spinal cord spasticity; hits a2 receptors.

  3. Methoxamine and rilmenidine – use for neurogenic shock.

Nonselective b Agonists

• Activates b1 b2 b3 receptors

• Vagal reflex adds to direct effect of drug (see chart above)

• Net effect: pronounced HR; vasodilation of all vascular beds.

  1. Isoproterenol – [heart] used for Torsade de pointes (ventricular tachycardia) and b-blocker overdose; less hyperglycemia than epinephrine since no 2 insulin inhibition

b 1 Adrenergic Agonists

• Effects myocardium and renin producing juxtaglomerular cells of kidneys

• Inotropic cardiovascular effect (Increased contractility and conduction)

• Adverse effects: fear, anxiety, tremors, hypertension, palpitations, anginal pain, arrhythmias, pulmonary edema, hyperglycemia, tolerance

1. Dobutamine – [heart] used for in emergencies for cardiac failure and cardiogenic shock.

b 2 Adrenergic Agonists

• Effects visceral and vascular smooth muscle and liver

• Bronchodilation and enhanced mucociliary clearance (mucous secretion is increased)

• Tolerance due to receptor down regulation

• Adverse effects: headache drowsiness, dizziness, anxiety, tachycardia, palpitations; hypokalemia (stimulates K⁺ reentry into skeletal muscle); hyperglycemia and hypoxemia ( ventilation/perfusion ratio; asthma)

1. Albuterol, terbutaline, metaproterenol, salmeterol – used for asthma and chronic obstructive pulmonary disease (COPD); aerosol administration.

2. Ritodrine – used as a uterine relaxant in premature labor

Indirect Acting Adrenergics

• Stimulates release of norepinephrine, dopamine and seratonin from peripheral and CNS

• Effects similar to norepinephrine; enters CNS; tolerance to central effects

• Toxicity includes hypertension, negative psychic effects, nausea and vomiting, dependence.

1. Amphetamine, methamphetamine, methylphenidate – used for narcolepsy (no tolerance) and attention–deficit hyperactivity disorders.

Other Indirect/Mixed Action Adrenergics

1. Tyramine, methyldopa – used for hypertension (m); false neurotransmitters which are taken up by adrenergic neurons then transformed into octopamine which displaces norepinephrine form adrenergic vesicles; causes sympathetic effects if administered with MAO inhibitor (prolonging effect of norepinephrine)

2. Cocaine – used as anesthetic; indirect acting adrenergic drug that blocks catecholamines uptake.

3. Ephidrine – used for asthma, COPD; enhances release of norepinephrine; less potent than epinephrine.

• Remember, these drugs have parasympathetic effects (dumbels)

Nonselective alpha Receptor Antagonists

• Blocks alpha receptors effecting: smooth muscle (vasodilation causing orthostatic hypertension) and increase in HR (reflex sympathetic stimulation); presynaptic terminals (abolish/reverse catecholamine effects); pancreatic beta cells (decreased insulin release); trigone and sphincter of bladder (urination)

• Larger doses hits more receptors

1. Phenoxybenzamine – pheochromocytoma; used for irreversible alpha blockade

2. Phentolamine – used for frost bite

alpha 1 Receptor Antagonists

• Similar to above: slight increase in HR (reflex sympathetic stimulation); increased contractility due to inhibition of phosphodiesterase (degrades cAMP); "first dose phenomenon" causing syncope (fainting) and subduing reflex response.

1. Prazosin, doxosin – chronic hypertension and hypertensive emergencies; Raynaud's disease; frost bite; benign prostatic hypertrophy, heart failure (decreased preload/afterload)

alpha 2 Receptor Antagonists

1. Yohimibine – used for male sexual dysfuntion

Beta Receptor Antagonists (Beta Blockers)

• Competitively reduce Beta receptor occupancy causing parasympathetic effects

• Indicated for: hypertension, cardiac arrhythmia, angina pectoris, glaucoma, migraines, anxiety/panic attacks

• Contraindications: (see chart above); pt's with diabetes (masking of symptoms of caused by hypoglycemia); asthma and COPD; elderly (induced hypothermia)

• Intrinsic sympathomimetic activity (ISA) and partial agonists – "PAL" (propranolol, acebutolol, labetalol)

• Membrane stabilizing activity (MSA); local anesthetic – "LAMPP" (labetalol, acebutolol, metoprolol, pindolol, propranolol)

Nonselective Beta Receptor Antagonists

1. Propranolol – used as a local anesthetic, enters CNS; similar to carvedilol but without 1 effects

2. Nadolol, timolol, pindolol, careolol, sotalol – used as a local anaesthetic; nadolol  CNS

Beta 1 Receptor Antagonists

1. Acebutolol, atenalol, betaxolol, esmolol, metoprolol – esmolol IV only; metoprolol enters CNS; atenalol  CNS

Alpha - Beta Receptor Antagonists

• Predominantly alpha and beta1 blockers causing decrease TPR (orthostatic hypotension), no change in HR and CO (partial agonist activity), reflex tachycardia

1. Labetalol, carvedilol – partial agonist (l)

Indirect Acting Anti–Adrenergics

1. Metyrosine –used for pheochromocytoma (too much catecholamines) with alpha blockers to inhibit tyrosine hydroxylase in catecholamine synthesis

2. Guanethidine – inhibits release of norepinephrine and depletion of norepinephrine stores

3. Reserpine – blocks storage of norepinephrine

Ganglionic Drugs

• Receptor Agonists – Nicotine, carbachol, cholinesterase inhibitors

• Receptor Antagonists – Trimethaphan, mecmylamine, tubocurarine (blocks at Nn receptor), anti–muscarinics

Nicotine

• Low/intermediate dose – stimulates cardiovascular system, anorexia, nausea, urination

• Large dose – depolarization blockade, depression, apnea, paralytic ileus.

There are three treatment possibilities for cancer: surgery, radiotherapy, and chemotherapy. This lecture will address chemotherapy and some cancer basics.

Cancer Stats:

1. > 1 million people are diagnosed with cancer in the US each year.

2. 550,000 deaths occur due to cancer each year. That’s one person every 62 seconds.

3. Cancer is the second most frequent cause of death in the US. (Heart disease is #1.)

4. Cancer is the leading cause of death in women between the ages of 30-74. The most common causes of cancer in women are breast, lung, and colorectal.

5. The most common causes of cancer in men are prostate, lung, and colorectal.

6. Cancer is the main non-accidental cause of death in children 1-14 years old. 76,000 children die each year from cancer.

History of Cancer Chemotherapeutics:

We’ve come a long way...

decade	Five year survival
1930’s	20 %
1940’s	25 %
1960’s	33 %
1990’s	50 %

The paper describing Nitrogen Mustards was published in 1946 by Goodman, Gilman, and some other folks, and it is regarded as the beginning of cancer chemotherapy. The story of first patient treated with Nitrogen Mustard demonstrates certain problems with chemotherapy that we are still dealing with today - only a certain amount of the drug can be tolerated and resistance often develops. This patient had terminal stage lymphosarcoma with big mediastinal and axillary masses that made breathing, chewing, and swallowing difficult. 2 days after treatment started, there was softening of the tumor tissue. In 4 days his obstructive difficulties were ameliorated. But in 3 ½ weeks his white blood cell count dropped to 200 cells/ml, and the treatment had to be stopped. The tumor grew again, so a second course of treatment was started. This course gave a transient improvement, but also had to be stopped when the patient could no longer tolerate it. A third course of chemo showed no improvement at all.

Causes of Cancer:

1. 30 % is due to smoking: lung, mouth, pharynx, larynx, esophagus, urinary bladder, pancreas, and kidney.

2. Lifestyle – diet, alcohol consumption, reproductive behavior, sexual behavior, exposure to sunlight, etc.

3. These are the only ones she listed, so I guess these are the only causes that exist... Right?

Characteristics of Tumors:

1. Benign – we are not going to talk about these ones.

2. Malignant – Malignant tumors metastasize via direct extension, via lymphatic routes or via blood. It is important to know the methods of metastasis of a given cancer so you can treat both the primary location and the locations to which the cancer has spread.

Hallmarks of cancer cells:

1. Persistent cell proliferation

2. Invasive growth

3. Metastasis

Etiology of cancer:

Genomic instability and loss of regulatory proteins (e.g. p53) contribute to the immortalization of cell lines. DNA is altered via mutagens including chemical carcinogens, viruses, and radiation. The mutations cause by these mutagens lead to activation of oncogenes and inactivation of tumor suppressor genes.

Growth Fraction:

1. Growth Fraction = _____# of proliferating cells____

# of cells in Go phase of cell cycle

2. Cells with a high growth fraction are cells that are frequently proliferating. These include:

• Epithelial cells

• Bone marrow cells

• Hair follicle cells

• Sperm cells

3. Chemotherapeutic drugs tend to work in all phases of the cell cycle except for Go, the resting phase.

4. Growth fraction has an impact on the ability of chemotherapy to effectively treat a given cancer. For example, solid tumors characteristically have a low growth fraction, and this contributes to their poor response to chemotherapy.

5. Leukemia, a disseminated tumor, has a high growth fraction, and it often responds very well to chemo therapy.

Recruitment:

The response of a solid tumor to chemotherapy can be improved through recruitment, a process which increases the growth fraction of a tumor. When you have a big tumor, it may out grow its blood supply to a certain extent and be under-nourished. This causes many of the cells to be in the resting phase. In recruitment, you initially reduce the size of the tumor via irradiation therapy or surgery. This induces the remaining tumor cells to re-enter the G1 phase of the cell cycle, and increases the number of proliferating cells. This improves the tumor response to chemotherapy.

Cancers where chemotherapy works very well:

• Childhood leukemia

• Wilm’s Tumor

• Retinoblastoma

• Rhabdomyosarcoma

• Ewing’s Sarcoma

• Osteosarcoma

• Testicular Cancer

• Choriocarcinoma in women

• Hodgkin’s Disease

• Some lymphomas

• Some early breast cancers

Cancers that are very difficult to treat with chemotherapeutics:

• Colon

• Lung

• Late stage breast cancer

• Pancreatic cancer

With antibiotics we can exploit the differences between bacterial and human cells to treat the infection. With chemotherapeutics, cancer cells are so similar to normal human cells, that selective toxicity is not really possible to attain. This brings us to the topic of Chemotherapy Toxicity.

Chemotherapy Toxicity:

1. Normal cells in the body that tend to be injured the most due to chemotherapy are those which have a high growth fraction. This is the limiting element to chemotherapy drug use.

2. Chemotherapeutic drugs lack selective toxicity.

3. Catch 22 of chemotherapy – Most of the drugs used have condierable toxicity yet in order for them to be effective they have to be used long enough to destroy all of the tumor cells present in the body. If even one cell is left over, it can proliferate and produce another tumor. So you have to find a balance between the duration of drug use and the eradication of the cancer.

4. Specific tissue toxicities due to chemotherapy:

• Bone marrow

• GI Tract

• Hair follicles

• Reproductive toxicity

Injury to:	Results in:	Time Course:	Treatment of this side effect:	Other:
Bone marrow: Decreased Neutrophils	Infection	Begins 10-14 days after tmt initiation. Takes 3-4 wks for recovery.	Give colony stimulating factors (CSFs)	If you have <>
Bone marrow: Decreased Platelets	Bleeding, especially from nose and gums		Platelet infusion
Bone marrow: Decreased Erythrocytes	Anemia	120 days after therapy is initated. By this time therapy has usually stopped, so this is a rare effect.	erythropoetin
GI tract	Stomatitis – pain and infection Nausea + vomiting	Begins a few days after tmt initiation and lasts until two weeks after termination of tmt.	Treat stomatitis with anesthetics and antifungals. Treat nausea with anti-emetics like Zolfran and cannabinoids.	You can also use glucocorticoids to reduce the inflammation.
Hair follicles	Alopecia	Begins 7 –10 days after initiation of tmt and continues until 1 – 2 months post tmt.
Reproductive tract	Irreversible sterility in males, teratogenic

Other Toxicities:

• Hyperuricemia – Increased uric acid in blood. Can be treated with allopurinol and large amount of fluid. Allopurinol works by inhibiting xanthine dehydrogenase which is needed in uric acid synthesis.

• Local injury from extravasation of vesicants. If a given chemotherapeutic drug were to come into contact with the skin due to a leaky IV it could cause burning and necrosis. Make sure the IV is securely in place.

Strategies used in Chemotherapy:

1. Intermittent Chemotherapy: Method of giving chemotherapeutic drugs in intervals. It is beneficial only if the patient’s normal cell population can recover quicker than the cancer cell population.

2. Combination Therapy: This multi-drug therapy is used more frequently today. Advantages to this method include increased numbers of killed cancer cells, reduced injury to normal cells, and supression of drug resistance. There are several requirements for its use.

• Each drug has to be effective if given independently

• Each drug should have a different mechanism of action from the other drugs being used.

• Minimal overlapping toxicities should exist between the drugs.

The specific combinations of drugs are decided empirically.

3.) Risks involved in chemotherapy must be weighed against the benefits when deciding a course of treatment. One tool used for this is the Karnofsky Performance Scale, which takes into account the stage of the illness, the possibility of cure, and other factors.

Problems with Chemotherapy and treating Cancer:

There are several problems that we have to deal with in the treatment of cancer:

1. 100% cell kill is required. If there is one remaining tumor cell after treatment, hte cancer is not cured and can reestablish itself.

2. The kinetics of cancer chemotherapy are always first order. This means that a certain dosage of the drug kills a constant fraction of cells as opposed to killing an absolute number of cells. (i.e. In order to kill off 50% of 1000 cells you have to use the same dosage that you would use to kill of 50% of 100 cells.) This is problematic because this dosage may not be tolerated by the patient.

3. Detection. The smallest tumor detectable is approximately 1 cm in size or 109 cells. This is a lot of cells and means that approximately 30 divisions have already taken place. If detection is late the tumor has a better chance of having metastasized. These larger tumors are often less responsive to chemotherapy. (Think about recruitment as a strategy to deal with this.)

4. Resistance to chemotherapy may develop by several mechanisms.

• Decrease in the amount of drug uptake by cancer cells

• Increase in the amount of drug removed by cancer cells. (Transporters.)

• Decrease in drug activation – certain drugs require activation by the liver in order for them to work.

• Decrease in target molecule sensitivity – this is cause by mutation in the molecule targeted by the drug

• Increase in DNA repair ability of the cell via an increased expression of DNA repairing enzymes.

Supportive Therapy:

1. Anti-emetics. Nausea and vomiting are major problems with cancer chemotherapy. The nausea and vomiting experienced by these patients cannot be compared to what one experiences when one has a stomach flu or a bacterial infection. When these patients say they would rather die, believe them. But don’t kill them. Give them anti-emetics. Anti-emetics not only make the patients feel better, but they improve compliance.

2. G-CSF 1 (granulocyte - colony stimulating factor) and GM-CSF (granulocyte macrophage – colony stimulating factor). These stimulate bone marrow growth and reduce leukopenia. This is important in reducing infection.