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Pharmacology: Studying the principles of Drug Action

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Pharmacology: Studying the principles of Drug Action Pharmacokinetics Pharmacodynamics: Drug action Two ways to measure drug effects: Psychopharmacology.

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1 Pharmacology: Studying the principles of Drug Action
Pharmacokinetics Pharmacodynamics: Drug action Two ways to measure drug effects: Psychopharmacology—look at changes in mood, cognition, and action after taking a drug Neuropharmacology—examine changes in the way cells function after exposure to a drug

2 Pharmacokinetics I. Administration II. Absorption & distribution
III. Binding and bioavailability IV. Inactivation/Biotransformation (metabolization) V. Elimination/excretion

3 I. Administration A. Dose or dosage
Calculation: Take the desired or prescribed dose (typically in mg/kg) and multiply by the person’s mass (in kg). Thus, for example, 0.10mg/kg x 60kg = 6 mg dose Dosage may also be measured in mg/dl of blood plasma, but that is after administration and absorption.

4 B. Administration methods
1. Oral Advantages and disadvantages Formulations: Elixirs and syrups Tablets, capsules, and pills Historic formulations: Powder (“Take a powder”) Cachets Lozenges and pastilles Oral: PO. Ggastrointestinal. (Issues of pH and permeability will be discussed under absorption). Irritation, dosage control, gi upset, acid environment destroys eg. insulin, natural protection from natural bitter poisons, slow absorption (5 min to 30 min, up to 8 hours) provides a safety margin. Elixir: Drug(s) mixed in alcohol solution, usually sweetened. Syrup: Drug(s), including possibly alcohol, mixed in a vehicle of sugar and water. Suspension: Drugs not soluble in water suspended in water. Tablet, capsule, pill: binders. Parenteral methods : Lit. outside the intestine, ie non-gi administration: Overcome problems of oral route, but add problems. Hypodermic needle (1856): Some pain and local irritation, risk of infection, esp. AIDS from needle-sharing. Intravenous: IV(mainlining) Precise dosage control, multiple drugs at once, rapid onset of effect (15 sec for heroin to brain). But no safety margin (shock reaction) if no antidote, risk of introversion or clot, esp w/repeated admins. Only water-soluble drugs. Intramuscular:IM Slower, extended absorption from a bolus or depot injection--hours to weeks (Depo-Provera [aqueous suspension], Depo-testosterone [cottonseed oil], antipsychotics. Oil depots longest lasting with drugs that have high oil-affinity. More painful. Only oil-soluble, non-irritating drugs. Most inoculations are IM: DPT or DT, MMR, typhoid, influenza. Subcutaneous: SC, sub-Q (skin-popping). 9The bolus or vaccination injected under or placed through a cut in the skin: Smallpox vaccination, TB test. Slow absorption, limited amounts. Intracranial: Sometimes sub-dural, sometimes intraventricular or by cannula, most commonly in animal research. Epidural: Epi or spinal, place above or next to (epi) the dura. Intraperitoneal: IP, only for small animals, old rabies method.

5 B. More administration methods
2. Parenteral (Injection) a. Intravenous b. Intramuscular c. Subcutaneous d. Intracranial or intracerebroventricular e. Epidural f. Intraperitoneal

6 B. Administration methods, continued
3. Respiratory a. Inhalation v. intranasal (snorting) b. Smoke (Solids in air suspension) c. Volatile gases 4. Transcutaneous or transdermal 5. Orifice membranes a. Sublingual b. Rectal: Suppositories or enemas c. Vaginal: pessaries or douches (1860) d. Other orifices: bougies 6. Topical These teachniques all cross membranes by solubility/diffusion. Inhalation: Respiratory system. Except for IN, risk hypoxia. Intranasal (snorting) Snuff, cocaine may be partly oral via post-nasal dripping. Fairly fast to brain, local damage to septum. Some of the volatile gases also appear to cross nasal membranes. Smoke (Solids in air suspension, vapors) absorbed across lung alveoli: Nicotine, opium, THC, freebase and crack cocaine, crystal meth.Particles or vapors dissolve in lung fluids, then diffuse. Longer action than volatile gases. Tissue damage from particles, tars, CO. Volatile gases: Some anaesthetics (nitrous oxide, ether) [precise control], petroleum distillates. Diffusion and exhalation (alcohol). Lung-based transfer may get drug to brain in as little as five seconds. Transcutaneous: Directly, from a transdermal patch, or via a carrier, like DMSO. (nitro, estrogen, anti-emetics, nicotine) Sublingual: Across mucous membranes of mouth (nitroglycerine, chewing tobacco, coca leaves) Rectal or vaginal (Suppositories) Vomiting or unconscious patient, or large amounts of drug. In wax vehicle, unreliable dosage control. Topical (Ointment, local anaesthetic)

7 Pharmacokinetics I. Administration II. Absorption & distribution
Bioavailability III. Binding IV. Inactivation/biotransformation (metabolization) V. Elimination/excretion

8 II. A. Absorption 1. Absorption Principles 2. Absorption Barriers
3. Absorption Mechanics

9 1. Absorption Principles
a. General principle: Diffusion, which depends on i. Solubility (fat and/or water) ii. Molecular diameter iii. Volatility (air) iv. Affinity (Proteins, water [hydrophilic], oil b. Absorption is influenced by amount of blood flow at the site of administration

10 2. Absorption Barriers Barriers to absorption include Mucous layers
Membrane pores Cell walls First-pass metabolism Placenta Blood proteins Fat isolation Blood-brain barrier Exceptions: Area postrema, median eminence of hypothalamus

11 The blood-brain barrier
Glial feet Basement membrane (Pia mater)

12 2. Absorption Barriers To review, barriers to absorption include
Mucous layers Membrane pores Cell walls First pass metabolism Placenta Blood proteins Fat isolation Blood-brain barrier

13 mq-fig jpg

14 3. Absorption Mechanics a. For each drug, water and fat solubility vary. Some of the molecules of a given drug are fat soluble while other molecules of the same drug are water soluble. b. Relative solubilities (fat soluble % and water soluble %) depend on i. pH of the drug ii. pH of the solution iii. pKa of the drug c. Solubility percentages depend on ionization ratios

15 Determining the pKa of a drug
Solution pH: 1 2 3 4 5 6 7 Solution pH: 8 9 10

16 Determining the pKa of a drug
% Ionized 2 8 16 26 38 50 62 74 Solution pH: 1 2 3 4 5 6 7 % Ionized Solution pH: 8 9 10

17 % Ionization for Darnital

18 Relative solubilities

19 Computing Ionization Ratios
According to the Henderson-Hasselbalch equation, the difference between the pH of the solution and the pKa of the drug is the common logarithm of the ratio of ionized to unionized forms of the drug. For acid drugs log(ionized/unionized) = pH - pKa, or ratio of ionized to unionized is 10X / 1, where X = pH – pKa

20 Computing ionization ratios, 2
For basic drugs, everything is the same except that the ratio reverses: Log(unionized/ionized) = pH – pKa, or Ratio of unionized to ionized is 10X / 1, where X = pH – pKa

21 Examples Darnital, a weak acid, has a pKa of Taken orally, it is in a stomach solution of pH 3.5. pH – pKa = 3.5 – 5.5 = -2 Since Darnital is an acid drug, we use the alphabetical formula ionized/unionized. ionized/unionized = 10-2/1= 1/100 For every 1 molecule of Darnital that is ionized, 100 are unionized. Darnital in the stomach is highly fat soluble.

22 But look what happens… The highly fat soluble Darnital readily crosses the stomach membranes and enters blood plasma, which has a pH of 7.5 pH – pKa = 7.5 – 5.5 = 2 ionized/unionized = 102/1= 100/1 For every 100 molecules of Darnital that are ionized, only 1 is unionized. Darnital in the blood is not very fat soluble. Darnital will be subject to ion trapping.

23 mq-fig jpg

24 Another example Endital, a weak base with a pKa of 7.5 is dissolved in the stomach, pH 3.5 pH – pKa = 3.5 – 7.5 = -4 Since Endital is a base drug, we use the ratio backwards: unionized/ionized. unionized/ionized = 10-4/1= 1/10,000 In the stomach, Endital will be mostly ionized, and not very fat soluble.

25 But… If we inject Endital intravenously into the blood, with a pH of 7.5, pH – pKa = 7.5 – 7.5 = 0 unionized/ionized = 100 = 1/1 In the blood, Endital will be equally ionized and unionized. Half of the molecules of Endital will be fat soluble, and will readily leave the blood and enter the brain. A dynamic equilibrium follows.

26 An oddity Caffeine is a base drug, but it has a pKa of 0.5
pH – pKa = 3.5 – 0.5 = 3 Since caffeine is a base drug, we use the ratio backwards: unionized/ionized. unionized/ionized = 103/1= 1000/1 In the stomach, caffeine will be mostly unionized, and fat soluble! In the blood, caffeine will be even more unionized and fat soluble: pH – pKa = 7.5 – 0.5 = 7, ratio = 107/1= 10,000,000/1. Caffeine is a 600 pound gorilla.

27 2b. Distribution The generalized distribution of a drug throughout the body controls the movement of a drug by its effect on ionization ratios Distribution also controls how long a drug acts and how intense are its effects Generalized distribution of a drug accounts for most of the side effects produced Is there a magic bullet?

28 Mechanisms of distribution
Blood circulation: The crucial minute But blood flow is greater to crucial organs than to muscle, skin, or bone. Blood circulation is the main factor affecting bioavailability. Lymphatic circulation Depot binding CSF circulation: The ventricular system

29 Distribution half-life and therapeutic levels
Distribution half-life: the amount of time it takes for half of the drug to be distributed throughout the body Therapeutic level: the minimum amount of the distributed drug necessary for the main effect.

30 Half-life curves Resultant Blood level Elimination Distribution
Time in hours

31 Pharmacokinetics 1. Administration 2. Absorption and distribution
3. Binding and bioavailability 4. Inactivation/biotransformation 5. Elimination/excretion

32 Pharmacokinetics 1. Administration 2. Absorption
3. Distribution and bioavailability 4. Biotransformation and elimination

33 4. Elimination Routes of elimination: All body secretions
Air Perspiration, saliva, milk Bile Urine Regurgitation Kidney action Liver enzyme activity: Generalized

34 Enzyme activity Enzymes in gi tract cells Enzymes in hepatocytes
Buspirone and grapefruit juice Enzymes in hepatocytes Cytochrome P-450 families: CYP1-3 Cross-tolerance Biotransformation Type I and type II Metabolites are larger, less fat soluble, more water soluble Metabolite activity is usually lowered

35 Elimination phenomena
Elimination half-life and side effects Tolerance and Mithradatism Metabolic tolerance or enzyme-induction tolerance Cross-tolerance: Carbamazepine and fluoxetine (Tegretol and Prozac) Cellular-adaptive tolerance Behavioral conditioning and state-dependent tolerance

36 Tolerance More tolerance phenomena Tachyphylaxis
Acute tolerance: The BAC curve Mixed tolerance Reverse tolerance or sensitization and potentiation: Fluvoxamine (Luvox®) and clozapine (Clozaril®); Zantac® or Tagamet® and alcohol

37 Balancing distribution and elimination
Elimination half-life and hangovers Accumulation dosing: The 6 half-life rule and regular dosing Steady-state dosing Therapeutic drug monitoring (TDM)

38 Accumulation dosing Plasma level, mg/dl A 1 B 2 C 3 D 4 E 5 F 6 G 7
A 1 B 2 C 3 D 4 E 5 F 6 G 7 Letters = doses; numbers = half-lives

39 An example: Clozapine pharmacokinetics
Pharmacokinetics and metabolism After oral administration the drug is rapidly absorbed. There is extensive first pass metabolism and only 27-50%of the dose reaches the systemic circulation unchanged. Clozapine's plasma concentration has been observed to vary from patient to patient. Various individual factors may vary response such as smoking, hepatic metabolism, gastric absorption, age, and possibly gender. Clozapine is rapidly distributed; it crosses the blood-brain barrier and is distributed in breast milk. It is  95% bound to plasma proteins. Steady state plasma concentration is reached after 7-10 days. The onset of anti-psychotic effect can take several weeks, but maximum effect may require several months. In treatment resistant schizophrenia, patients have been reported to continue to improve for at least two years after the start of clozapine treatment.  Clozapine metabolizes into various metabolites, out of which only norclozapine (desmethyl metabolite) is pharmacologically active. The other metabolites do not appear to have clinically significant activity. Its plasma concentration declines in the biphasic manner, typical of oral anti-psychotics and its mean  elimination half-life ranges from 6-33 hours. About 50% of a dose is excreted in urine and 30% in the  faeces.

40 Dependence and Addiction
Physiological dependence: The abstinence syndrome Cross-dependence Habituation and conditioning Addiction and behavioral reinforcement Positive reinforcement Negative reinforcement

41 Automatic enemas

42 Nineteenth century inhaler

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