Pharmacology 8:00-10:00 a.m. A Longhorn Production

Tuesday November 28, 2000

Dr. Machu/Dr. McMahon

STIMULANTS/NONOPIOD DRUGS OF ABUSE

SYMPATHOMIMETIC AMINES

  1. Amphetamine (d, l or d)
  2. D = dextrorotatory, l = levorotatory form
  3. L form has more cardiovascular effects than the d form
  4. Prepared in the d from or as a racemic mixture of both d and l
  5. Methamphetamine (Ritalin)
  6. Methylphenidate
  7. Pemoline
  8. Cocaine – although it is a stimulant, it is not used clinically as one

AMPHETAMINE

  1. Has been around since the 1920s
  2. Sold OTC until the 1950s – abuse dropped dramatically after regulation
  3. Extensive use in WWII – solders injected them to stay awake and alert for days at a time
  4. Used by truck drivers to fight fatigue

METHAMPHETAMINE

  1. Solid form – “crystal or ice” – smoked (as opposed to amphetamine which is injected or taken orally) for rapid onset due to the huge surface area of the lung. The effects can be felt in 5-10 seconds.
  2. Very popular due to rapidity of onset and the fact that it is a “cleaner high” – methamphetamine’s effects are more central than peripheral
  3. Still has a high potential for abuse

PLEASURABLE EFFECTS

  1. Mood elevation/euphoria – intensely pleasurable euphoric feeling particularly when smoked
  2. Increased confidence
  3. Increased physical performance – many athletes abuse it for this reason
  4. Increased speed at performing repetitive tasks – however accuracy does not improve
  5. Increased wakefulness and alertness
  6. Reduced feelings of fatigue

CLINICALLY RELEVANT EFFECTS

  1. Increased attentiveness, vigilance, concentration – we will focus on AD/HD (see below) today since it is one of the main uses of stimulants in the US
  2. Reduction of narcoleptic episodes - there are far fewer people with narcolepsy than AD/HD
  3. Anorexia
  4. Mood elevation – sometimes used as an anti-depressant

MECHANISM OF ACTION

  1. Inhibition of DA/NE/5-HT uptake
  2. DA is affected the most and then NE. 5-HT is least affected and only at higher concentrations
  3. Noncompetitive inhibitors of pumps that remove up to 85% of these biogenic amines from the synapse (major action). As a result, these neurotransmitters stay in the synapse longer.
  4. Enhances calcium independent release of catecholamines – reverses the same pump that takes catecholamines up into the neuron. This is a minor effect of amphetamines because in neuronal function, calcium induced neurotransmitter release following depolarization is more important.
  5. Weak inhibition of monoamine oxidase (MAO)
  6. Stimulation of 5-HT receptors – whether or not this is clinically relevant is uncertain

STIMULANT ACTION: DA

  1. Euphoria, dependence liability, sleep antagonism, increased concentration, motor stimulation, psychosis, increased respiration

STIMULANT ACTION: NE

  1. Euphoria, sleep antagonism, anorexia, respiratory stimulation

STIMULANT ACTION: 5-HT

  1. Euphoria, anorexia, anxiety, psychosis (maybe)

ATTENTION DEFICIT/HYPERACTIVITY DISORDER

  1. One of the main uses of stimulants in this country
  2. Clinical phenomena vs. disease state
  3. We don’t understand the neurological dysfunction that is behind AD/HD. We do, however, see the symptoms in patients.
  4. Persistent pattern of inattention that may be accompanied by hyperactivity and impulsivity
  5. Patient is a kid that has difficulty concentrating
  6. Easily distracted and looks like his/her mind is elsewhere
  7. Lack of attention to detail with a tendency to lose important things (e.g. homework)
  8. Lack of organizational skills
  9. Apparent restlessness with excessive talking
  10. Poor social skills, low self esteem, tendency to get frustrated, poor compliance
  11. Learning disabilities
  12. Most common psychiatric disorder in children:
  13. 5-10% elementary kids
  14. 3-7% elementary school kids receive stimulants
  15. 90% of those receiving stimulants receive methylphenidate (Ritalin)
  16. Predominantly in males
  17. 9:1 males in the clinic
  18. 4:1 males in epidemiologic studies
  19. Only a small percentage has an identifiable disorder that causes AD/HD (e.g. Fragile X Syndrome and Fetal Alcohol Syndrome). In most cases, the underlying cause of AD/HD cannot be found
  20. Large percentage have co-morbid behavioral disorder(s) (e.g. learning disorders, conduct disorders, Tourette’s Syndrome and chronic tics)
  21. Heritable factors are important however psychosocial and environmental factors (e.g. children eating an excessive amount of sugar) are NOT important in causing AD/HD.
  22. Outcomes:
  23. 30%: developmental delay but as they reach adulthood they outgrow their AD/HD with no more problems
  24. 40%: continual display – some form of the disease (e.g. concentration problems) into adulthood
  25. 30%: developmental decay with serious psychopathology – substance abuse or another serious type of psychiatric disorder
  26. One putative cause – reduction in DA in brain-orbitofrontal cortex. Must be part of the mechanism since stimulants relieve symptoms. Also, in PET scans of children with AD/HD, activation of orbitofrontal cortex is diminished but returns to normal upon administration of stimulants.
  27. Stimulant Treatment:
  28. In children: big improvement: 30-50%, some improvement: 70-80%
  29. In adults: only variable success
  30. Some patients are refractory to stimulants: guanfacine/clonidine, TCA’s and valproic acid sometimes help these children
  31. Side effects of Treatment
  32. Insomnia, anorexia
  33. Tolerance develops quickly, so insomnia and anorexia are not experienced for long
  34. Dose is given in the morning to combat insomnia
  35. Growth suppression – temporary, overall stature and weight is not affected
  36. Exacerbation of any underlying mania or psychosis
  37. Toxic psychosis – rare
  38. Treatment
  39. Methylphenidate (Ritalin) – 90% of AD/HD children receive this
  40. Children: BID dosing, <60 mg/day
  41. Adults: BID – TID dosing, 20-60 mg /day (variable response)
  42. d-amphetamine (Dexedrin) – QD, up to 40 mg/day
  43. Pemoline (Cylert)
  44. Not a first line drug due to hepatic dysfunction
  45. QD, 56.25-75 mg/day
  46. Behavioral Modification
  47. Therapists will give rewards to children with AD/HD for learning appropriate behaviors

STIMULANTS

  1. Contraindications
  2. MAO inhibitors – could cause a hypertensive crisis
  3. Pressor Agents – could also cause a hypertensive crisis
  4. Tourette’s Syndrome is treated with DA antagonists. Stimulants would exacerbate Tourette’s.
  5. Chronic (not transient) motor and phonic tics
  6. Glaucoma
  7. Toxicity/Overdose
  8. Extension of therapeutic effects: CNS and CV stimulation, psychosis, anxiety, GI distress
  9. Fatal overdose: convulsions, coma, cerebral hemorrhages, MI
  10. Treatment:
  11. Acidify urine to increase excretion of stimulants
  12.  and  blockers treat CV stimulation
  13. Diazapem for convulsions and anxiety
  14. Cooling to reduce body temperature
  15. Haloperidol to reduce symptoms of psychosis
  16. Tolerance
  17. If taken properly there is not a problem with dependence because tolerance does not develop much to the therapeutic effects of stimulants
  18. Tolerance does develop quickly in those abusing stimulants for euphoric effects (need to take anywhere from 15 mg to 400 mg/day). No tolerance develops to toxic psychosis in these people.
  19. Extreme irritability and aggressive behavior develops
  20. Withdrawal – depression, lethargy, deep sleep
  21. Other uses – narcolepsy (no tolerance develops), obesity (tolerance develops), depression

COCAINE

  1. Similar subjective effect as amphetamine
  2. Blockade of DA, NE, 5-HT (minor) transporters
  3. Use has declined since the mid ‘80s. ~650,000 frequent users (individuals who use cocaine at least once a week). ~16% of people who try cocaine will develop a problem with dependence.
  4. Short half-life (~50 minutes) – someone using cocaine will want to repeat dosing because the euphoric effects wear off even before elimination of the drug from the bloodstream
  5. Snorting inhibits its own absorption since cocaine causes vasoconstriction in the nasal mucosa. IV administration gives the most intensely pleasurable effects and is also associated with overdosing and death.
  6. Combined with opiates (speedball) for intensely pleasurable feeling. Involved in polydrug abuse.

CRACK COCAINE

  1. Less expensive, “rock” (free base) form that is smoked
  2. Huge surface area of lungs leads to rapid absorption: 5-10 seconds to see CNS effects

COCAINE – POWDER AND CRACK

  1. Acute toxicity: CV (arrhythmias, MI, stroke), hyperpyrexia, seizures, psychosis, rhabdomyolysis, pulmonary problems due to inhalation, death (seizures, respiratory depression, ventricular fibrillation)
  2. Abuse: repeated use: personality changes, short temper, anhedonia – loss of interest in anything that has a pleasurable effect (e.g. hobbies, eating, sex), suspicion and withdrawal, difficulty concentrating, psychosis, hallucinations
  3. Very addicting – huge psychological dependence with mild physical withdrawal
  4. Intense craving – high relapse
  5. Treatments are very modest: group therapy sometimes helps
  6. Fetus – in utero exposure: spontaneous abortion, premature birth, reduce blood flow to fetus leading to hypoxia, growth retardation, malformations – heart and GU tract, CNS irritability, cerebral agents

PHENCYCLIDINE (PCP)

  1. Related to ketamine (disassociative anesthetic)
  2. Smoked (applied to tobacco or marijuana), snorted, or taken orally
  3. Effects (dose-dependent): psychostimulation, analgesia, anesthesia, euphoria, dysphoria, confusion (tend to have accidents), psychosis, hallucinations
  4. Toxicity: aggressive behavior, toxic psychosis, seizures, gross motor impairment, injuries from accidents, coma, cardiac arrest
  5. Treatment:
  6. Supportive
  7. Haloperidol for psychosis
  8. Activated charcoal and continuous gastric suction to prevent enterogastric recycling (drug diffuses from the bloodstream, becomes ionized and trapped in stomach until it drains into the small intestine, and then gets reabsorbed)
  9. Reduce external stimuli because they are disturbing to patients experiencing toxic psychosis
  10. Restraints so the patient does not inadvertently hurt him/herself.

STUDY GUIDE

  1. Know the MOA of stimulant drugs
  2. Drug list on last page of notes
  3. If prescribed in the US, know the indications
  4. What are the major side effects and limitations of the drug

PHARMACEUTICAL CONSIDERATIONS IN TREATING

VERY-YOUNG AND GERIATRIC PATIENTS

The main point of today’s lecture is that you have to very careful in very young and very old to avoid toxicities and problems. Thus as a physician, address dosages cautiously and monitor blood levels closely rather than relying on estimates of what the drug dosage should be. For example, if your patient is 90 years old and has very low kidney function, then the half-life of a drug, which is excreted by the kidney, will probably increase.

POTENTIAL POINTS OF VARIATION

Pharmacokinetics (most important): absorption, distribution, metabolism, and elimination (sometimes metabolism and elimination are the same thing)

Pharmacodynamics

One thing that we will not go into significant detail about is the teratogenic effect of a drug in the fetus and embryo. (However, one point was made). In the first trimester, while the baby’s organs are being developed, drugs are most teratogenic. That’s not necessarily true for the brain because the brain develops past the first trimester. Drugs are still teratogenic throughout the entire pregnancy and thus must be approached cautiously.

VERY YOUNG

  1. Embryo/fetus
  2. Must take into account not only the baby’s metabolism and physiology, but also the maternal physiology and pathology and what impact that will have on a drug’s delivery to the fetus or embryo.
  3. The placenta is not only a barrier but also a site of metabolism for many drugs.
  4. Organ development has great effects on the pharmacokinetics a drug. E.g. fetus with immature liver, metabolism of a drug is decreased
  5. If the fetus has a pathology, then that pathology will impact a drug’s effects
  1. Perinate/neonate/infant
  2. Maternal physiology and pathology come into context if the baby is nursing
  3. A preterm baby will have incomplete organ development and is more likely to be ill
  4. Pathology of the baby
  5. All the organs are developing quickly and thus the pharmacokinetic effects are also changing quickly
  6. Not a lot of testing is done in neonates due to ethical reasons but this leads to not a lot being known about drugs’ effects on the neonates

DRUG ABSORPTION IN VERY YOUNG

  1. Fetus
  1. Placental barrier – similar to the BBB, having the same permeability properties as any lipid membrane in terms of charge, size and lipid solubility. However, any drug the mother takes will make it into the fetus even if it is at a level that has no observable effects. Thus, you cannot assume the placental barrier is absolute and will keep a drug out completely (even if it is very large and polar).
  2. Warfarin v. heparin
  3. Warfarin is teratogenic, small in size
  4. Heparin is a large molecule that does not pass through the placenta to any observable extent. Thus if the mother needs anti-coagulation, this is a better drug than warfarin (but still it is still not without its own side effects).
  5. Blood flows comes in from venous system and out through an artery. Not all of the blood coming in through this circulation goes through and gets metabolized by the liver.
  1. Neonate
  2. Oral: the gut has a higher pH and less bacteria, affecting the absorption of a drug
  3. Topical: the skin is more absorbent
  4. IM: less muscle mass (particularly in the preterm baby) and also perfusion of muscles is highly variable

DRUG DISTRIBUTION AND METABOLISM IN THE VERY YOUNG

  1. Distribution
  2. Percentage of water in the neonate also changes very rapidly
  3. Proteins in the blood that bind drugs are usually in lower abundance and have lower affinity for drugs. This would lead to a higher percentage of free unbound drugs in the blood.
  4. Theophylline – used in neonates for respiratory problems. Free levels are significantly higher in neonate than in the adult
  5. Metabolism
  6. Immature liver has decreased or different metabolism of drugs
  7. Theophylline will actually be metabolized to a different end-product, caffeine, than that seen in the adult
  8. Chloramphenicol will not conjugated as much and thus the half life will increase, leading to “gray baby” syndrome

DRUG ELIMINATION AND PHARMACODYNAMICS IN VERY YOUNG

  1. Elimination
  1. On page 2 of the handout there is a table looking at glomerular filtration in different age groups. Note the rapid change in kidney function with growth of the neonate.
  2. Many antibiotics are excreted in their active form. They are not metabolized. Their half-lives are also increased leading to overdosing.
  3. Digoxin, which has a narrow therapeutic window, is excreted in its active form. Overdosing can be a major problem.
  1. Pharmacodynamics
  2. The heart is much less sensitive to Digoxin than in the adult. This combats the increased half-life due to the pharmacokinetics just mentioned.

PHARMACOLOGY IN GERIATRIC

  1. Very similar problems, not because the organs are developing, but because they are decreasing in function
  2. Most organs are functioning their best between the ages of 20-30 years old. From that point on, most begin to decline.
  3. The organs we are most interested in are the kidney and liver (metabolism and elimination) and the heart (organ perfusion)
  4. Any pathology (aging and morbidity) of these organs is of particular interest
  5. The number of drugs taken by the elderly population is very high (Rx and OTC) leading to pharmacokinetic interactions.

PHARMACOKINETICS IN GERIATRIC

  1. Absorption
  1. GI pH is increased due decreased activity of the stomach. In general this does not have a significant impact on most drugs.
  2. Decreased stomach metabolism of levodopa does, however, lead to increased absorption
  1. Distribution – significantly affected
  1. Decreased blood flow to various organs: metabolism by the liver and elimination by the kidney is reduced.
  2. Increased fat/lean mass ratio: there are more lipophilic drug (e.g diazepam) depots.
  3. Decreased albumin, which binds acidic drugs. Increased blood warfarin levels will result.
  4. Increased -glycoprotein, which binds basic drugs.
  5. Decreased water volume (not taking into account any pathological situations such as edema). Procainamide is water-soluble and thus its blood level is affected.
  1. Metabolism
  1. Liver mass, function and perfusion are decreased.
  2. Mixed function oxidases (phase 1) actually increase in activity while conjugation reactions (phase 2) are unchanged or changed less.
  3. Drugs with high extraction ratios are affected the most.
  4. Propanolol has a high first pass metabolism but in the elderly it is metabolized much less and thus the half-life is increased. (Scribe note – this seems to contradict her previous statement about liver enzymes increasing in function. Dr. McMahon’s notes say that propanolol’s half-life does increase due to decreased metabolism but they do not mention any specifics about liver enzymes and their functions. So ... I don’t know)
  1. Elimination
  1. The major function that affects pharmacokinetics in the elderly.
  2. Decreased kidney function and perfusion
  3. On page 3 in the handout there is a table on creatine clearance. Look at it.
  4. If a drug is eliminated without being metabolized by the liver, such as digoxin, then its half-life will increase
  5. Decreased lung function: volatile anesthetics will be affected.

PHARMACODYNAMICS IN GERIATRIC

A. Sensitivity to a drug can be increased (e.g. opiates and benzodiazepines), decreased (e.g.  adrenergics) or unchanged at their target organ

OTHER ISSUES AFFECTING PHARMACOLOGY

  1. Young
  2. Accuracy of the dosing
  3. A pill may not be swallowed correctly
  4. An elixir (alcohol solution) or a water soluble solution can be left open, leading to evaporation and a change in concentration of the drug
  5. A suspension must be shaken so that it is homogenous
  6. Measurement must be made accurately (e.g. what exactly is a teaspoon) and the child has to swallow it
  7. Parental/caretaker compliance – may forget to give a dose
  8. Dosage is calculated by surface area rather than weight. In an adult, if the dosage is not known then estimation can be made by weight. In a neonate, it is done by surface area.
  9. Old
  10. Compliance – patient thinks a drug won’t work
  11. Fear
  12.  blockers are proven to help after MI but are under-prescribed
  13. Estrogen replacement therapy can cause breast cancer
  14. Opiates are not used because of fear by the physician of their adverse effects
  15. Comorbidities
  16. Polypharmacology

Scribe Note – Drugs in the drug list at the end of the handout are the ones that will be tested. Any drugs mentioned throughout the handout that are not on that list will not be tested. Also, if it’s not in the handout, it won’t be on the test.

Good luck on exams and happy holidays.

-Pete

43-17 … enough said

Hook ‘em!

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