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 PharmacokineticsPharmacodynamics: Drug actionTwo ways to measure drug effects:Psychopharmacology—look at changes in mood, cognition, and action after taking a drugNeuropharmacology—examine changes in the way cells function after exposure to a drug
2 Pharmacokinetics I. Administration II. Absorption & distribution III. Binding and bioavailabilityIV. 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 doseDosage may also be measured in mg/dl of blood plasma, but that is after administration and absorption.
4 B. Administration methods 1. OralAdvantages and disadvantagesFormulations:Elixirs and syrupsTablets, capsules, and pillsHistoric formulations:Powder (“Take a powder”)CachetsLozenges and pastillesOral: 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. Intravenousb. Intramuscularc. Subcutaneousd. Intracranial or intracerebroventriculare. Epiduralf. Intraperitoneal
6 B. Administration methods, continued 3. Respiratorya. Inhalation v. intranasal (snorting)b. Smoke (Solids in air suspension)c. Volatile gases4. Transcutaneous or transdermal5. Orifice membranesa. Sublingualb. Rectal: Suppositories or enemasc. Vaginal: pessaries or douches (1860)d. Other orifices: bougies6. TopicalThese 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 BioavailabilityIII. BindingIV. 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 oni. Solubility (fat and/or water)ii. Molecular diameteriii. Volatility (air)iv. Affinity (Proteins, water [hydrophilic], oilb. Absorption is influenced by amount of blood flow at the site of administration
10 2. Absorption Barriers Barriers to absorption include Mucous layers Membrane poresCell wallsFirst-pass metabolismPlacentaBlood proteinsFat isolationBlood-brain barrierExceptions: Area postrema, median eminence of hypothalamus
11 The blood-brain barrier Glial feetBasementmembrane(Pia mater)
12 2. Absorption Barriers To review, barriers to absorption include Mucous layersMembrane poresCell wallsFirst pass metabolismPlacentaBlood proteinsFat isolationBlood-brain barrier
14 3. Absorption Mechanicsa. 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 oni. pH of the drugii. pH of the solutioniii. pKa of the drugc. Solubility percentages depend on ionization ratios
15 Determining the pKa of a drug Solution pH:1234567Solution pH:8910
16 Determining the pKa of a drug % Ionized28162638506274Solution pH:1234567% IonizedSolution pH:8910
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 drugslog(ionized/unionized) = pH - pKa, orratio of ionized to unionized is 10X / 1, whereX = pH – pKa
20 Computing ionization ratios, 2 For basic drugs, everything is the same except that the ratio reverses:Log(unionized/ionized) = pH – pKa, orRatio of unionized to ionized is 10X / 1, whereX = pH – pKa
21 ExamplesDarnital, 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 = -2Since Darnital is an acid drug, we use the alphabetical formula ionized/unionized.ionized/unionized = 10-2/1= 1/100For 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 7.5pH – pKa = 7.5 – 5.5 = 2ionized/unionized = 102/1= 100/1For 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.
24 Another exampleEndital, a weak base with a pKa of 7.5 is dissolved in the stomach, pH 3.5pH – pKa = 3.5 – 7.5 = -4Since Endital is a base drug, we use the ratio backwards: unionized/ionized.unionized/ionized = 10-4/1= 1/10,000In 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 = 0unionized/ionized = 100 = 1/1In 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 = 3Since caffeine is a base drug, we use the ratio backwards: unionized/ionized.unionized/ionized = 103/1= 1000/1In 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. DistributionThe generalized distribution of a drug throughout the body controls the movement of a drug by its effect on ionization ratiosDistribution also controls how long a drug acts and how intense are its effectsGeneralized distribution of a drug accounts for most of the side effects producedIs there a magic bullet?
28 Mechanisms of distribution Blood circulation: The crucial minuteBut blood flow is greater to crucial organs than to muscle, skin, or bone.Blood circulation is the main factor affecting bioavailability.Lymphatic circulationDepot bindingCSF 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 bodyTherapeutic 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 bioavailability4. Inactivation/biotransformation5. Elimination/excretion
32 Pharmacokinetics 1. Administration 2. Absorption 3. Distribution and bioavailability4. Biotransformation and elimination
33 4. Elimination Routes of elimination: All body secretions AirPerspiration, saliva, milkBileUrineRegurgitationKidney actionLiver enzyme activity: Generalized
34 Enzyme activity Enzymes in gi tract cells Enzymes in hepatocytes Buspirone and grapefruit juiceEnzymes in hepatocytesCytochrome P-450 families: CYP1-3Cross-toleranceBiotransformationType I and type IIMetabolites are larger, less fat soluble, more water solubleMetabolite activity is usually lowered
35 Elimination phenomena Elimination half-life and side effectsTolerance and MithradatismMetabolic tolerance or enzyme-induction toleranceCross-tolerance: Carbamazepine and fluoxetine (Tegretol and Prozac)Cellular-adaptive toleranceBehavioral conditioning and state-dependent tolerance
36 Tolerance More tolerance phenomena Tachyphylaxis Acute tolerance: The BAC curveMixed toleranceReverse tolerance or sensitization and potentiation: Fluvoxamine (Luvox®) and clozapine (Clozaril®); Zantac® or Tagamet® and alcohol
37 Balancing distribution and elimination Elimination half-life and hangoversAccumulation dosing: The 6 half-life rule and regular dosingSteady-state dosingTherapeutic 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 7Letters = 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 syndromeCross-dependenceHabituation and conditioningAddiction and behavioral reinforcementPositive reinforcementNegative reinforcement